short essay questions in hematology

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9. Hematology Questions and Answers

• Published: August 2013
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Chapter 9 presents multiple-choice, board review questions on hematology including anemia, myeloid malignancies, coagulation disorders, and lymphoid malignancies. Full explanations are provided with the correct answers.

Multiple Choice (choose the best answer)

Anemias and Myeloid Malignancies

1. A 67-year-old man is evaluated for exertional dyspnea. He recalls that 3 years ago he was told that he had anemia. In reviewing his records, you note that at that time his hemoglobin level was 9.5 g/dL and his hematocrit was 33% with an increased mean corpuscular volume (MCV); the remainder of his complete blood cell count was normal. On physical examination, he had conjunctival pallor, normal heart and lung findings, no lymphadenopathy, no hepatomegaly or splenomegaly, and no petechiae or ecchymoses. Diagnostic testing results are shown in Table 9.Q1 .

Which of the following is the most likely explanation for these findings?

Acute myeloid leukemia (AML)

Vitamin B 12 deficiency

Hemolytic anemia

Myelodysplastic syndrome (MDS)

Primary myelofibrosis

2. A 45-year-old woman is admitted to the surgical service with severe arterial insufficiency of the right second toe. She has no prior medical history and takes no medications. Physical examination findings are normal except for mild splenomegaly and signs of early gangrene in the right second toe. All pulses are full and equal throughout. Diagnostic testing results are shown in Table 9.Q2 .

Which of the following is the most likely diagnosis?

Essential thrombocythemia

Philadelphia chromosome–negative chronic myeloid leukemia (CML)

Primary myelofibrosis (PMF)

3. A 22-year-old man is admitted to the hospital for an elective cholecystectomy. You are asked to see him because he had anemia on preoperative testing. He tells you that he has always been told by his physicians that he has mild anemia; his medical history is otherwise unremarkable. His vital signs are normal. His conjunctivae are mildly icteric, and the spleen is palpable in the left upper quadrant. Findings on the remainder of the physical examination are normal. Diagnostic testing results are shown in Table 9.Q3 .

Which of the following tests would most likely help confirm the diagnosis?

Hemoglobin electrophoresis

Osmotic fragility test

Direct and indirect antiglobulin (Coombs) tests

Bone marrow aspiration and biopsy

4. A 28-year-old black man with sickle cell disease presents to the emergency department with abdominal pain, chest pain, and shortness of breath. His dyspnea evolved over 36 hours after a visit with his niece and nephew. His history is significant for approximately 2 emergency department visits or hospital admissions per year for painful crises. Three years ago, he spent 4 weeks in the hospital after an episode of acute chest syndrome. He has been taking hydroxyurea but only intermittently because of financial concerns. His pulse is 116 beats per minute and regular, his blood pressure is 138/76 mm Hg, his respiratory rate is 18 breaths per minute, and his temperature is 38.3°C. Pulse oximetry shows 91% oxygen saturation with room air and 93% with 4 L of oxygen by nasal cannula. His lungs have scattered inspiratory crackles in the right midlung field. His spleen is not palpable. The remainder of the physical examination findings are normal. Diagnostic testing results are shown in Table 9.Q4 .

A chest radiograph shows a right middle and upper lobe air space infiltrate. The patient is given supplemental oxygen, adequate pain control, and intravenous antibiotics. Which of the following should you now order?

Hydroxyurea

Erythrocyte exchange transfusion

Plasma exchange

Anticoagulation with unfractionated heparin

Aggressive intravenous fluid hydration

5. A 70-year-old man presents with weakness of his right arm and leg. His symptoms began yesterday and are now resolved. He also reports a 6-month history of recurrent headaches and fatigue. He is a nonsmoker. His medical history is significant for high blood pressure. His blood pressure is 167/88 mm Hg, his oxygen saturation is 93% on room air, his face is plethoric, and a right carotid bruit is heard. Other findings on physical examination are normal. Diagnostic testing results are shown in Table 9.Q5 .

Carotid ultrasonography shows a 30% stenotic lesion in the right carotid. The patient is hospitalized and begins antiplatelet therapy. Which of the following should you order next?

JAK2 V617F mutation testing

Fluorescence in situ hybridization (FISH) for BCR-ABL testing

Arterial blood gas analysis

6. A 42-year-old woman with a history of systemic lupus erythematosus (SLE) presents with fatigue. She has been receiving anti–tumor necrosis factor therapy and has been managing the SLE well. However, she has recently experienced worsening fatigue. Her vital signs are normal. Her face and conjunctivae are jaundiced, and she has a fading butterfly rash on her face. The spleen is palpable on deep inspiration. Diagnostic testing results are shown in Table 9.Q6 , and the peripheral blood film is shown in Figure 9.Q6 .

Which of the following is the best interpretation of these data?

The hemolysis is predominantly intravascular.

The bone marrow is not responding to the anemia.

Direct Coombs testing results should be positive.

Urine hemoglobin testing results should be positive.

7. A 58-year-old woman with active rheumatoid arthritis presents with fatigue and joint pain. She received the diagnosis of rheumatoid arthritis 5 years earlier and has been taking prednisone 10 mg daily and methotrexate with folate weekly. She has had chronic fatigue and anemia. Her vital signs are normal. Her conjunctivae are pale, and she has active synovitis affecting both knees, her wrists, and elbows, with rheumatoid nodules on the extensor surface of her right forearm. The remainder of the physical examination findings are normal. Diagnostic testing results are shown in Table 9.Q7 .

Which of the following laboratory findings are consistent with this condition?

Elevated hepcidin, elevated ferritin, elevated total iron-binding capacity (TIBC), elevated serum iron

Elevated hepcidin, elevated ferritin, decreased TIBC, elevated serum iron

Decreased hepcidin, elevated ferritin, decreased TIBC, elevated serum iron

Elevated hepcidin, elevated ferritin, decreased TIBC, normal serum iron

Decreased hepcidin, elevated ferritin, elevated TIBC, normal serum iron

Coagulation

8. A 62-year-old man underwent right total knee replacement 8 days ago. Swelling has developed in his right lower extremity, and Doppler ultrasonography confirms the presence of a right superficial femoral vein thrombosis. His current medications include oxycodone and subcutaneous unfractionated heparin. Results of preoperative tests, including a complete blood cell count and liver and kidney function, were normal. Other laboratory data include the following: hemoglobin 12.2 g/dL, leukocyte count 8.5×10 9 /L, and platelet count 60×10 9 /L. In addition to stopping the use of subcutaneous heparin, what is the next most appropriate step in management of this patient?

Start low-molecular-weight heparin therapy.

Start intravenous therapeutic doses of heparin.

Start direct thrombin inhibitor therapy.

Start aspirin therapy.

9. A 45-year-old man presents with deep vein thrombosis of the right femoral vein. Three months ago, he received a diagnosis of systemic lupus erythematosus (SLE). In addition to confirming SLE, laboratory testing also documented the presence of a lupus anticoagulant (LAC). There is no family history of venous thrombosis. Current medications include hydroxychloroquine. Laboratory testing shows normal results for a complete blood cell count and for tests of liver and kidney function. Special coagulation testing confirms the persistence of an LAC. What is the most reasonable duration of warfarin anticoagulation for this patient?

10. A 20-year-old white woman has been admitted to the hospital with pulmonary embolism. She has no chronic illnesses and is receiving no medications except for combination estrogen-progesterone birth control pills that she started using approximately 1 year earlier. Results were normal for a complete blood cell count, baseline prothrombin time, activated partial thromboplastin time (aPTT), and tests of kidney and liver function. The patient is currently receiving therapeutic doses of intravenous unfractionated heparin, and her aPTT is therapeutic at 72 seconds. A panel of thrombophilia tests has been performed. Which of the following statements about her thrombophilia test results is correct?

DNA-based testing for factor V Leiden and prothrombin G20210A mutations are reliable.

Low antithrombin confirms a hereditary deficiency state.

A positive result on lupus anticoagulant (LAC) testing confirms antiphospholipid antibody syndrome.

Low protein S confirms the presence of a hereditary deficiency state.

11. A 62-year-old man with chronic atrial fibrillation has been treated with warfarin. He has no other chronic illnesses and is receiving no other medications long-term except for lipid-lowering agents. Results of his complete blood cell count and tests of renal and kidney function are normal. He checks his prothrombin time monthly and has kept the international normalized ratio (INR) within the therapeutic range (2–3) for the duration of his therapy with warfarin. He has heard about recent US Food and Drug Administration (FDA) approval of dabigatran, which requires no monitoring, and he would like a prescription for this new drug. Which of the following statements is true about the use of dabigatran in atrial fibrillation compared with the well-managed use of warfarin?

Switching to dabigatran would result in superior outcomes.

Switching to dabigatran would result in inferior outcomes.

Switching to dabigatran would provide no significant benefit.

Dabigatran is FDA approved for postoperative thromboprophylaxis for knee and hip replacement surgery.

Dabigatran is FDA approved as an anticoagulant for patients who have received a mechanical heart valve.

12. A 22-year-old woman is brought to the emergency department after having 1 witnessed tonic-clonic seizure. She had appeared confused for the preceding few hours. On examination, she is febrile and appears slightly confused; otherwise, neurologic and physical examination findings are normal. Laboratory testing results are shown in Table 9.Q12 , and the peripheral blood smear is shown in Figure 9.Q12 .

What is the most appropriate next step in management?

Red blood cell transfusion

Platelet transfusion

Gamma globulin administration

13. A 72-year-old man with chronic atrial fibrillation has been receiving dabigatran 75 mg twice daily for the past 6 months. He has not had any thrombotic or hemorrhagic complications. He has a history of colon polyps, for which he needs to undergo a colonoscopy with possible polypectomy. Apart from an irregular pulse, his physical examination findings are normal. Results were normal for a complete blood cell count and tests of renal and liver function. The calculated creatinine clearance is 28 mL/min. For how long should dabigatran use be discontinued before the colonoscopy?

No need to discontinue

Lymphoid Malignancies

14. At her annual physical examination, an asymptomatic 68-year-old woman has lymphocytosis (32×10 9 /L) with a normal hemoglobin level and platelet count. On examination, she has 1-cm lymphadenopathy in the cervical region and no palpable liver or spleen enlargement. A peripheral blood smear shows identically appearing mature lymphocytes with smudge cells. Flow cytometry of the peripheral blood lymphocytes shows a monoclonal B population with dim expression of λ light chain and CD20 that is positive for expression of CD5, CD19, and CD23. Which of the following is the best next step in her management?

Combination chemoimmunotherapy

Chlorambucil therapy

Allogeneic peripheral blood stem cell transplant

Combination monoclonal antibody therapy

Active monitoring for disease progression and complications

15. Ten years ago, a previously healthy 20-year-old woman presented to her physician with a 2-month history of pruritis, drenching night sweats, unintentional weight loss, and nonproductive cough. On examination, she had 2-cm cervical lymphadenopathy. A computed tomographic scan showed a 12-cm-diameter anterior mediastinal mass. An excisional biopsy of a cervical lymph node showed nodular sclerosing Hodgkin lymphoma. After she was treated with ABVD (doxorubicin [ A driamycin], b leomycin, v inblastine, and d acarbazine) combination chemotherapy followed by involved field radiotherapy, the disease was in complete remission. Now you see her for the first time for an annual physical examination. The disease remains in complete remission. Compared to her peers, this patient is at increased risk of which of the following conditions?

Breast cancer

Coronary artery disease

Hypothyroidism

Skin cancer

All of the above

16. An 80-year-old man is admitted to the hospital after falling on an icy sidewalk and fracturing his hip. He undergoes open reduction and internal fixation of the fracture. At surgery, there does not appear to be any bone disease at the fracture site. The patient was previously asymptomatic. Physical examination findings are otherwise unremarkable. Serum protein electrophoresis and immunofixation show an IgM κ monoclonal protein (0.3 g/dL). The complete blood cell count and serum creatinine levels are normal. Skeletal survey shows no additional bone defects. Which of the following statements is true for this patient?

He has multiple myeloma and requires treatment.

He has a lower risk of a clinically significant lymphocytic or plasma cell malignancy than patients with an IgG monoclonal protein.

He requires a radioisotope bone scan to evaluate his bone integrity.

He requires regular follow-up and serial measurements of his monoclonal protein level.

He has a 10% annual risk of multiple myeloma.

17. A 75-year-old African American man was seen last week by his primary care physician for mild dyspnea. He has also noted intermittent peripheral edema. During the evaluation, an electrocardiogram showed low-voltage QRS complexes in the limb leads. The troponin T level was elevated (0.07 ng/mL). This finding suggested the need for a coronary angiogram, which showed no significant coronary artery disease. An echocardiogram showed diffuse left ventricular thickening with a granular texture to the myocardium and a septal thickness of 2.5 cm (normal <1.1 cm). The complete blood cell count results were normal. Serum and urine protein electrophoresis and immunofixation were unremarkable. Serum free light chain levels were not increased. What is the most likely diagnosis?

AA amyloidosis

Light chain–related amyloidosis

Hypertrophic obstructive cardiomyopathy

Amyloidosis due to transthyretin deposition

Amyloidosis due to β 2 -microglobulin deposition

18. A 55-year-old man presented to his primary care physician for evaluation of fatigue. He was previously healthy with the exception of chronic musculoskeletal low back pain, for which he occasionally takes nonsteroidal anti-inflammatory drugs. On examination, he is pale. Complete blood cell count results are as follows: hemoglobin 8.3 g/dL, mean corpuscular volume 73 fL, leukocyte count 6.9×10 9 /L, and platelet count 398×10 9 /L. Results of the fecal occult blood test are positive. During upper and lower endoscopy, a 1.2×2.5-cm ulcerative lesion is noted in the lesser curvature of the stomach. The lesion is biopsied and identified as a MALT lymphoma. Which of the following is characteristic of MALT lymphoma?

Most cases are treated with anthracycline-based chemotherapy.

It is caused by chronic stimulation with Chlamydophila psittaci .

Radiotherapy is necessary in most cases.

It frequently undergoes transformation to a large-cell lymphoma.

The combination of amoxicillin, omeprazole, and clarithromycin is the most appropriate first-line treatment.

19. A 73-year-old woman presented to the emergency department with new-onset back pain, confusion, and constipation over the past week. Her past medical history is significant only for hypertension. On examination, she is slightly pale with slow cognition and point tenderness over the lumbar spine. Plain films of the lumbar spine show osteolytic lesions in L2, L3, and L5. Laboratory values are as follows: hemoglobin 9.3 g/dL, leukocyte count 4.6×10 9 /L with a normal differential count, platelet count 230×10 9 /L, creatinine 1.6 mg/dL, total calcium 13.1 mg/dL, albumin 3.6 g/dL, and total protein 9.1 g/dL. What is the most likely diagnosis?

Metastatic breast cancer

Hydrochlorothiazide use

Multiple myeloma

Primary hyperparathyroidism

Milk alkali syndrome

20. A 48-year-old man presents to the emergency department with a 6-week history of progressively worsening abdominal pain and night sweats. Physical examination findings were significant for palpable bilateral 2-cm axillary lymph nodes and diffuse abdominal tenderness with no rebound or guarding. Computed tomography of the abdomen and pelvis showed retroperitoneal and mesenteric lymphadenopathy. Excisional biopsy of an axillary node was positive for diffuse, large B-cell lymphoma. Positron emission tomography showed fluorodeoxyglucose-avidity in the axillary, mesenteric, and retroperitoneal lymph nodes. Results of the bone marrow examination were normal. Which of the following is the best next step?

Combination therapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)

Observation

Combination therapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)

Autologous stem cell transplant

Involved field radiotherapy

1. Answer d.

MDS most commonly manifests as isolated macrocytic anemia. MDS can evolve to include pancytopenia over several years; the typical peripheral smear findings include a dimorphic erythrocyte population (microcytes and oval macrocytes) with an overall prominent macrocytosis and an MCV around 110 fL. The chronicity of MDS—in particular, anemia preceding the diagnosis of pancytopenia by several years—is in contrast to the typically acute manifestation of AML, which is therefore an unlikely possibility in this patient. Primary myelofibrosis, a myeloproliferative neoplasm, causes fibrosis in the bone marrow, resulting in extramedullary hematopoiesis and significant splenomegaly, and typically does not cause a macrocytic anemia. Vitamin B 12 deficiency can cause a megaloblastic anemia and manifest with slowly evolving macrocytic anemia and eventually pancytopenia, but the peripheral smear would not show a dimorphic erythrocyte population. (See Tefferi and Vardiman in the “Suggested Reading” list.)

2. Answer a.

Extreme thrombocytosis may be reactive and occur with severe iron deficiency or inflammatory states (with elevated erythrocyte sedimentation rates) or after splenectomy; patients are typically asymptomatic. Clonal thrombocytosis is related to a myeloproliferative neoplasm, which usually causes splenomegaly. Typical bone marrow findings include a hypercellular bone marrow with increased atypical megakaryocytes in clusters. Essential thrombocythemia may cause extreme thrombocytosis (platelet count >1,000×10 9 /L); however, it can also occur less commonly with polycythemia rubra vera (typically with erythrocytosis), the cellular phase of PMF, or rarely CML. The normal karyotype makes CML much less likely since it typically manifests with the Philadelphia chromosome t(9;22). Increased reticulin fibrosis would have been seen on the bone marrow biopsy if the patient had PMF. (See Tefferi in the “Suggested Reading” list.)

3. Answer b.

When a patient presents with premature gallstones, one should consider whether they may be due to pigment gallstones from chronic hemolysis causing indirect hyperbilirubinemia. The presence of microspherocytes is consistent with hereditary spherocytosis, and the diagnostic test is an osmotic fragility test, which identifies a congenital membrane defect. Typically, acquired warm autoimmune hemolytic anemia, which produces positive Coombs test results, can cause spherocytes as well; however, the history of lifelong anemia makes this diagnosis unlikely. A hemoglobin electrophoresis would help in diagnosing thalassemia or a hemoglobinopathy; however, these conditions do not manifest with microspherocytes on the peripheral blood film. There is no indication for a bone marrow biopsy since the reticulocyte response is appropriate and no other cytopenias are apparent. (See Gallagher in the “Suggested Reading” list.)

4. Answer b.

The patient has acute chest syndrome, a sickle cell anemia complication that is an indication for urgent red cell (not plasma) exchange transfusion to decrease the hemoglobin S level to less than 30% to 35%. Gentle fluid resuscitation is appropriate (along with oxygen support and antibiotics, since about one-third of acute chest syndrome events are initiated by or associated with bacterial pneumonia). Aggressive fluid resuscitation, leading to overhydration, might cause pulmonary edema and worsen the oxygenation. Pulmonary embolism is possible, but full anticoagulation is not warranted until embolism is documented. Use of hydroxyurea might have prevented this crisis, but it is of no value for the acute condition. (See Vij and Machado in the “Suggested Reading” list.)

5. Answer a.

Polycythemia may be secondary, as with erythropoietin- mediated causes such as chronic hypoxemia, living at high altitude, and high oxygen affinity hemoglobinopathies. Polycythemia vera is a myeloproliferative neoplasm that can manifest with arterial thrombosis secondary to hyperviscosity from the increased concentration of erythrocytes. The low erythropoietin rules out erythropoietin-mediated causes, leaving the presumptive diagnosis of polycythemia vera. With JAK2 V617F mutation testing of peripheral blood, results are positive for approximately 90% of patients who have polycythemia vera. FISH for BCR-ABL testing would screen for chronic myeloid leukemia, which does not manifest with polycythemia. Although bone marrow aspiration and biopsy would be helpful, it is not immediately necessary and could be considered later. (See Patnaik and Tefferi in the “Suggested Reading” list.)

6. Answer c.

Hematologic complications of SLE include anemia of chronic disease, pure red cell aplasia, and warm autoimmune hemolytic anemia (WAIHA). The presentation and laboratory data suggest hemolysis, and the blood smear shows spherocytes. These findings are consistent with WAIHA, which causes extravascular hemolysis. The reticulocytosis suggests that the bone marrow response is adequate. In intravascular hemolysis, the urine is positive for hemoglobin. (See Packman in the “Suggested Reading” list.)

7. Answer d.

Rheumatoid arthritis is a chronic inflammatory disorder that may lead to anemia of chronic disease. Anemia of chronic disease results from the effect of elevated cytokines on hematopoiesis, including upregulation of hepcidin, leading to increased ferritin from iron malutilization and downregulation of ferroportin, the main iron exporting system. Transferrin is also downregulated, leading to decreased TIBC and normal to decreased serum iron levels. (See Weiss and Goodnough in the “Suggested Reading” list.)

8. Answer c.

The timing and degree of thrombocytopenia are consistent with immune-mediated heparin-induced thrombocytopenia type II. Unfractioned heparin and low-molecular-weight heparin are contraindicated. Aspirin would not be the sole management agent for established thrombosis. The most appropriate step is to start a direct thrombin inhibitor.

9. Answer d.

Presentation with a vascular thrombosis and persistence of a LAC for 12 weeks or more satisfies the criteria for an antiphospholipid syndrome. This patient has a high risk for recurrent venous thrombosis on discontinuing anticoagulation; thus, long-term warfarin is recommended with periodic reassessment for safety.

10. Answer a.

DNA-based testing is reliable for patients receiving heparin or warfarin and for patients who have acute thrombosis. However, acute thrombosis and heparin can cause lower antithrombin activity results, which should be verified at another time, when heparin and acute thrombosis are not factors. A single positive test result for LAC does not confirm antiphospholipid syndrome; follow-up testing at 12-week intervals is required to demonstrate persistence of LAC. Acute thrombosis and estrogen use can lower protein S levels; thus, abnormally low results require follow-up confirmation.

11. Answer c.

Among patients randomly assigned to receive dabigatran, overall outcomes were noninferior when compared with the well-managed use of warfarin, thus providing no significant advantages. The group of patients that derived the most benefit from dabigatran was the group with INRs outside the recommended therapeutic range. Dabigatran is FDA approved only to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

12. Answer d.

Plasma exchange is the treatment of choice for thrombotic thrombocytopenic purpura (TTP). Although red blood cell transfusion may be indicated, it does not address the underlying pathogenesis of TTP. Platelets are thought to be contraindicated in TTP because of the theoretical possibility of worsening the TTP. Gamma globulin is ineffective in increasing the platelet count in TTP.

13. Answer d.

Dabigatran is cleared through the kidneys. It has a prolonged half-life in patients who have a creatinine clearance less than 30 mL/min compared with patients who have a creatinine clearance greater than 30 mL/min.

14. Answer e.

Chronic lymphocytic leukemia (CLL) is a clonal lymphoproliferative disorder of mature lymphocytes. The clinical diagnosis requires a B-lymphocyte count of more than 5×10 9 /L. Peripheral blood smears typically show smudge cells, which are lymphocytes that have broken during processing of the slide. The clinical course of CLL is chronic in most patients. For those with early-stage disease, standard practice is to withhold treatment until the disease is active or progressive. However, patients need to be monitored for disease progression, autoimmune complications, infections, and second cancers.

15. Answer e.

Hodgkin lymphoma therapy is curative in about 80% of cases. However, there are late complications of therapy, particularly in those treated before modern chemotherapy and radiotherapy. At 15 years, the risk of death from other causes surpasses that of risk of death from Hodgkin lymphoma. Patients are at higher risk of secondary malignancies, cardiovascular disease, thyroid disorders, and infertility than the general population. Many of these conditions can be attributed to chemotherapy and radiotherapy.

16. Answer d.

This patient has monoclonal gammopathy of undetermined significance (MGUS), the most common dysproteinemia. In MGUS, the M protein level is typically less than 3 g/dL, the bone marrow has less than 10% plasma cells, and the hemoglobin, creatinine, calcium, and bone radiographs are normal. The risk of progression to a lymphocytic or plasma cell malignancy is about 1% per year. Patients with an IgM or IgA monoclonal protein are at higher risk of progression than those with an IgG protein. Patients with MGUS need to be observed.

17. Answer d.

The patient has senile cardiac amyloidosis. This syndrome is usually isolated to the heart with few clinically significant deposits elsewhere, and the echocardiographic findings are often out of proportion to the degree of symptoms. Transthyretin is the protein causing the amyloid deposits; most patients have wild-type transthyretin.

18. Answer e.

With combination antibiotic therapy, 70% of gastric MALT lymphomas are cured. In cases refractory to antibiotics, tumors may carry the t(11;18) translocation, and involved field radiotherapy is effective. Combination chemotherapy is reserved for advanced disease. The majority of cases are associated with Helicobacter pylori infection.

19. Answer c.

This patient has multiple myeloma with evidence of end-organ damage from the plasma cell proliferative disorder (hypercalcemia, renal failure, anemia, and osteolytic bone lesions). The other answer choices are possible causes of hypercalcemia, but only multiple myeloma accounts for all the presenting symptoms, including the elevated level of total protein.

20. Answer a.

This patient has advanced-stage, diffuse, large B-cell lymphoma, and R-CHOP chemotherapy is the standard of care. Rituximab is an anti-CD20 monoclonal antibody that improves overall survival when added to CHOP chemotherapy for aggressive B-cell lymphomas. For patients whose disease relapses or is refractory, autologous stem cell transplant is the standard therapy. Radiotherapy can be used in combination with chemotherapy in early-stage (I-IIA) nonbulky disease but is not standard therapy for advanced disease.

Suggested Reading

Gallagher PG . Red cell membrane disorders. Hematology Am Soc Hematol Educ Program.   2005 :13–8.

Packman CH . Hemolytic anemia due to warm autoantibodies.   Blood Rev.   2008 Jan;22(1):17–31. Epub 2007 Sep 27.

Google Scholar

Patnaik MM , Tefferi A . The complete evaluation of erythrocytosis: congenital and acquired.   Leukemia.   2009 May;23(5):834–44. Epub 2009 Mar 19.

Tefferi A . Annual clinical updates in hematological malignancies : a continuing medical education series: polycythemia vera and essential thrombocythemia: 2011 update on diagnosis, risk-stratification, and management. Am J Hematol. 2011 Mar;86(3):292–301.

Tefferi A , Vardiman JW . Myelodysplastic syndromes.   N Engl J Med.   2009 Nov 5;361(19):1872–85.

Vij R , Machado RF . Pulmonary complications of hemoglobinopathies.   Chest.   2010 Oct;138(4):973–83.

Weiss G , Goodnough LT . Anemia of chronic disease.   N Engl J Med.   2005 Mar 10;352(10):1011–23.

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Flow Cytometry

• Coagulation
• Transfusion
• Learning Cases

The FRCPath Haematology Exam: An Overview

The FRCPath exam consists of two parts.

Part 1 comprises two three-hour papers in a single day. It can be attempted at various centres around the world. The first paper is an MCQ paper which tests knowledge of a broad range of Haematology problems. The second paper is an essay paper with four questions, each from one of the following four domains: General Haematology, Coagulation (aka Haemostasis and Thrombosis), Transfusion and Malignant Haematology. The essays are designed to assess in-depth knowledge of core topics, and are usually broken into 2-3 main areas of questioning, with further sub-sections.

Part 2 is a three-day examination which can only be attempted in the United Kingdom. Time-keeping is very important in the Part 2 examination, as each question has a pass/fail mark associated with it, and the total number of questions passed (as opposed to the total number of marks per se) is what determines the passing mark. Therefore, passing 6/10 questions may result in you passing the paper, but if you score 60% of available marks but only pass 3 questions, you will still fail the paper. All papers and the viva must be passed to pass the part 2 exam.

• Morphology shorts (10-12 questions, 90 minutes)
• Morphology long cases (3 questions, 90 minutes)
• Coagulation (8-10 questions, 2 hours)
• Transfusion (8-10 questions, 2 hours)
• General Haematology
• Malignant Haematology

Morphology (Day 1)

The first day is the morphology paper, which comprises one 90 minute “morphology shorts”, and one 90 minute paper for long cases. For the shorts, there are typically 10-12 sets of slides (usually peripheral blood films, but some cases will have bone marrow aspirates / trephines as well), each with two to three short answer questions to attempt.

The long cases will usually include at least one haemoglobinopathy case, and one of the cases may require you to report a bone marrow trephine biopsy. One or more of the short and long of the cases will typically include flow cytometry findings for interpretation.

Bear in mind that the morphology paper may include diagnoses which are not classically haematological – i.e., infections such as malaria, histoplasmosis, leishmaniasis etc. 

Coagulation (Day 2)

The coagulation paper will require you to have an understanding of the assays which are done in the laboratory to assess haemostasis and thrombosis. Pregnancy and its specific management often features in at least one of the questions. Other important topics which may often be encountered include: anticoagulation (indications, intensity and reversal), quality control (NEQAS), congenital bleeding disorders (rare bleeding disorders, Haemophilia, von Willebrand’s disease) and platelet function defects.

Transfusion (Day 2)

The transfusion paper often has a significant component aimed at ensuring that you are able to ensure safe blood provision. Pre-transfusion testing and blood product selection / specifications are hence important to know. There are often questions on platelet refractoriness, transfusion reactions and blood product selection for patients with ABO incompatible transplants. As with coagulation, expect specific pregnancy scenarios such as management of anti-D prophylaxis in pregnancy, allo-antibodies in pregnancy and neonatal alloimmune thrombocytopaenia to feature. There is usually also a question on quality control (NEQAS) and antigram interpretation.

Viva (Day 3)

The viva lasts an hour for each candidate, and happens on the last day of the examination. There are four vivas, each with two lines of questioning. The domains are: General Haematology, Coagulation, Transfusion and Malignant Haematology.

The viva is conducted by a pair of examiners. The examiner conducting the viva should not be a sub-specialist in that field. Each line of questioning takes 7.5 minutes, and is broadly divided into an introductory and a competence set of questions. The aim is to assess if you can manage patients safely.

The viva may or may not be on topics which have previously come up in the written papers.

FRCPath Exam Preparation

Prepare for the FRCPath Haematology examination with our dynamic, expanding set of materials. We have over 300 digitised blood films, bone marrow aspirates and trephine biopsies with descriptions and differential diagnoses for you to work through. The morphology section also includes a comprehensive overview of the common thalassaemias and haemoglobinopathies, together with acid and alkaline gel electrophresis and HPLCs.

For the other sections, we have summarised available guidance from NHSBT, BCSH and SHOT to aid your preparation. We also have worked examples for commonly-encountered problems such as coagulation assay interpretation, antigrams, ABO discrepancies and NEQAS.

Flow cytometry allows phenotyping characterisation of cell populations by analysing

FRCPath Haematology Part 2: Morphology

The FRCPathy Haematology Part 2 Morphology paper comprises two 90

FRCPath Haematology Part 2: Transfusion

This course covers transfusion for the Haematology FRCPath Part 2

Haemostasis and Thrombosis (Advanced)

This course covers haemostasis and thrombosis for haematology trainees. Review

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Welcome To HOQ

Since I created this site in 2014, over 11,000+ Hematologists/Oncologists have registered. The feedback has been overwhelmingly positive and I am honored that so many have used the website to help in preparation for their Hematology/Oncology Board examination. I wrote all 2570+ questions/answers myself, and I tried to create high-yield questions with succinct explanations. The latter should be helpful for rapid-fire review prior to a board examination.  The questions cover all of the Benign Hematology, Malignant Hematology, and Solid tumors.  As of October 2022, all questions have been updated/edited. 

It only costs 49.99 for 6 months of access.  Group rates are also available. For group purchase please contact us [email protected], or [email protected] 

We now have an exam format available, where a user can take a 60 question test composed of a mix of questions from a variety of Oncology and Hematology topics.  We also have an image bank available.

Based on clinical situations I encounter in my clinic, I will update the questions to keep them up-to-date and relevant. As the field of Hematology and Oncology constantly evolves, so will the questions. 

We have an App available for Android and the iPhone; it is part of the subscription.

These questions should be helpful in preparing for the Medical Oncology and Hematology Board examinations. In addition, these questions will serve as a refresher for those who are recertifying for their boards or for the ASCO inservice exam. Lastly, the site is outstanding for Hematologists/Oncologists who are interested in increasing their knowledge base.

I hope these questions will serve as an adjunct to other outstanding resources including ASH-SAP, ASCO-SEP, ASCO Question Bank, the MD Anderson, and George Washington Board Review Course, and the NCCN guidelines.

  The Number 1 Source of Hematology and Oncology Board Exam Preparation. Trusted by more than 11,000+ doctors, fellows, residents. Used Worldwide by International Doctors. Over 2570+ Regularly Updated High-quality Questions. The Best Source for the ASCO In-service Exam, Medical Oncology Board Exam and the Hematology Board Exam.   Great Value for the money. Subscription starts from $49.99 for 6 months of access.  There are group rates available. Please contact us for Group Rates. Sign Up today and get access to more than 30 High-Quality Image Bank Questions

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Anatomy Study Guide

Hematology question and answers.

August 7, 2023 by Joankessler parkland Leave a Comment

Disorders Of Red Blood Cell:

Introduction Hemoglobin Structure:

A hemoglobin molecule is a conjugated protein composed of iron-containing pigment called heme and protein globin. About 65–70% of hemoglobin is synthesized in normoblasts and 30−35% is synthesized at the reticulocyte stage.

• Each molecule of heme consists of protoporphyrin with an iron in ferrous state (Fe++). Heme synthesis occurs mainly in the mitochondria of normoblasts.
• Each globin chain is made up of two pairs of distinct polypeptide chains (composed of a number of amino acids) bound to a heme molecule.

Read And Learn More: General Medicine Question And Answers

• Hemoglobin A (HbA) is composed of two α and two β globin chains (α 2 β 2 ) and normally represents more than 95% of the hemoglobin in adult red blood cells (RBCs). Fetal hemoglobin is replaced by adult hemoglobin during the first year of life (hemoglobin switching).
• Fetal hemoglobin (HbF) contains two α and two γ globin chains (α 2 γ 2 ). It is the major hemoglobin (70–90%) during fetal development and is normally found in low levels in adults.
• Hemoglobin A 2 (α 2 δ 2 ) is normally found at low levels in adults (2%).
• Normal hemoglobin in the adult are HbA (α 2 β 2 ) and HbA 2 (α 2 δ 2 )
• Normal hemoglobin in the fetus are HbF (α 2 γ 2 ) and Hb-Bart’s (γ 4 ).

Red Cell Indices:

• Normal range: 82–98 fL (fL stands for femtoliters) Microcytic anemia has MCV < 80 fL and macrocytic anemia has MCV >100 fL.
• Normal range: 27–32 pg MCH < 26 pg is seen in microcytic anemia and MCH > 33 pg is seen in macrocytic anemia.
• Normal range: 31–35 g/dL MCHC < 31 g/dL is seen in hypochromic RBC such as iron deficiency anemia (IDA) and thalassemia. MCHC is increased in hereditary spherocytosis.
• RDW is a quantitative measure of anisocytosis.
• Normal RDW is 11.5−14.5%. RDW = (Standard deviation + mean cell volume) × 100
• Significance: RDW is used for differentiating anemia due to iron deficiency and thalassemia. Increased in IDA (along with low MCV) and megaloblastic anemia (with high MCV) while in thalassemia trait, RDW is normal with low MCV.
• RBC count: Normal range in males 4.5–5.5 millions/cu mm; females 4–4.5 millions/cu mm

Reticulocyte Count:

Reticulocytes are immature, non-nucleated RBCs released from bone marrow. They are demonstrated by using visual method brilliant cresyl blue/new methylene blue stain or by automated method.

Reticulocyte count is expressed as a percentage of RBC count (normal <2.5%). Reticulocyte count reflects the erythropoietic activity of the bone marrow and provides an estimate of red cell production. Increased erythropoiesis results in increased reticulocyte release. The reference range of the corrected reticulocyte percentage in adults is 0.5 1.5%. Causes of increased and reduced reticulocyte count are listed in Table

Reticulocyte production index (RPI) is expressed as % and it accounts for premature release of reticulocytes from M bone marrow in anemia. It is important in determining if a patient’s bone marrow is responding appropriately to the Level of anemia.

Reticulocyte index = Recticulocyte count × [latex]\frac{Hematocrit}{Normal hematocrit for the age}[/latex]

Reticulocyte production index (RPI) = Recticulocyte count × [latex]\frac{Hematocrit}{Normal hematocrit for the age}[/latex] × 0.5

Significance: Normal RPI is 1.0−2.0. However, RPI < 2 with anemia indicates decreased RBC production (hypoproliferative anemia) and RPI > 2 with anemia indicates hemolysis or loss of RBCs leading to compensatory production of reticulocytes and is observed in hyperproliferative anemia.

RBC Abnormalities:

Various RBC abnormalities are presented:

Question 1. Discuss the RBC abnormalities seen on a peripheral blood smear examination. (or) Define, describe, and classify anemia based on red blood cell size and reticulocyte count. Answer:

Question 2. Describe and discuss the morphological characteristics, etiology, and prevalence of each of the causes of anemia. Answer:

Anemia Defiition:

Anemia is defined as decrease in circulating red blood cell mass. It is characterized by decrease of hemoglobin concentration (Hb)/RBC count/hematocrit (PCV) below normal for the patient’s age, sex, and altitude of residence.

Normal adult hemoglobin level is in the range of 13−17 g/dL in males and 12−15 g/dL in females.

Classifiation of Anemia:

Anemia may be classified:

• Based On The Morphology Of Red Cells (Morphological Classification)
• Based on the etiology/cause of anemia.

Morphological and Etiological Classifiation:

Question 3. Write short essay/answer on etiology of anemia. Answer:

Morphological classification:

Clinical Features:

Question 4. Discuss the clinical features of anemia. How to approach a case of anemia? Answer:

They depend on:

• Speed Of Onset Of Anemia
• Severity Of Anemia
• Age Of The Patient
• Underlying illness.

General clinical features are due to either tissue hypoxia or compensatory mechanisms.

• Nonspecific symptoms: Weakness, malaise, lassitude, and easy fatigability
• Dyspnea on mild exertion, angina, intermittent claudication, transient cerebral ischemia
• Central nervous system (CNS): Headache, vertigo, tinnitus, dizziness, syncope, irritability, sleep disturbances, and lack of concentration
• Gastrointestinal tract (GIT): Anorexia, indigestion, nausea, bowel disturbances
• Female genital tract: Amenorrhea, polymenorrhea.
• Cardiac features: Dyspnea on mild exertion, palpitation, tachycardia, and congestive cardiac failure.

Anemia Signs:

• Pallor is observed on skin, palms, mucous membranes (oral, vaginal, rectal), nail beds, and palpebral conjunctiva.
• Pulse: Tachycardia, wide pulse pressure:
• Cardiovascular system (CVS): Cervical venous hum, hyperdynamic precordium, ejection systolic murmur (best heard over the pulmonary area), cardiac dilatation and later, signs of cardiac failure
• Ankle edema.

Signs suggesting etiology of anemia:

History in diagnosis of anemias:

Iron Metabolism:

Iron is required for synthesis of normal heme of hemoglobin. Its deficiency leads to decreased erythropoiesis and anemia.

Distribution of Iron:

Iron is an essential metal present in the human body. The total body iron content (3–4 g) is divided into functional and storage compartments. Iron in the body is extensively recycled between the functional and storage pools.

• Functional: Approximately 80% (2.5 g) of the functional iron is present in hemoglobin. The remaining functional iron is found in myoglobin and iron-containing enzymes (catalase, cytochromes, and peroxidases).
• Storage: The storage pool contains 15–20% (0.5–1.5 g) of total body iron. Free iron is highly toxic because it can result in tissue damage due to its capacity to form free radicals.
• Ferritin (Fe3+) is a protein−iron complex (apoferritin + iron) found in all tissues but particularly in liver, spleen, bone marrow, and skeletal muscles. Very small amounts of ferritin circulate in the serum, the value normally being 15–300 μg/L. Serum ferritin levels reflect the iron stores and are a sensitive indicator of the amount of iron in the body. Serum ferritin level is usually below 12 μg/L in iron deficiency and it is very high (as high as 5,000 μg/L may be observed) in conditions associated with iron overload. Ferritin is water-soluble and not visible by light microscopy.
• Hemosiderin is an aggregate of iron and protein which is found in the reticuloendothelial cells of bone marrow, spleen, and liver. It is formed when iron is in excess (amorphous iron deposition).

Daily requirements: The recommended dietary allowance 10–15 mg. The daily requirement in adult males is 5–10 mg/day and in females 20 mg/day.

Dietary sources: The diet contains iron either in the form of heme contained in animal products and/or nonheme iron in vegetables. Of 10–50 mg in the diet, only 10–15% is normally absorbed.

Iron Absorption:

Site of absorption: Iron is absorbed from the duodenum and proximal jejunum. Iron balance is maintained mainly by regulating the dietary absorption of iron (by the synthesis of apoferritin within mucosal cells).

Transport of Iron:

• Transferrin: Iron is transported in plasma by the iron transport protein transferrin, which is synthesized in the liver. The major function of plasma transferrin is to deliver iron to erythroid precursors for the synthesis of hemoglobin. In normal individuals, transferrin is about 33% saturated with iron, with an average serum iron level of 120 μg/dL in men and 100 μg/dL in women. Thus, the total iron-binding capacity of serum is in the range of 310−340 μg/dL. Unsaturated transferrin protects against infections (iron overload and infection).
• Lactoferrin: It binds iron in milk. It has antimicrobial effect (protects newborns from gastrointestinal infections).
• Haptoglobin: It binds hemoglobin in the plasma.

Iron Excretion/Loss:

Iron metabolism is unique as it is very efficiently utilized and reutilized by the body. There is no physiological regulated mechanism for iron excretion and 1−2 mg/day is lost by shedding of epithelial cells of GI tract, skin epithelial cells (by sweat), and renal tubules and by menstruation, pregnancy, multiple births, lactation, and bleeding.

Regulation of Iron Balance:

Iron is essential for cellular metabolism; at the same time, excess of it is highly toxic. Therefore, the total body iron stores must be properly regulated. Iron balance is mainly achieved by regulating the absorption of iron in the diet. As body stores decrease, the absorption of iron rises and vice versa.

Question 5. Write short note on role of hepcidin. Answer:

It is synthesized in the liver and is the central (key) regulator of iron homeostasis and it controls intestinal iron absorption, plasma iron concentrations, tissue iron distribution, and storage.

• From absorptive enterocytes,
• From macrophages that recycle the iron of senescent erythrocytes, and
• From hepatocytes that store iron.
• The major mechanism of hepcidin is the regulation of transmembrane iron transport. Hepcidin binds to ferroportin and forms hepcidin−ferroportin complex. This complex is degraded in the lysosomes and thus degrades its receptor ferroportin. By this mechanism, hepcidin reduces resorption of iron in the intestine and inhibits iron transfer from the enterocyte to plasma (thereby reduces concentration of iron in plasma).
• When hepcidin levels rise, it lowers iron absorption in the intestine, iron gets stored (locked) within enterocytes forming mucosal ferritin, and iron is shed with the cells. It also lowers iron release from hepatocytes and macrophages (through degradation of ferroportin) leading to decreased serum iron.

Signifiance of hepcidin:

• Increased hepcidin concentration is seen in inflammation (chronic disease anemia)
• Reduced hepcidin production → hereditary hemochromatosis.

Functions of Iron:

• Heme iron: Hemoglobin, myoglobin, cytochrome c oxidase, catalase
• Nonheme iron: Fe-S complexes (xanthine oxidase), DNA synthesis (ribonucleotide reductase).

Iron Deficiency Anemia (Ida):

Question 6. Discuss the etiology, clinical features, investigations, and management of iron deficiency anemia. Answer:

Iron Deficiency Anemia Etiology:

• IDA is due to deficiency of iron causing defective heme synthesis. Iron deficiency anemia is the most common cause of anemia.
• Daily requirement of iron is 10–15 mg. Children consuming large amounts of cow milk develop IDA because iron from cow milk is poorly absorbed and calcium in the milk inhibits iron absorption.

Stages of Iron Defiiency:

Stage 1: Negative iron balance is characterized by decreased bone marrow iron stores.

Stage 2: Iron-deficient erythropoiesis—erythropoiesis is impaired when serum iron falls to <50 mcg/dL (<9 µmol/L) and transferrin saturation to <16%.

Stage 3: Iron deficiency anemia—microcytosis and then hypochromia develop. Eventually iron deficiency affects tissues, resulting in symptoms and signs.

Question 7. Discuss the clinical manifestations and complications of iron deficiency anemia. (or) Write short note on Plummer-Vinson syndrome. Answer:

Plummer-Vinson syndrome Clinical Features:

• Characteristic signs of advanced iron deficiency include:
• Cheilosis (fissures at the corners of the mouth)/angular stomatitis
• Atrophic glossitis
• Brittle fingernails, platonychia, and koilonychia (spooning of the fingernails) brittle hair

• Blue-tinged sclerae, alopecia
• Pica is the unusual craving for substances which have a “crunching” sound with no nutritional value like clay or chalk. Craving for ice (pagophagia) specific to iron deficiency or less commonly for clay (geophagia) or starch (amylophagia); pagophagia is believed to be the most specific to iron deficiency.
• Restless leg syndrome is seen in around 25% of patients with IDA.
• Beeturia is a phenomenon in which the urine turns red following ingestion of beets. Beeturia is increased in individuals with iron deficiency (49–80% of individuals with iron deficiency).
• Iron deficiency (microcytic hypochromic) anemia
• Esophageal/post-cricoid webs resulting in dysphagia for solids than liquids. The web can be demonstrated either by endoscopy or by barium swallow.
• These patients have increased risk of squamous cell carcinoma of pharynx and esophagus.

Diagnosis of Iron Defiiency Anemia:

Question 8. Discuss the investigations/diagnosis of iron deficiency anemia. Answer:

Laboratory Investigations:

These investigations may be divided into two major categories, namely:

• To confirm iron deficiency.
• To determine the cause of iron deficiency

Treatment of Plummer-Vinson syndrome:

Administration of iron. Severe obstruction by the web may require dilatation. Regular upper GI endoscopy may be required for the early detection of cancers.

Soluble transferrin receptor (sTfR) and sTfR-ferritin index—reflect overall erythropoiesis, which is increased in iron deficiency. sTfR-ferritin index (sTfR ÷ log[ferritin]).

The sTfR reflects erythropoiesis, while the ferritin reflects the tissue iron stores; thus, a high sTfR-ferritin index (above 2−3) is a sign of iron deficiency due to increased erythropoietic drive and low iron stores. In anemia of chronic disease/anemia of inflammation, sTfR-ferritin index <1.

Diffrential Diagnosis:

The microcytic hypochromic anemia does not necessarily mean only iron deficiency. The various causes of microcytic hypochromic anemia.

Complications of severe iron deficiency anemia

Differential diagnosis of microcytic hypochromic blood picture:

• Iron deficiency
• Thalassemia: It is an inherited defect in globin chain synthesis. It can be differentiated from iron deficiency by serum iron values, normal or increased serum iron levels, and transferrin saturation. The red blood cell distribution width (RDW) index is generally normal or reduced in thalassemia and elevated in iron deficiency.
• Anemia of chronic disease
• Sideroblastic anemia
• Lead poisoning

Complications of severe iron deficiency anemia:

• During pregnancy: Poor pregnancy outcomes such as premature births and low birth weight babies
• Heart failure
• Delayed growth and development in infants and children
• Increased susceptibility to infections
• Exacerbates cardiorespiratory problems, especially in the elderly

Question 9. Discuss the management/treatment of iron deficiency anemia. (or) Write short note on

• Iron Therapy And
• Parenteral Iron Therapy.

Deficiency anemia Management:

Treatment can be divided into:

• Treatment of underlying cause for iron deficiency. The correct management of iron deficiency is to identify and treat the underlying cause for deficiency.

Oral iron therapy:

Most patients can be treated with oral iron preparations.

• Iron preparations and dose: Oral iron dose is 6 mg/kg/day. Commonly used and best are ferrous sulfate (200 mg three times daily, a total of 180 mg ferrous iron), ferrous gluconate (300 mg twice daily, only 70 mg ferrous iron), ferrous fumarate (325 mg two or three times daily), and others.
• Alternate-day dosing appears to result in equivalent or better iron absorption than daily dosing, usually with fewer adverse effects.
• Side effects: Few patients may develop metallic taste, nausea, dyspepsia, constipation, black tarry stools, or diarrhea. These can be reduced by taking iron tablets with food or reducing the dose or by using preparation with less iron (e.g., ferrous gluconate) or a controlled-release preparation or a liquid preparation.
• Iron should be given to correct the Hb level to normal range and usually occurs within 4–6 weeks. If it does not occur, it may be due to failure of response to therapy.
• Once the hemoglobin returns to normal, oral iron therapy should be continued to replace the iron stores. This may take 6 months to 1 year.
• Patients having iron deficiency due to malabsorption, deficient intake, continuing blood loss, etc., may require long-term iron supplements at a minimum dose.
• Response to oral iron therapy: The response appears within 7–10 days of treatment with iron in the form of an increased reticulocyte count (usually not exceeding 10%, normal <2.5%).
• Failure to take the iron tables: Patients taking iron preparations have gray- or black-colored stools.
• Continuing hemorrhage/blood loss.
• Incorrect/wrong diagnosis: For example, thalassemia trait.
• Ingestion of drugs which reduce iron absorption: Certain drugs if taken along with oral iron (e.g., H 2-receptor blockers, proton-pump inhibitors, antacids, tetracyclines) may interfere with iron absorption.
• Severe malabsorption.

Parenteral iron therapy:

Parenteral iron therapy should be given only after the definite diagnosis of iron deficiency; otherwise it may lead to iron overload and its consequences. Iron stores are replaced much faster with parenteral iron than with oral iron, but the hematological response is not quick.

Indications of parenteral iron therapy:

• Intolerant to oral iron preparation.
• Primary blood loss is uncontrollable: When rate of iron (blood) loss exceeds the rate of its absorption.
• Chronic GI tract disease (e.g., inflammatory bowel disease) which may worsen with oral iron.

Calculation of total iron dose required:

Iron dose in mg = Body weight (kg) × 2.3 × (normal Hb—patient’s hemoglobin, g/dL) + 500 or 1,000 mg (to provide body iron stores).

Route of administration: Parenteral iron can be given by slow intravenous infusion or by intramuscular injection. Types of parenteral iron preparations: These include iron-sorbitol, iron-dextran (imferon), and preparations with much lower rates of adverse effects such as iron sucrose or sodium ferric gluconate, ferric carboxymaltose, and iron isomaltoside.

Iron-sorbitol:

• It is administered only intramuscularly and never by the intravenous route.
• Dose is 1.5 mg of iron/kg body weight daily, to a dose not exceeding 2.5 g.

Iron-dextran (Imferon):

Low-molecular-weight iron dextran is most commonly used. It may be given either intramuscularly or intravenously (more ideal). Test dose is required before administration to prevent anaphylaxis.

• Intramuscular: Dose is 100 mg daily till the total required dose is administered or to a maximum of 2 kg. It should be given deep intramuscularly into the buttocks using a “Z-tract technique.”
• Slow intravenous infusion: Total dose intravenous infusion is rarely required. If a large dose is to be given (>100 mg), it should be diluted in 5% dextrose in water or 0.9% NaCl solution and infused slowly.

Iron-sucrose:

• It has lesser adverse effects and is considered to be the safe intravenous iron preparation.
• It is given as a single dose of 100–200 mg as an intravenous injection or up to 500 mg infused over a period of 3 hours.

Sodium ferric gluconate:

• It is the preferred form of parenteral iron owing to the lo incidence of adverse reactions.
• It is administered intravenously at a dose of 125 mg over 10 minutes.

Ferric carboxymaltose: A novel iron complex that consists of a ferric hydroxide core stabilized by a carbohydrate shell allows for controlled delivery of iron to target tissues. Administered intravenously, it is effective in the treatment of iron-deficiency anemia, delivering a replenishment dose of up to 1,000 mg of iron during a minimum administration time of ≤15 minutes with least reactions.

Ferumoxytol: It is a superparamagnetic iron oxide nanoparticle coated with a low-molecular-weight (LMW) semisynthetic carbohydrate. It can be given in doses of 17 mL (equivalent to 510 mg of elemental iron).

Iron isomaltoside/ferric derisomaltose can be administered in a single infusion, at a dose of 20 mg/kg, over 15 minutes.

Side effcts/toxicity of parenteral iron preparations:

• Pain and swelling at the site of injection/infusion
• Anaphylactic reactions: Fever, generalized urticarial rash, lymphadenopathy, splenomegaly, and arthralgias
• Hemochromatosis

Red Cell Transfusion:

Indication: It is reserved for patients who have symptoms of anemia, cardiovascular instability, continued and excessive loss of blood loss from any site, and require immediate intervention.

Transfusions correct the anemia acutely as well as transfused red cells provide a source of iron for reutilization.

Macrocytic Anemia:

Question 10. Describe the metabolism of vitamin B 12 and the etiology and pathogenesis of B 12 deficiency. Answer:

Vitamin B 12 and folic acid are closely related, and both are essential for normal DNA synthesis and nuclear maturation.

Vitamin B 12 Metabolism:

• Vitamin B 12 is present only in animal proteins and dairy products and not present in vegetables. Therefore, strict vegetarians do not get an adequate quantity of vitamin B 12 .
• A balanced diet (not rigid vegetarian!) contains significantly large amounts of vitamin B 12 which accumulates in the body (liver) and is enough for several (about 3) years. Hence, if there is any dietary deficiency or malabsorption of vitamin B 12 , its clinical manifestations appear only after about 2-4 years.
• Normal daily requirement is about 2−3 μg.

Absorption, Transport, and Storage:

• Vitamin B 12 in food is usually in coenzyme form (as deoxyadenosylcobalamin and methylcobalamin) and bound to binding proteins in the diet.
• In the stomach, peptic digestion at low pH is required for release of vitamin B 12 from binding protein in the food.
• The released vitamin B 12 binds with salivary protein called haptocorrin, which is secreted in salivary juice.
• These haptocorrin-B 12 complexes leave stomach along with unbound special protein called intrinsic factor (IF), which is produced by gastric (fundus and cardia) parietal (oxyntic) cells.
• As haptocorrin-B 12 complexes pass into the second part of the duodenum, pancreatic proteases release vitamin B 12 from haptocorrin. Vitamin B 12 then associates with the intrinsic factor and forms IF-B 12 complex.
• This stable IF-vitamin B 12 complex is transported to the ileum, where it is endocytosed by ileal enterocytes. These ileal enterocytes express a receptor on their surfaces for the intrinsic factor. These receptors are called cubilin.
• In the ileal epithelium, vitamin B 12 combines with a major carrier protein, transcobalamin II, and is actively transported into the mucosal cells and then into the blood.
• Transcobalamin II-vitamin B 12 complex delivers vitamin B 12 to the liver and other cells of the body, particularly rapidly proliferating cells in the bone marrow and mucosal lining of the gastrointestinal tract.

Role of Vitamin B 12 :

Vitamin B 12 is essential for:

• Normal hemopoiesis
• Maintenance of normal integrity of the nervous system

Vitamin B 12 is indirectly required for DNA synthesis in various metabolic steps and its deficiency impairs DNA synthesis. There are two biologically active forms of cobalamin in the body; both act as coenzymes, namely:

• Methylcobalamin and
• Adenosylcobalamin.

1. Methylcobalamin is the main form of vitamin B 12 in plasma and is an essential coenzyme for conversion of homocysteine to methionine and formation of tetrahydrofolate (THF) from methyl THF.

During the former reaction, vitamin B 12 loses its methyl group and this is replaced from methyl THF, the principal form of folic acid in plasma. Tetrahydrofolate is essential for the generation of a precursor of DNA known as deoxythymidine monophosphate (D TMP).

In vitamin B 12 deficiency, the main cause of impaired DNA synthesis is that methyl THF is not converted into THF. Methyl THF accumulates in the cell and is known as “Methyl THF trap”. Lack of folic acid is the next cause of anemia in vitamin B 12 deficiency, as the anemia invariably improves with folic acid administration.

2. Deoxyadenosylcobalamin form of vitamin B 12 is a coenzyme required for conversion of methylmalonyl CoA to succinylmalonyl CoA. Deficiency of vitamin B 12 causes increased levels of methylmalonic acid in plasma and urine. This results in the formation of abnormal fatty acids which get incorporated into neuronal lipids. Consequently, this predisposes to myelin breakdown and is probably responsible for neurologic complications of vitamin B 12 deficiency.

Folic Acid Metabolism:

Question 11. Write short essay/note on folic acid. Answer:

Daily requirement: 50–200 mg

Source: Green vegetables, yeast, legumes, fruits, and animal proteins are the richest sources. The folic acid in these foods is largely in the form of polyglutamates. Polyglutamates are sensitive to heat (thermolabile), boiling, steaming or frying, which destroy most of the folic acid (destroyed by cooking). Intestinal conjugates split the polyglutamates into monoglutamates.

Site of absorption: Proximal jejunum. During intestinal absorption, they are modified to 5-methyltetrahydrofolate, the normal transport form of folic acid (FA).

Storage: Folate is mainly stored in the liver and is enough for about 3 months and hence the manifestations of folate deficiency appear after about 3 months.

Role of Folic Acid:

The active form of folic acid is tetrahydrofolate (THF) which is the biologic “middleman” involved in metabolic processes which synthesize DNA. The various reactions in which folic acid plays a main role are:

• Purine (required for DNA and RNA) synthesis
• Conversion of homocysteine to methionine, a reaction also requiring vitamin B 12
• Deoxythymidylate monophosphate synthesis: 5,10-methylene THF polyglutamate is required for conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) and DNA, a rate-limiting step in pyrimidine synthesis.

Folic acid is associated with metabolism of histidine:

Histidine is metabolized to formiminoglutamic acid (FIGLU) which combines with THF to form glutamic acid. In FA deficiency, this reaction cannot take place and therefore FIGLU accumulates and is excreted as such in urine. This is used as a test to measure folic acidm deficiency.

Manifestations of Megaloblastic Anemia:

Question 12. Discuss the causes, clinical features/manifestations, and management of vitamin B 12 deficiency/megaloblastic anemia. (or) Discuss the causes, clinical features/manifestations, and management of folate deficiency. Answer:

Megaloblastic anemias are a group of disorders characterized by defective/impaired DNA synthesis and distinct megaloblasts in the bone marrow and macrocytes in the peripheral blood. Megaloblastic anemias are common among anemias due to impaired red cell production. They are usually caused due to deficiency of either cobalamin (vitamin B 12 ) or folate (folic acid) but may occur because of genetic or acquired abnormalities that affect the metabolism of these vitamins.

Etiology of Megaloblastic Anemia:

Pathogenesis (Mechanism) of Megaloblastic Anemia:

• Megaloblastic anemias are commonly due to deficiency of vitamin B 12 (cobalamin) or folic acid, which are coenzymes required for the synthesis of one of the four bases found in DNA, namely thymidine.
• Deficiency of cobalamin or folate results in failure of DNA synthesis and delayed/arrested nuclear maturation. Synthesis of RNA and protein is normal resulting in normal cytoplasmic maturation. Thus, the nuclear maturation lags behind the cytoplasmic maturation producing nucleocytoplasmic asynchrony. This results in abnormal cell proliferation thataffects rapidly dividing cells in the bone marrow (erythroid, myeloid, and megakaryocyte series).
• Impaired DNA synthesis causes delay in cell division and increases time between divisions and size of the cells become large and are called as “megaloblasts.” The megaloblasts have an open, stippled, and lacy chromatin. The megaloblastic changes are most prominent in the early nucleated red cell precursors.
• Erythroid precursor cells show a reduced number of mitoses, and synthesis of hemoglobin is unimpaired. The mature RBCs derived from these megaloblasts are large (macrocytes) and oval but well hemoglobinized.
• In the bone marrow, a large number of megaloblastic precursors do not mature enough to be released into the blood and are destroyed in the bone marrow (ineffective erythropoiesis). There is also mild hemolysis of red cells in the peripheral blood. This releases large amounts of lactate dehydrogenase (LDH) resulting in raised levels in the blood.
• In the bone marrow, abnormal proliferation affects myeloid series producing giant metamyelocytes and the megakaryocyte series resulting in dysplastic megakaryocytes.
• All rapidly dividing cells of the body (including skin, GI tract, bone marrow) exhibit megaloblastic changes, and anemia is only a manifestation of a more generalized defect in DNA synthesis.

Pathogenesis of Neurological Changes in Vitamin B 12 Defiiency:

Two mechanisms are responsible for neurologic changes seen of vitamin B 12 deficiency. Deficiency of vitamin B 12 causes:

• Impairment in the conversion of homocysteine to methionine: Methionine is required for the production of choline and choline-containing phospholipids. These are needed by the neuronal cells.
• Lack of adenosylcobalamin: It is a vitamin B 12 –containing cofactor required for the conversion of methylmalonyl CoA to succinyl CoA. Lack of this cofactor results in increased levels of methylmalonyl CoA and its precursor, propionyl CoA. This causes production of nonphysiologic fatty acids and incorporated into neuronal lipids.

Pernicious Anemia:

Question 13. Discuss the etiology of Addisonian pernicious anemia. Answer:

Pernicious anemia (PA) is a chronic autoimmune disorder characterized by atrophic gastritis with loss of parietal cell in the gastric mucosa which causes failure of production of intrinsic factor. Absence of intrinsic factor results in failure of absorption of dietary vitamin B 12 and deficiency which eventually produces megaloblastic macrocytic anemia.

Age and gender: PA is a disease of older age and generally presents in the fifth to eighth decades of life. Females are more involved than males.

Pernicious Anemia Etiology:

• Pernicious anemia is an autoimmune disease causing destruction and permanent atrophy of gastric mucous membrane. The evidences for autoimmune etiology are as follows:
• It is associated with other autoimmune diseases such as Graves’ disease, Hashimoto’s thyroiditis, vitiligo, and Addison’s disease.
• Microscopically, stomach shows chronic atrophic gastritis with damage to gastric parietal cells.
• Response to steroids is seen.
• There is presence of autoantibodies in most of the patients.
• Type I (blocking) antibody: This blocks the binding of vitamin B 12 to IF and is present in 50–75% of the cases and can be detected in both plasma and gastric juice.
• Type II (binding) antibody: It attaches to the IF–vitamin B 12 complex and prevents their binding to receptors in the ileal mucosa. They are present in about 40% of patients.
• Parietal cell (type III) antibody: It is directed against α and β subunits of the gastric proton pump (H+, K+-ATPase) in parietal cells but is neither specifi for PA nor other autoimmune disorders. Thy are found in 90% of patients with PA as well as in older patients with chronic nonspecifi gastritis.

Role of Helicobacter pylori: H. pylori gastritis may play a role in PA. There is a higher incidence of gastric carcinoma in patients with PA. The incidence is higher in patients with blood group A.

Clinical Features of Macrocytic Anemias:

Question 14. Discuss clinical manifestations of vitamin B 12 deficiency/folate deficiency/pernicious anemia. Answer:

The onset is insidious in origin and progresses slowly unless halted by therapy.

Clinical features related to vitamin B 12 deficiency:

• Classic triad: Weakness, sore throat, and paresthesias
• Tongue: Painful red “beefy” tongue due to glossitis and atrophy of papillae. The patient complains of loss of taste and appetite.
• Patients may have a lemon-yellow color due to combination of pallor and mild jaundice caused by excess breakdown of hemoglobin.

Pigmentation: Pigmentation of knuckles and creases is common. The generally accepted mechanism of pigmentation is an increase in the melanin synthesis.

The other hypotheses proposed are:

Deficiency of vitamin B 12 decreases the level of reduced glutathione, which activates tyrosinase and thus leads to transfer to melanosomes.

Defect in the melanin transfer between melanocytes and keratinocytes, resulting in pigmentary incontinence.

Neurological Features:

Question 15. Write short essay/note on neurological complications of pernicious anemia/megaloblastic anemia. Answer:

• Peripheral nerves-peripheral neuropathy: Glove and stocking distribution of numbness or paresthesia. This tingling begins in tips of toes and progresses proximally and is bilateral and symmetric. It is characterized by loss of ankle reflexes.
• Posterior columns: Impaired/diminished vibration and position sensation
• Corticospinal tracts: Upper motor neuron signs—ataxic, uncoordinated gait. Bilateral extensor plantar with absent ankle jerks
• Cerebrum: Depression and loss of memory (dementia), optic atrophy
• A positive Romberg sign and Lhermitte sign may be elicited.
• Folate deficiency in adults does not give rise to significant neurologic findings.
• Prematurely gray-haired
• Atherosclerosis: Serum homocysteine level is raised and is a risk factor for atherosclerosis and thrombosis (myocardial infarction, stroke).
• Pernicious anemia: Symptoms are same as those of vitamin B 12 deficiency. In addition:
• Hypochlorhydria: Atrophic gastritis causes decreased secretion of hydrochloric acid and IF. The symptoms include dyspepsia, postprandial fullness, and early satiety.

Clinical Features Related to Folate Defiiency:

They are similar to those of vitamin B 12 deficiency except for neurological features.

Diagnosis/Laboratory Findings of Megaloblastic Anemia:

Question 16. Discuss the diagnosis of megaloblastic anemias. (or) Discuss the diagnosis of anemias due to vitamin B 12 deficiency. Answer:

Blood findings in vitamin B 12 (including pernicious anemia) and/or folic acid deficiency are similar.

Common Findings:

Peripheral blood:

Question 17. Describe the peripheral blood and bone marrow picture in megaloblastic anemia. Answer:

• Hemoglobin and hematocrit (PCV): Reduced
• Red cell indices: MCV raised above 100 fL (normal 82–98 fL)
• RBC, WBC, and platelet count: All are reduced.
• Macrocytic and oval (egg-shaped macro-ovalocytes) and are diagnostic
• Marked variation in the size and shape of red cells (anisopoikilocytosis)
• Evidence of dyserythropoiesis: Basophilic stippling, Cabot ring, and Howell-Jolly bodies

• Decreased WBC count (leukopenia)
• Hypersegmented neutrophils (more than five nuclear lobes): First and specific morphological sign of megaloblastic anemia. These neutrophils are also larger than normal.
• Platelets: Decreased
• Reticulocyte count: Normal or low. Reticulocytosis occurs in response to very small doses of parenteral vitamin B 12 .

Peripheral blood Bone marrow:

• Markedly hypercellular
• Megaloblastic type of erythropoiesis
• Granulocytic precursors display nuclear-cytoplasmic asynchrony in the form of giant metamyelocytes and band forms.
• Megakaryopoiesis: Normal or increased in number
• Bone marrow iron: Moderately increased

Biochemical tests (common for both vitamin B 12 and folic acid defiiency):

• Deoxyuridine suppression test: It is a sensitive measure of deficiency of 5, 10-methylene THF, which occurs in both folic acid and vitamin B 12 deficiency.
• Serum homocysteine levels are raised.
• Serum bilirubin: Indirect bilirubin is mildly increased due to increased breakdown of red cells in bone marrow and produces mild jaundice.
• Serum iron and ferritin are raised and iron-binding capacity is reduced.
• Plasma lactate dehydrogenase (LDH) is markedly increased.
• Serum vitamin B 12 /folate is decreased.

Diagnostic/Specifi Tests for Vitamin B 12 Defiiency:

• Serum vitamin B 12 levels: Reduced and levels are very low (<200 pg/µL).
• Serum methylmalonic acid (MMA) and homocysteine levels: Raised.
• Urinary excretion of methylmalonic acid: Raised.
• Schilling test (refer below) for vitamin B 12 absorption, which was discontinued in 2003, once provided invaluable information on the locus and mechanism of cobalamin malabsorption.

Diagnostic/Specifi Tests for Folic Acid Defiiency:

• RBC folic acid levels: Reduced
• FIGLU in urine: Excessively excreted.

Determining the Cause of the Vitamin (Folate/Vitamin B 12 ) Defiiency:

• The cause of folate deficiency is usually determined from the history, physical examination, and clinical features.
• In adults, the cause of vitamin B 12 deficiency is either due to vitamin B 12 malabsorption or dietary deficiency of vitamin B 12 .
• To determine the basis for malabsorption, one needs additional diagnostic tests (e.g., intestinal biopsy, examination of stool for malabsorption, or Diphyllobothrium latum infestation) and requires specific therapy (e.g., gluten-free diet, folate, antibiotics, antihelminthics). A detailed dietary history or past medical history (e.g., gastroduodenal disease, pancreatic insufficiency, impaired bowel motility, or other autoimmune diseases) and physical examination can provide additional clues for other causes.

Schilling Test for Vitamin B 12 Absorption:

Question 18. Write short essay on Schilling test/vitamin B 12 absorption test. Answer:

Use: Schilling test helps in distinguishing megaloblastic anemia due to IF deficiency (pernicious anemia) from other causes of vitamin B 12 deficiency. It is diagnostic of PA, is of historical interest, and is now very infrequently performed.

Method and interpretation:

Radioactive vitamin B 12 (1 µg) is given orally to a fasting patient. This is followed by nonradioactive 1,000 µg of vitamin B 12 intramuscularly. The injected vitamin B12 saturates vitamin B12-binding proteins and flushes out the ingested radioactive vitamin B 12 which will be excreted in urine. The urine is collected for 24 hours.

• Normal persons excrete more than 10% of oral radioactive dose in 24-hour urine.
• Patients with pernicious anemia excrete less than 5% of the oral dose.

• The test is repeated with addition of oral intrinsic factor to radioactive vitamin B 12 .
• If the urinary excretion is now normal, the diagnosis is intrinsic factor deficiency due to either pernicious anemia or gastrectomy.
• Stage 3: Giving pancreatic enzyme extracts with the oral vitamin B 12 should guide toward pancreatic insufficiency if it corrects the abnormality.
• If the excretion is still abnormal, the lesion must be in the terminal ileum or there may be bacterial overgrowth. The bacterial overgrowth may be corrected by a 7-day course of oral tetracycline/antibiotics. The test is repeated after a course of oral tetracycline.
• If the excretion returns to normal, it confirms that malabsorption of vitamin B 12 is due to bacterial overgrowth in the intestine.

Specifi diagnostic tests for pernicious anemia:

• Anti-intrinsic factor antibodies in serum (in 70% of patients; highly specific for pernicious anemia)
• Antiparietal cell antibodies (in 85–90%; less specific compared to anti-intrinsic antibodies)
• Achlorhydria with histamine stimulation:
• Severe deficiency of intrinsic factor.

Other Nonspecifi Tests:

• Serum gastrin is raised.
• Pepsinogen I is decreased.
• Gastric biopsy shows mucosal atrophy and inflammatory infiltrate of lymphocytes and plasma cells.

Question 19. Discuss the management of megaloblastic macrocytic anemias. (or) Discuss the management of Addisonian pernicious anemia. Answer:

Management of Megaloblastic Macrocytic Anemia:

Treatment consists of treating the underlying cause, whenever possible.

Specific therapy:

• Treatment of underlying cause of vitamin B 12 or folate deficiency.
• Vitamin B 12 /Cobalamin deficiency
• Vitamin B 12 therapy (cyanocobalamin, hydroxocobalamin, or methylcobalamin may be used)
• Initial dose: It is treated with six intramuscular injections of hydroxycobalamin 1,000 μg given at 3-7-day intervals.
• Maintenance dose: Maintenance dose of 1,000 μg to be given intramuscularly every 3 months for the rest of the patient’s life. Methylcobalamin, a metabolically active form of vitamin B 12 , can also be used.
• An aggressive scheme to replace vitamin B 12 rapidly is 1 mg of intramuscular cyanocobalamin per day (week 1), 1 mg twice weekly (week 2), 1 mg/week for 4 weeks, and then 1 mg/month for life.
• Response: Clinical improvement may occur within 48 hours (LDH and bilirubin will normalize) and a reticulocytosis peak by the 3–4th day after therapy and may be as high as 50%. Anemia will correct by 4 6 weeks. Improvement of the sensory polyneuropathy may take 6–12 months to correct, but longstanding spinal cord damage is irreversible. Hypokalemia may occur during the initial week of treatment as there is marked potassium uptake during production of new blood cells.
• Dimorphic anemia: If there is associated iron deficiency, ferrous sulfate 200 mg thrice daily orally should be started soon after the commencement of vitamin B 12 therapy.

Folate deficiency:

• Dosage: Oral dose of 5 mg folate (folic acid) daily for 3 weeks will treat acute deficiency and 5 mg once weekly is adequate maintenance therapy.
• Folinic acid is of value to bypass the block of dihydrofolate reductase by methotrexate and trimethoprim-sulfamethoxazole.
• Congenital folate malabsorption arising from inadequate folate transport across the gastrointestinal tract and blood-brain barrier responds to parenteral leucovorin in high doses.
• Response is same as seen after treatment of vitamin B 12 deficiency.
• Precaution: Large doses of folic acid alone should not be given to treat megaloblastic anemia (such as pernicious anemia or other vitamin B 12 deficiency anemias) unless the serum vitamin B 12 level is known to be normal. If vitamin B 12 deficiency is present, it should be corrected first; otherwise cobalamin neuropathy may be aggravated or precipitated despite a response of the anemia of cobalamin deficiency to folate therapy.
• Prophylactic folic acid in pregnancy: Prophylactic folic acid in the dose of 400 μg daily is recommended for all women planning a pregnancy to reduce the risk of fetal neural tube defects.

Supportive therapy:

• Blood transfusions: Transfusion is usually not necessary and not advisable. It should be given in significantly symptomatic and severely anemic patients with angina or heart failure.
• Other measures: Treatment of infection and physiotherapy in nervous system involvement.
• Clinical and hematological examination should be carried out every 6 months.
• Pernicious anemia: Carcinoma of stomach and gastric carcinoids are more common in patients with pernicious anemia and early detection is important.

Causes of Macrocytosis:

Question 20. Enumerate the causes of macrocytosis/macrocytic anemia. Answer:

Macrocytes are large red blood cells with a diameter of more than 9 µ and MCV of more than 95 fL. The macrocytic anemias can be divided into megaloblastic and nonmegaloblastic types, depending on the appearance of developing red cell precursors in the bone marrow.

Megaloblastic Macrocytic Anemia:

It is characterized by raised MCV with macrocytosis on the peripheral blood and the presence of abnormal red precursors of the bone marrow known as megaloblasts. Causes of megaloblastic anemia include deficiency of vitamin B 12 , folate or copper and drugs that interfere with purine or pyrimidine metabolism. The peripheral blood smear shows macro-ovalocytes and hypersegmented neutrophils.

Nonmegaloblastic Macrocytic Anemia:

It is characterized by a raised MCV with macrocytosis on the peripheral blood film with a normoblastic rather than a megaloblastic bone marrow. Common causes are

Causes of nonmegaloblastic macrocytic anemia:

Abnormalities of DNA metabolism:

• Azathioprine or 6-mercaptopurine
• Capecitabine
• Cytosine arabinoside
• Hydroxyurea
• Imatinib, sunitinib
• Methotrexate

Shift to immature or stressed red cells:

• Reticulocytosis
• Action of erythropoietin—skip
• macrocytes, stress erythrocytosis
• Aplastic anemia/Fanconi anemia
• Pure red cell aplasia

Primary bone marrow disorders:

• Myelodysplastic syndromes
• Congenital dyserythropoietic anemias
• Some sideroblastic anemias
• Large granular lymphocyte (LGL) leukemia

Lipid abnormalities:

• Liver disease
• Hypothyroidism

Mechanism unknown:

• Alcohol abuse
• Multiple myeloma

Hemolytic Anemias:

Question 21. Define and classify hemolytic anemia. Discuss the clinical features, diagnosis, and management of hemolytic anemias. Answer:

Hemolytic Anemias Defiition:

Hemolytic anemias are defined as anemias that result due to increase in the rate of red cell destruction. The life span of red cells (normal life span is 90–120 days) is shortened.

Compensated Hemolytic Disease:

Shortening of red cell survival may not always cause anemia as bone marrow can compensate by increased production of red cells by six to eight times.

Classifiation of Hemolytic Anemias:

Question 22. Define and classify hemolytic anemia. Answer:

The hemolytic anemias are classified in a variety of ways.

• Location of hemolysis: Depending upon the site of red cell destruction, it can be classified as intravascular and extravascular hemolytic disorders.
• Source of defect causing hemolysis: Hemolysis may be due to a defect intrinsic to the red cell itself (intracorpuscular defect)or due to an abnormality outside the red cell (extracorpuscular mechanism).
• Mode of onset: Hereditary and acquired disorders
• Clinical point of view: Acute or chronic

Clinical Features of Hemolytic Anemia:

Diagnosis of Hemolytic Anemias:

Question 23. Write short essay on laboratory investigations/features of hemolysis/hemolytic anemia. Answer:

Recognition of Hemolysis:

Features of increased RBC production: As a compensatory mechanism to hemolysis, there is increased production of red cells.

• Bone marrow shows compensatory erythroid hyperplasia.
• Peripheral smear shows increased reticulocytes (reticulocytosis), nucleated red cells, and polychromasia. Other findings vary depending on the cause mentioned below.
• Radiological changes: Hair-on-end appearance in skull radiograph (thalassemia, sickle cell anemia) is seen.

Recognition of Cause of Hemolysis:

• Spherocytosis, autoimmune hemolytic anemia),
• Sickle cell (sickle cell anemia)
• Target cell (thalassemia)
• Acanthocyte
• Schistocyte (intravascular hemolysis-fragmented red cells, helmet cells, triangular cells), and
• Malarial parasite.
• Coombs test
• Osmotic fragility, sucrose lysis, and Ham’s test
• Heinbody preparation
• Hemoglobin electrophoresis
• High-performance liquid chromatography (HPLC)
• Measurement of enzyme activity
• Specific tests: Identification of specific cause of hemolysis is dealt under individual diseases.

Defects In Hemoglobin Production:

Question 24. Write short note on classification of disorders of hemoglobin (hemoglobinopathies/hereditary disorders of hemoglobin). Answer:

Hemoglobin defects may be in the form of production of abnormal (qualitative) or reduced production (quantitative) of normal hemoglobin. The term hemoglobinopathy, unless specified, usually indicates a qualitative hereditary disorder.

Sickle Cell Disease:

Question 25. Discuss the etiopathogenesis, clinical features, investigations, and management of sickle cell anemia. Answer:

Sickle cell disease (SCD) is an important group of autosomal recessive hereditary disorders of hemoglobin characterized by production of defective hemoglobin synthesis called sickle hemoglobin (HbS). HbS imparts sickle shape to red cells on low oxygen tension or deoxygenation. The term sickle cell disease includes all entities associated with sickling of hemoglobin within the red blood cells.

The major entities included are:

• Sickle cell anemia (SS) is a homozygous state in which both the β globin chains are abnormal.
• Sickle cell trait (AS) is a heterozygous state in which one gene is defective for HbS (abnormal) while the other gene is for HbA (normal).
• Compound heterozygous is characterized by both the β-globin chains having different abnormalities (e.g., Hb SC, HbS- β-thalassemia). In India, it is seen in certain tribes of South India, Assam, Bihar, and Odisha.

Sickle Cell Disease Etiology and Pathogenesis:

Sickle cell anemia is caused by production of abnormal hemoglobin called sickle hemoglobin (HbS). In HbS, there is an adenine (A) to thymidine (T) substitution (GAG → GTG) in codon 6 of the β-globin gene. This point mutation results in replacement of the normal glutamic acid residue by a valine and alters the solubility or stability of the hemoglobin.

Sickle Cell Disease Pathogenesis:

The change in the shape is due to dehydration, partly caused by potassium leaving the red cells via calcium-activated potassium channels called the Gárdos channel.

Deoxygenated HbS molecules are insoluble and polymerize to form pseudocrystalline structures known as “tactoids”.

RBCs become rigid, deformed, and assume a characteristic sickle/crescent shape (sickle-shaped cells). Initially, on reoxygenation this process is reversible. But with repeated episodes of sickling, the RBCs eventually lose their membrane flexibility and become irreversibly sickled cells (ISCs). Factors that favor and hinder sickling are listed in Table.

Consequences of Sickling:

Irreversibly sickled cells are dehydrated and dense and will not return to normal when oxygenated. Sickling can produce:

• Microvascular occlusions: Impaired passage of ISCs through the microcirculation, produce obstruction of small vessels, and lead to tissue ischemia and infarction
• Hemolytic anemia: It is due to shortened survival of the sickle cells which are destroyed by the reticuloendothelial system.

Question 26. Write short essay/note on the complications of sickle cell anemia. Answer:

The clinical features change as life advances.

In Children:

• An infant till 3 months may be asymptomatic, because of the protective role of HbF. Since HbF disappears after the 3rd month, majority of cases present after 3 months and before the 1st year of life.
• Prone to infections: Children are susceptible to acute infections with encapsulated organisms. Common infections are pneumococcal pneumonia, meningitis due to S. pneumoniae, and osteomyelitis due to Salmonella. Increased susceptibility to infections is because of hypofunction of spleen and defects in the alternative complement pathway which impair opsonization of encapsulated bacteria such as pneumococci and Haemophilus influenzae. Septicemia and meningitis are the most common causes of death in children. Increased frequency of osteomyelitis is because of repeated bone infarcts which act as nidus for infection.
• In children, bone involvement may resemble acute osteomyelitis. They manifest as the hand-foot syndrome and dactylitis of the bones of the hands or feet or both. It is due to microinfarcts in the carpal and tarsal bones.
• Sequestration crisis: It usually occurs in children with chronically enlarged but normal functioning spleen. Sudden trapping of blood in spleen or liver causes rapid enlargement of the organ with resultant drop in hematocrit and hypovolemic shock. This may require blood transfusions.
• Changes in spleen: Splenomegaly is observed during early childhood. Repeated episodes of splenic infarct result in atrophy of the spleen (autosplenectomy).
• Acute chest syndrome can develop in both children and adults. It is due to infection or infarction in the lung and presents with pain in the chest, fever, respiratory distress, and hypoxemia.
• Others include acute coronary syndrome and stroke. Chronic hypoxia in children is responsible for generalized impairment of growth and development.

Anemia: Patients develop severe hemolytic anemia which is exacerbated by secondary folate deficiency. Chronic anemia presents with fatigue, frequent infections, cardiomegaly, and systolic murmurs. Chronic hemolytic anemia causes increased levels of unconjugated (indirect) bilirubin, which predisposes to development of pigmented bilirubin gallstones. Cholelithiasis may lead to cholecystitis.

Question 27. Write short essay/note on sickle cell crises. Answer:

• Crises: Irreversibly sickled cells have a shortened survival and plug vessels in the microcirculation. Any new syndrome or episode that develops rapidly in sickle cell anemia is termed crises. The protracted course of sickle cell anemia is frequently exacerbated by a variety of crises. Four types of crises are encountered. These are:
• It is most common and the hallmark of sickle cell disease.
• It clinically presents with acute, severe pain in the affected region. It commonly involves bones, lungs, liver, and spleen.
• Bone: Sudden attacks of bone pain are due to ischemia and infarction. Avascular necrosis of the head of femur is also common.
• Lung: Involvement presents with fever, cough, chest pain, and pulmonary infarcts and is known as acute chest syndrome (dangerous). These are sometimes initiated by a simple lung infection.
• Spleen: Acute abdominal pain is caused by infarcts of spleen and leads to autosplenectomy.
• Other sites of infarction: Mesenteric infarction results in acute abdominal pain, cerebral infarctions result in hemiplegia, and infarction of renal papillae results in hematuria. Retinal microinfarcts result in loss of vision.
• Aplastic crisis: Temporary suppression of bone marrow erythropoiesis may develop due to an acute infection of erythroid progenitor cells by parvovirus B19.
• Hemolytic crisis is characterized by episodes of increased sequestration and destruction of red cells. It presents with marked increase in hemolysis with a sudden lowering of hemoglobin, rapid enlargement of liver and spleen, and reticulocytosis.
• Sequestration crisis (described above).
• Other crises encountered rarely are hypoplastic crisis and megaloblastic crisis (due to inadequate folate).

Question 28. Discuss the long-term complications of sickle cell anemia. Answer:

They are described in Table:

Sickle cell anemia Investigations:

• Evidences of hemolysis:
• Blood count: Hb is in the range 6–8 g/dL with a high reticulocyte count (10–20%).
• Peripheral smear: The characteristic red cell which appears in smear is the sickle cell. These appear as long, curved cells with pointed ends. Features of hyposplenism include: HowellJolly bodies (small nuclear remnants), target cells (due to red cell dehydration), and ovalocytes.
• ESR is low because sickle cells do not form rouleaux.
• Sickling test is induced by adding a reducing (oxygen-consuming) agent like 2% sodium metabisulfite or sodium dithionite to blood sample.
• Sickle solubility test: A mixture of HbS in a reducing solution (e.g., sodium dithionite) gives a turbid appearance because of precipitation of HbS, whereas normal Hb gives a clear solution.
• Hemoglobin electrophoresis: There is no HbA, 80–95% HbSS, and 2–20% HbF. HbS is slow-moving hemoglobin compared to HbA and HbF. In sickle cell trait (heterozygous state), HbS is 20–40% and the rest is HbA.
• Tests for iron overload: Serum ferritin levels, transferrin saturation, liver iron concentration using liver biopsy specimen, measurement of liver iron using MRI.
• Prenatal diagnosis can be done by analysis of fetal DNA obtained by amniocentesis or chorionic villous biopsy.

Sickle cell anemia Investigations Management:

General Measures:

Sickle cell disease is a chronic disorder which requires the following general measures:

• Good nutrition and folic acid supplementation (5 mg daily) are to be given to all patients with hemolysis.
• Timely immunizations against Streptococcus pneumoniae, seasonal influenza, Neisseria meningitidis, Haemophilus influenzae type B, and hepatitis B virus are recommended.
• Antibiotic prophylaxis with phenoxymethylpenicillin 500 mgdaily starting at the age of 2 months. Older children do not routinely need continued antibiotic prophylaxis.
• Precipitating factors should be avoided or treated quickly. These include avoidance of cold, dehydration, and hypoxia.
• Prevention, prompt identification, and treatment of infections with antibiotics are required.
• Transfusions should only be given for clear indications. Transfusion should not be given to patients with chronic stable anemia, those having minor surgery, or those having painful episodes without complications.
• Indications for blood transfusion: Transfusion is required to increase the oxygen-carrying capacity, replace the rigid, sickle-shaped RBCs with normal cells, and restore blood flow. Acute transfusions with packed RBCs can be life-saving and chronic transfusions reduce the incidence and severity of most complications.
• Repeated transfusions may be used to reduce the proportion of circulating HbS to less than 20% to prevent sickling, before elective operations and during pregnancy. Chronic RBC transfusion reduces the chance of recurrent ischemic stroke.
• Exchange transfusions may be necessary in patients with severe or recurrent crises or before emergency surgery. Whether exchange transfusion is preferable to simple transfusion in the acute chest syndrome, stroke or other acute complications has not been established by clinical trials.
• Infarction crises are managed with hydration, oxygen, analgesics, and transfusion with RBC concentrate in selected cases.
• Iron overload: With repeated transfusion, iron overload inevitably develops and can result in heart and liver failure and other complications. Iron overload is treated by using iron chelators (deferoxamine or deferasirox).

Hydroxycarbamide (hydroxyurea): It may be used as therapy for patients with severe symptoms. Hydroxyurea (10–30 mg/kg/day) increases HbF and suppresses the neutrophil and reticulocyte counts (which may play a major role in the pathogenesis of sickle cell crisis).

Hydroxycarbamide reduces the episodes of pain, the acute chest syndrome, and the need for blood transfusions. Senicapoc, a Gárdos channel inhibitor, prevented erythrocyte dehydration in clinical trials of patients with sickle cell disease. This drug has antiplasmodium activity.

Acute Painful Crisis:

It requires supportive therapy with intravenous fluids, oxygen, antimicrobial agents, and adequate analgesia. Acute severe pain is treated with narcotic and analgesia (morphine) and milder pain can be relieved by codeine, paracetamol, and nonsteroidal anti-inflammatory drugs (NSAIDs). Inhaled nitric oxide inhibits platelet function, reduces vascular adhesion of red cells, and is also a vasodilator. It can provide shortterm pain relief and is shown to reduce opiate requirements in acute painful episodes. But it should be restricted to experts to avoid hypoxia and respiratory depression. Nasal oxygen should be employed as appropriate to protect arterial saturation.

Acute chest syndrome is treated with antibiotics, maintenance of arterial oxygenation, pain relief, bronchodilators, and, if required, exchange transfusion.

Chronic leg ulcers: They are treated with elevation of limb, daily dressings with zinc sulfate, and exchange transfusion in extreme cases.

• Bone marrow/stem cell transplantation: In children and adolescents younger than 16 years of age who have severe complications (strokes, recurrent chest syndrome, or refractory pain), bone marrow/stem cell transplantation can provide definitive cure.
• Gene therapy is intensively pursued, but no safe measures are currently available.

Hereditary Spherocytosis:

Question 29. Write short note on hereditary spherocytosis (HS). Answer:

• It is the most common inherited hemolytic anemia in adults
• Autosomal dominant inheritance is present in more than 75% cases
• Defect in the RBC membrane is due to cytoskeleton protein (e.g., ankyrin, band 3, spectrin, or band protein 4.2) deficiency.
• This results in red cells losing part of the cell membrane as they pass through the spleen and assume a spheroidal shape (spherocytes) that is less deformable (rigid) and more susceptible to osmotic lysis.
• Red cells have a decreased life span of as low as 10−20 days.

Hereditary Spherocytosis Clinical Features:

• Disease may present during anytime from the neonatal period to adulthood.
• Family history: Most (75%) HS are inherited as autosomal dominant trait and there is a strong family history of anemia, jaundice, splenomegaly, and cholelithiasis.
• Anemia is usually mild to moderate.
• Jaundice: There are intermittent attacks of jaundice.
• Splenomegaly: Moderate splenic enlargement is characteristic and constant feature.
• Children: Growth retardation due to hemolysis and bone changes due to marrow hyperplasia are found in children.
• Adults: Anemia, intermittent jaundice, and moderate splenomegaly are found in adults.
• Complications of hereditary spherocytosis.

Complications of hereditary spherocytosis:

• Cholelithiasis (pigment gallstones)
• Chronic leg ulcers
• Aplastic crises due to parvovirus B19 infection
• Hemolytic crises (rare)

Hereditary Spherocytosis Investigations:

• Anemia: It is usually mild, but occasionally can be severe.
• Peripheral blood film shows spherocytes and reticulocytes. MCHC is increased.
• Demonstration of a hemolytic state: Raised serum bilirubin and urinary urobilinogen
• Specific diagnostic tests are listed in Box 8.5. Increased osmotic fragility may be absent in mild cases and may be positive in autoimmune hemolytic anemia.
• Negative Coombs test
• Strong family history will be present.

Hereditary Spherocytosis Treatment:

• Splenectomy is the treatment of choice and should not be done before the age of 6 years. Splenectomy corrects the anemia and its complications but increases the risk of infections. Hence, it should be preceded by pneumococcal and Haemophilus influenzae immunization and followed by lifelong penicillin prophylaxis.
• Folic acid supplementation in patients without splenectomy is recommended.
• Regular blood transfusions are required in few patients with severe disease.
• Cholecystectomy is indicated only for symptomatic gallstones

Specific diagnostic tests for hereditary spherocytosis:

• Osmotic fragility testing
• Ektacytometry
• Acidified glycerol lysis test
• Cryohemolysis test
• Eosin-5-maleimide binding test

Thalassemia Syndrome:

Question 30. Write short essay/note on definition, common forms, and genetics of thalassemias. Answer:

Thalassemia syndrome is a heterogeneous group of inherited disorders which result from reduced or absence of synthesis of one of the globin chains (either α or β globin chain).

Thalassemia Syndrome Classifiation:

Thalassemic syndromes are mainly classified into two main types depending on the defective globin chain α or β thalassemia. The mode of inheritance is autosomal recessive. Rarely, HBB gene mutation is inherited as autosomal dominant.

α-Thalassemia Syndromes:

Each cell has four genes coding for α-globin, two on each chromosome. Each of the four α-globin genes normally contributes 25% of the total α-globin chains. Severity of α-thalassemia depends on the number of α-globin genes deleted or affected. Deleted genes may vary from 1 to 4.

• Silent carrier state develops with deletion of one α-chain gene.
• α-thalassemia trait: It is due to deletion of two α-genes.
• HbH disease: It is due to deletion of three α-genes.
• Hb Bart’s hydrops fetalis: It develops if all four genes are absent. It is incompatible with life and the infants are either stillborn or die shortly after birth. They are pale, edematous, and have large liver and spleen.

Classical thalassemia syndromes (genotypes and laboratory findings) are presented in Table:

β-Thalassemia Major:

Question 31. Discuss the clinical features, salient investigations, diagnosis, and management of β-thalassemia major (Cooley’s anemia). Answer:

• β-thalassemia major (Mediterranean or Cooley’s anemia) is the homozygous form of β-thalassemia characterized by absent or reduced synthesis of β-chain.
• It is most common in Mediterranean countries and parts of Africa and Southeast Asia. In India, it is common among certain communities (e.g., Sindhi, Punjabi, Gujarati, Parsee) in North India and less common in South India.
• Anemia is produced due to diminished synthesis of HbA, ineffective erythropoiesis, and extravascular hemolysis.
• Marked erythroid hyperplasia: Severe hemolytic anemia stimulates erythropoietin (EPO) production by kidney leading to marrow erythroid hyperplasia.
• Changes in the bone: Thalassemic facies and hair-on-end appearance of skull X-ray
• Extramedullary hematopoiesis.

β-Thalassemia Majo Clinical Features:

• Severe anemia: Infants with thalassemia major are well at birth but develop moderate-to-severe anemia 6-9 months after birth, when hemoglobin synthesis switches from HbF to HbA.
• Retardation of growth and development: Untreated/untransfused children fail to thrive (growth retardation) and die early within 4–5 years of age from the effects of anemia. They are susceptible to recurrent bacterial infections.
• Thalassemic (Chipmunk) facies: Due to enlargement and distortion of craniofacial bones (frontal bossing of the skull, prominent malar eminence, depression of bridge of nose, and hypertrophy of the maxillae, which tends to expose the upper teeth)
• Hair-on-end (crew-cut) appearance: It can be seen in the skull X-ray due to new bone formation.
• Splenomegaly may be massive and enlarges up to 1,500 g due to hyperplasia and extramedullary hematopoiesis.
• Liver (hepatomegaly) and lymph nodes also may show extramedullary hematopoiesis.
• Cardiac hemosiderosis results in arrhythmias, heart blocks, and congestive heart failure.
• Hepatic hemosiderosis results in cirrhosis.
• Pancreatic hemosiderosis results in diabetes.
• Pituitary: It leads to hypogonadotropic hypogonadism.
• Treated patients can survive beyond 40 years of age.

β-Thalassemia Majo Investigations:

• Peripheral smear: Marked microcytic hypochromic anemia with moderate to marked anisocytosis and poikilocytosis. Many target cells (hemoglobin collects in the center of RBCs) and nucleated red cells are visible.
• HbF level is increased (30–92%) on hemoglobin electrophoresis.
• There is markedly reduced or absent HbA.
• Osmotic fragility test shows increased resistance to hemolysis.
• Skull radiograph shows a “hair-on-end”/crew-cut appearance.
• There is evidence of thalassemia minor in both parents.
• Red cell distribution width (RDW) is within normal limits (in contrast to iron deficiency anemia).

β-Thalassemia Majo Management:

• Aims of treatment: To suppress ineffective erythropoiesis, prevent deformities of bone, and allow normal activity and development. Blood transfusions may be required every 4–6 weeks. Hypertransfusionto maintain Hb level between 10 and 12 g/dL is probably adequate. It decreases the effect of chronic anemia and prevents abnormal growth and development. Supertransfusion wherein the Hb level is maintained at 12 g/dL is designed to completely suppress hematopoiesis.
• Maintenance of Hb level: Long-term folic acid supplement and regular blood transfusions are recommended to keep the Hb >10 g/dL.
• Treatment of iron overload: The iron-chelating agent, desferrioxamine (administered parenterally), is indicated if serum ferritin >1,500 µg/L. Ascorbic acid 200 mg daily along with desferrioxamine increases the urinary excretion of iron in response to desferrioxamine.
• Deferiprone and deferasirox are oral iron chelators.
• Splenectomy is indicated in children with massive symptomatic splenomegaly and those with progressively increasing requirement of blood transfusion or hypersplenism.
• Bone marrow transplantation is done in young patients.
• Management of associated complications: For example, congestive heart failure and endocrinopathies.

β-Thalassemia Minor (Trait):

Question 32. Write short essay/note on thalassemia minor (trait) and thalassemia intermedia. Answer:

• β-thalassemia minor is more common than β-thalassemia major.
• It is a common carrier (heterozygous) state and is usually asymptomatic.
• Anemia is mild or absent.
• Peripheral blood smear shows severe microcytic and hypochromic red cells with target cells. It may be confused with iron deficiency.
• Serum ferritin and the iron stores are normal.
• Hb electrophoresis usually shows a raised HbA2 (3.5–7.5%) and often a raised HbF.
• Iron should not be given to these patients unless there is associated iron deficiency.
• Genetic counseling is recommended to prevent transmission of carrier state from both parents.
• Prenatal diagnosis by chorionic villi biopsy at 11 weeks is done.
• It may be associated with other hemoglobin abnormalities. Examples include HbS/β-thalassemia, HbC/β-thalassemia, and HbE/β-thalassemia.

β-Thalassemia Intermedia:

• It is a clinical entity in which patients have a clinical spectrum intermediate between thalassemia trait and thalassemia major.
• Patients are anemic and generally have mild-to-moderate anemia (Hb 7–9 g/dL).
• It is not transfusion dependent.
• Mild splenomegaly, bone deformities, gallstones, and chronic leg ulcers may be seen.
• Folic acid supplementation should be given.

Glucose-6-Phosphate Dehydrogenase Deficiency:

Question 33. Discuss the etiology, precipitating causes, clinical features, investigations, and management of glucose-6-phosphate dehydrogenase deficiency. Answer:

• Glucose-6-phosphate dehydrogenase (G6PD) is the initial and rate-limiting step in the hexose monophosphate (HMP) shunt of the Embden-Meyerhof pathway.
• G6PD is the only source of NADPH, and NADPH is required for the generation of glutathione (GSH), which protects red cells from oxidative stress.
• G6PD-deficient patients may develop acute hemolytic anemia after exposure to any oxidative stress.
• G6PD deficiency is an X-linked disorder and is the most common enzyme deficiency.
• RBCs deficient in G6PD are unable to keep glutathione in a reduced state. These RBCs are susceptible to injury by oxidants of both exogenous and endogenous origins.
• G6PD A : The minus sign indicates absence of enzyme activity. Hemolysis develops when exposed to oxidant drugs (primaquine) or infections. The hemolysis is mild to moderate and is limited to the older RBCs.
• G6PD (B) or G6PD Mediterranean/Wild type: It is prevalent in the Middle East and is the severe form of deficiency. This is the most common variant seen in India. Other variants in India include G6PD Kerala-Kalyan and G6PD Odisha.
• G6PD Canton is seen in Chinese.

Glucose-6-Phosphate Dehydrogenase Deficiency Clinical Features:

• Most patients with G6PD deficiency remain clinically asymptomatic; however, all of them have an increased risk of developing clinically significant syndromes:
• Acute Hemolytic Anemia (AHA)
• Neonatal Jaundice (NNJ), And Rarely
• Chronic nonspherocytic hemolytic anemia (CNSHA).
• Drugs: Antimalarials (primaquine, quinine, chloroquine), sulfonamides (sulfamethoxazole), antibacterial/antibiotics (cotrimoxazole, nitrofurantoins), antipyretics/analgesics (acetanilide phenazopyridine), dapsone, quinidine, methylene blue, nitrofurantoins, etc.
• Infections: Viral and bacterial.

The exposure to triggering agents produces hemolytic attack with rapid development of anemia and hemoglobinuria (cola colored urine). Rarely acute renal failure may develop. The onset can be extremely abrupt, especially following ingestion of the broad beans (favism) in children.

• Neonatal jaundice is a feature of Mediterranean type. Hemolytic anemia is very rarely severe. Jaundice may be due to decreased hepatic elimination of bilirubin. Severe neonatal jaundice, if not adequately treated with phototherapy, may result in kernicterus or even death.
• Chronic nonspherocytic hemolytic anemia (CNSHA): Develops in very small minority of patients. Such a patient is always a male and usually has a history of severe neonatal jaundice and chronic anemia. The degree of chronic anemia is variable and some patients may have required intermittent transfusions. They have reticulocytosis, gallstones, and splenomegaly. Hemolysis is mainly extravascular. G6PD deficiency (African variety) has a protective effect against Plasmodium falciparum.

Laboratory Findings (Investigations):

• Evidence of intravascular hemolysis: Raised unconjugated bilirubin, hemoglobinemia, hemoglobinuria, high LDH, and low or absent plasma haptoglobin.
• Anemia: It usually ranges from moderate to extremely severe. It is due to both intravascular and extravascular hemolysis.
• Normocytic and normochromic with anisocytosis, polychromasia (reticulocytosis), poikilocytes, and spherocytes
• Bite (blister) cells are red cells in which parts of them appear bitten away.
• Heinbodies consist of membrane-bound precipitates of denatured hemoglobin (methemoglobin) and represent oxidative damage. They are seen as dark inclusions within red cells and can be demonstrated by supravital staining with methyl violet.
• Confirmation of diagnosis: By estimating G6PD activity of the red cell. This should be estimated several days after the acute hemolytic episode. This is because if done during or immediately after acute hemolysis, it may give a falsely normal value as the young red cells and reticulocytes have near-normal G6PD levels.

Treatment (management) of G6PD deficiency:

• Removal of the triggering agent and avoiding its further exposure to triggering factors in previously screened patients. Once the cause is recognized, in most cases no specific treatment is required. Management of neonatal jaundice is similar to any other cause of neonatal hyperbilirubinemia.
• Blood transfusion
• Regular folic acid supplements in CNSHA
• Treatment of infection and genetic counseling

Miscellaneous Anemias:

Question 34. Write short essay/note on the causes and management of normocytic anemia. Answer:

Normocytic Normochromic Anemia:

Normocytic normochromic anemia is characterized by the normal size of the RBCs and normal MCV

Miscellaneous Anemias Management: Treatment of the underlying disease.

Diffrential Diagnosis of Hypochromic Microcytic Anemias:

Question 35. Describe the etiology, investigations, and differential diagnosis of hypochromic microcytic anemia. Answer:

Differentiating features of hypochromic microcytic anemias:

Sideroblastic Anemias:

Question 36. Write short essay/note on sideroblastic anemias. Answer:

Sideroblastic Anemias Defiition:

Sideroblastic anemias are rare inherited or acquired disorders of refractory anemia, characterized by:

• A dimorphic peripheral blood picture. Microcytic hypochromic red cells in hereditary form and macrocytic in the acquired forms of the disease mixed with normochromic cells.
• Presence of ring sideroblasts, excess storage iron in the bone marrow, and increased serum iron concentration. The diagnostic feature is the presence of ring sideroblasts in the bone marrow. The iron-laden mitochondria surround the nucleus of erythroblasts and appear as the pathognomonic “rings” of iron granules with Prussian blue staining (Perls’ reaction).
• Tiny iron-containing inclusions, called Pappenheimer bodies, are found in the red blood cells (stain positively by Prussian blue staining).
• Ineffective erythroid hyperplasia due to nonviable sideroblasts.

Classifiation of Sideroblastic Anemia:

Microcytosis is often seen in hereditary forms, but normochromic normocytic or even macrocytic RBCs may be seen, especially in the setting of myelodysplasia or in a rare X-linked hereditary form known as Pearson’s syndrome.

Sideroblastic Anemias Treatment:

• Withdrawal of causative agent: Some patients respond when the drugs, toxins, or alcohol are withdrawn.
• O ccasional cases may respond to pyridoxine or folic acid.
• Supportive treatment with transfusions.
• Erythropoietin can also be given.

Hereditary sideroblastic anemias:

Hereditary sideroblastic anemias comprise a clinically, genetically, and hematologically heterogeneous group of rare disorders. It may be inherited as an X-linked or an autosomal (dominant or recessive) disorder. These patients generally have low levels ofδ-aminolevulinic acid synthase (ALAS) enzyme in the normoblasts leading to defective synthesis of hemoglobin.

Paroxysmal Nocturnal Hemoglobinuria:

Question 37. Write short essay/note on paroxysmal nocturnal hemoglobinuria (PNH). Answer:

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired m nonmalignant, genetic defect due to mutation in the hematopoietic stem cell. These clones of red cells are particularly sensitive to destruction by activated complement. Platelets and granulocytes are also affected and there may be thrombocytopenia and neutropenia.

Paroxysmal Nocturnal Hemoglobinuria Etiology and Pathogenesis:

The stem cells and their progeny have deficient synthesis of glycosylphosphatidylinositol (GPI) linked proteins, namely:

• Decay-Accelerating Factor Or Cd55 And
• Membrane inhibitor of reactive lysis or CD59.

This is most important and a potent inhibitor of C3 and prevents activation of the alternative complement pathway on their membrane. In PNH, the red cells are abnormally sensitive to complement-mediated intravascular hemolysis. The severity of hemolysis is proportional to the number of these abnormal red cells. The molecular basis of PNH is the mutations in the pig-A (phosphatidylinositol glycan protein A) gene responsible for synthesis of the GPI anchor.

Paroxysmal Nocturnal Hemoglobinuria Clinical Features:

• It is mainly seen in adults, usually in middle age.
• Both sexes are equally affected.
• Intravascular hemolysis: Characteristically, only the urine voided at night (nocturnal) and in the morning on waking is dark in color. The hemolysis is due to reduced pH of blood during sleep which enhances the activity of complement. Hemoglobin in acidic urine is converted into acid hematin which colors the urine dark brown. Urinary iron loss may be sufficient to cause iron deficiency. Other features include abdominal pain/dysphagia, erectile dysfunction, pulmonary hypertension, and renal insufficiency.
• Mild jaundice and mild hepatosplenomegaly are often present.

Thrombosis: It is very common involving the hepatic (Budd-Chiari syndrome), portal, or cerebral veins and is often the leading cause of death.

It may begin or progress to aplastic anemia.

Paroxysmal Nocturnal Hemoglobinuria Diagnosis:

• Peripheral smear: Anemia, reticulocytosis, varying degrees of thrombocytopenia and leukopenia (pancytopenia) are diagnosed.
• Features of intravascular hemolysis such as raised bilirubin, hemoglobinemia, hemoglobinuria, and hemosiderinuria are present.
• Bone marrow is sometimes hypoplastic (or even aplastic) despite hemolysis.
• Ham’s acidified serum test: Checks whether red blood cells become more fragile when they are placed in mild acid. Ham’s test can also be positive in congenital dyserythropoietic anemia.
• Sucrose hemolysis test: A PNH patient’s red cell undergoes lysis when incubated in low-tonic-strength solution of sugar sucrose. It can be positive in megaloblastic anemia and autoimmune hemolytic anemia.
• Flow cytometry: It detects red cells that are deficient in GPI-linked proteins (CD55 and CD59). It is a rapid and sensitive test for diagnosis.
• Neutrophil alkaline phosphatase (NAP) score: NAP score is reduced (normal 40−100), because NAP is a GPI-linked protein.
• Progress: PNH patients are also at an increased risk for developing aplastic anemia or acute myelogenous leukemia or a myelodysplastic syndrome.

Paroxysmal Nocturnal Hemoglobinuria Treatment:

• Supportive measures: Blood transfusions (for patients with severe anemia) and control of infections
• Iron therapy is often necessary due to loss in urine.
• Anticomplement therapy: Eculizumab is a humanized monoclonal antibody that prevents the cleavage of C5 (thereby the formation of the membrane attack complex) and reduces intravascular hemolysis, hemoglobinuria, and the need for transfusion.
• Long-term anticoagulants may be necessary for patients with recurrent thrombotic episodes.
• Steroids may be useful in some cases.
• Bone marrow (stem cell) transplantation is curative

Methemoglobinemia:

Question 38. Write short essay/note on methemoglobinemia. Answer:

• Normal oxygen transport depends on the maintenance of iron in hemoglobin in ferrous (reduced) form (Fe++).
• Methemoglobin (Hi) is a hemoglobin in which the iron is in oxidized ferric form and unable to combine with oxygen. Normal RBCs contain less than 1% methemoglobin. Increased amount of methemoglobin in the RBCs is called methemoglobinemia.
• Clinically, when methemoglobin level is more than 1.5 g/dL, the patient develops cyanosis. At higher levels, it produces headache, weakness, and breathlessness. At higher methemoglobin levels, respiratory depression, altered sensorium, coma, shock, seizures, and death may occur.

Causes of Methemoglobinemia:

• Hereditary: Deficiency of methemoglobin reductase, cytochrome B5 reductase deficiency
• Acquired: Exposure to certain drugs and toxins (e.g., nitrites and nitrates, nitrofurantoin, chloroquine, naphthalene, local anesthetics (procaine, lidocaine), primaquine, dapsone, sulfa drugs phenacetin, phenazopyridine, metoclopramide, nitroglycerine], copper sulfate

Methemoglobinemia Treatment:

• Methemoglobin reductase deficiency: Oral methylene blue or ascorbic acid
• Severe methemoglobinemia: Intravenous methylene blue. Ensure adequate tissue oxyg

Autoimmune Hemolytic Anemia:

Autoimmune hemolytic anemias (AIHA) are a group of acquired disorders resulting from increased red cell destruction due to red cell autoantibodies.

Question 39. Write short essay/note on autoimmune hemolytic anemias. Answer:

Classifiation of Autoimmune Hemolytic Anemia:

It may be classified based on:

Type of antibody: Interaction of the autoantibody with the red cell antigen is dependent on the temperature, i.e., warm or cold type

Hemolytic Anemia Etiology:

Classification of autoimmune hemolytic anemia according to type of antibody:

Based on antibody type

Warm Antibody Type (IgG Antibodies Active at 37°C)

• Primary (Idiopathic)
• Autoimmune disorders (systemic lupus erythematosus and others)
• Drugs (e.g., Methyldopa, penicillins, quinidine)
• Lymphomas—Hodgkin’s lymphoma, chronic lymphatic leukemia

Cold Agglutinin Type (IgM Antibodies Active at 4−18°C):

• Mycoplasmal infection
• Infectious mononucleosis

Cold Hemolysin Type (Donath-Landsteiner Antibodies): Rare; seen mainly in children; usually postviral

Classification of autoimmune hemolytic anemia based on etiology:

Based on Etiology

Idiopathic (50%)

Secondary (50%)

• Drugs, e.g., methyldopa, penicillins, quinidine

Warm antibody immunohemolytic anemia:

• Warm antibody type is the most common type (50–70%).
• The antibodies are mainly ofIgG type. The antibodies combine with red cell antigen at 37°C and hence known as warm antibody.

Autoimmune hemolytic anemia Clinical features:

• They may occur at all ages and in both sexes, although most frequent in middle-aged females.
• They may present with anemia, jaundice, hepatosplenomegaly, and manifestations and underlying disease.
• Exclude underlying systemic lupus erythematosus, lymphoma, and leukemia.

Autoimmune hemolytic anemia Investigations:

• Evidence of hemolytic anemia
• Spherocytosis (due to red cell damage) and macrocytes in peripheral blood
• Direct antiglobulin (Coombs) test is positive.
• Autoantibodies may have specificity for the Rh blood group system (e.g., for the e antigen).
• In some cases, autoimmune thrombocytopenia and/or neutropenia may also be present (Evans’ syndrome).

Antiglobulin (Coombs) Test:

Question 40. Write short essay/note on significance of Coombs test. (or) Write short note on Coombs test. Answer:

There are two types, namely, direct and indirect.

• Direct (Coombs) antiglobulin test (DAT) detects the immunoglobulin (IgG) antibody and/or C3 complement (usually C3d) on a patient’s RBCs. A patient’s red cells are washed and suspended in saline. Antiglobulin serum is added. Agglutination of red cells indicates the presence of antibody on the surface of RBCs and interpreted as positive DAT.
• Indirect (Coombs) antiglobulin test (IAT) detects the immunoglobulin (IgG) antibody or C3 complement (usually C3d) in the patient’s serum. 0 Rh +ve normal red cells and antiglobulin serum are added to the patient’s serum. Agglutination of RBCs indicates the presence of antibodies in the patient’s serum and the test is reported as positive for an indirect antiglobulin test.

Antiglobulin (Coombs) Test Treatment:

• Corticosteroids (e.g., prednisolone in doses of 1 mg/kg daily) are effective in about 80% of patients. Initially for the first 2–4 weeks, prednisolone 60 mg daily is given, followed by gradual tapering of the dose. When a dose of 20−30 mg daily achieves a persistent remission (indicated by the stable Hb level and decreasing reticulocyte count), it is recommended to give prednisone on alternate day.
• Patients with rapid hemolysis may require intravenous methylprednisolone at a dose of 250–1,000 mg/day for 1 −3 days.
• Avoid blood transfusion as far as possible, because autoantibodies may cause difficulty in cross-matching the blood.
• Danazol can be used along with prednisone as first-line therapy allowing for a shorter duration of prednisone therapy.
• If there is no response to corticosteroids
• If the remission is not maintained when the dose of prednisolone is reduced
• If there is requirement of the equivalent of more than 10–15 mg prednisone per day to maintain an acceptable hemoglobin level
• Intravenous immunoglobulin may also be used as a temporary measure before performing splenectomy for patients refractory to conventional therapy with corticosteroids.
• Use: Useful in refractory cases and also in secondary type of warm AIHA.
• Adverse effects: Hypotension, fever, chills, rigors, hypertension, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, cardiogenic shock
• Contraindication: Untreated hepatitis B infection
• Other immunosuppressive drugs (e.g., azathioprine, cyclophosphamide, and cyclosporine) may be effective when there is no response to steroids, rituximab, and splenectomy.

Cold Agglutinin Autoimmune Hemolytic Anemia:

Question 41. Discuss cold hemagglutinin disease (CHAD) in brief. Answer:

• It is less common than the warm antibody type and is caused by so-called cold agglutinins.
• These antibodies bind to red cell antigens at low temperatures (4–18°C), i.e., avidity of red cell to antibody increases as the temperature falls.
• The antibodies are of IgM type.
• Clinically, it presents acrocyanosis (i.e., blue color of the fingertips, toes, nose, and ear lobes) after exposure to cold.
• Patients are advised to avoid exposure to cold.

Cold Agglutinin Autoimmune Investigations:

• Red cells agglutinate in the cold or at room temperature.
• Direct antiglobulin test is positive with complement alone.
• Monoclonal IgM antibodies.

Cold Agglutinin Autoimmune Treatment:

Rituximab (anti-CD20) is successful in some cases. It does not respond to steroids alkylating agents and splenectomy.

Paroxysmal Cold Hemoglobinuria:

Question 42. Write short essay/note on paroxysmal cold hemoglobinuria. Answer:

• Paroxysmal cold hemoglobinuria (PCH) is a rare condition which often follows common childhood viral infections (e.g., measles, mumps, and chickenpox).
• The autoantibodies are IgG type and bind to red cells at low temperatures and fix the complement. These are autoantibodies directed against the P antigen system on red cells.
• Since complement cascade functions more efficiently at 37°C, upon warming, complement gets activated resulting in intravascular hemolysis and hemoglobinuria.
• Donath-Landsteiner test: Hemolysis is demonstrated in vitro by incubating the patient’s red cells and serum at 4°C and then warming it to 37°C.
• Hemolysis is usually transient and found mostly in children. Supportive transfusions of warmed blood may be required.
• DAT is usually negative.

Anemias Due to Blood Loss:

Question 43. Write short essay/note on anemias due to blood loss. Answer:

Anemias due to blood loss can be acute or chronic. Blood loss causes anemia by two main mechanisms:

• By the direct loss of RBCs
• Continuous blood loss gradually depletes the iron stores resulting in iron deficiency.

Anemias Due to Acute Blood Loss:

A healthy adult can lose about 500 mL of whole blood without any untoward effect (e.g., blood donation). Acute blood loss (hemorrhage) causes loss of intravascular volume over a short period and if massive it can lead to hypovolemic shock and death. The clinical features of acute blood loss anemia depend on:

• Rate of hemorrhage
• Nature of the bleeding (external or internal).

Anemias Due to Blood Loss Clinical features:

After the sudden loss of a large volume of blood over a short period, three clinical/pathophysiologic stages can be identified.

• Stage 1: The dominant feature is hypovolemia during which the patient appears pale, cold, and sweating. The pulse rate is raised and blood pressure is maintained. The earliest signs, especially with internal bleeding, are postural hypotension and tachycardia. An ordinary blood count will not show anemia because the hemoglobin concentration is not affected.
• Stage 2: During this stage, the body will shift fluid from the extravascular to the intravascular compartment, producing hemodilution. Thus, the hypovolemia gradually converts to anemia. Anemia appears in 24–36 hours.
• If bleeding stops, anemia gets corrected in a few weeks, provided body iron supply is normal.
• If bleeding continues, compensatory mechanisms fail and hypovolemic shock develops and results in death.

Anemias Due to Blood Loss Investigations:

• Normal in early stages (before hemodilution)
• Reduced in 24–36 hours due to hemodilution
• Peripheral smear shows normocytic normochromic anemia and polychromasia (due to increased reticulocytes). A transient leukoerythroblastic blood picture may be seen in very early stages.

Anemias Due to Blood Loss Treatment:

Replacement of blood loss by transfusion of whole blood or packed red cells

Anemia Due to Chronic Blood Loss:

In chronic blood loss, compensatory mechanisms replenish the plasma volume and red cell loss. It produces anemia when the rate of blood loss exceeds the regenerative capacity of the bone marrow or when iron reserves are depleted and results in iron deficiency anemia.

Anemia of Chronic Disease:

Question 44. Write short essay/note on anemia of chronic disease. Answer:

It is one of the most common types of anemia in developing countries, occurring in patients with chronic infections (also known as anemia of inflammation).

Anemia of Chronic Disease Causes:

It occurs in a wide variety of chronic diseases.

• Chronic infections: Infective endocarditis, tuberculosis, osteomyelitis
• Chronic immune disorders: Crohn’s disease, rheumatoid arthritis, systemic lupus erythematosus (SLE)
• Associated with malignant tumors (e.g., carcinoma of lung and breast)
• Term anemia of chronic disease is not usually applied to anemias associated with renal, hepatic, or endocrine disorders.

Anemia of Chronic Disease Pathogenesis:

• Impaired iron utilization: Chronic inflammatory diseases activate macrophages to secrete cytokines such as interleukin-6 (IL-6) and tumor necrosis factor (TNF). There is decreased transfer of iron from the storage pool to bone erythroid precursors.
• Decreased erythropoietin (EPO) production and response: They result in inadequate proliferation of progenitors.
• Decreased RBC survival is due to extracorpuscular defect.

Anemia of Chronic Disease Investigations:

• Peripheral smear mainly shows normocytic normochromic red cells.
• Increased storage iron in the marrow and revealed by Prussian blue staining
• Raised serum ferritin because of the inflammatory process
• Reduced total iron-binding capacity (TIBC)
• Reduced serum iron
• Reduced transferrin levels
• Normal serum soluble transferrin receptor level.

Anemia of Chronic Disease Management:

• Treat the underlying disorder.
• Recombinant erythropoietin therapy may be tried if the anemia is not corrected after treatment of the underlying disorder.

Aplastic Anemia:

Question 45. Define aplastic anemia. Discuss the etiology/causes, clinical features, investigations, and management of aplastic anemia. Answer:

Aplastic Anemia Defiition:

Aplastic anemia is characterized by pancytopenia (anemia, neutropenia, and thrombocytopenia) with hypocellular (aplasia) bone marrow (less than 30% cellularity), and there are no leukemic or other abnormal cells in the peripheral blood or bone marrow.

Aplastic Anemia Causes:

Aplastic Anemia Clinical Features:

It is insidious in onset and the initial presenting feature depends on which cell line is predominantly affected.

• Anemia: Causes progressive weakness, lassitude, fatigability, pallor, and dyspnea
• Neutropenia: Presents as frequent infections (mucocutaneous bacterial) or fatal infections. These include sore throat, oral and pharyngeal ulcers, fever with chills and sweating, chronic skin infections, recurrent respiratory infections, pneumonia, and septicemia.
• Thrombocytopenia: Results in bleeding manifestations in the form of petechiae, bruises, and ecchymoses. These include: bleeding into skin (ecchymoses, petechiae), epistaxis, menorrhagia, bleeding from gums and GI tract, retinal hemorrhage, and cerebral hemorrhage. Bleeding is often the predominant initial presentation with bruising, with minimal trauma or blood blisters in the mouth.

Physical findings: These include ecchymoses, bleeding gums, and epistaxis. Mouth infections are common. Lymphadenopathy and hepatosplenomegaly are rare. In the presence of splenomegaly, the diagnosis of aplastic anemia should not be made.

• Aplastic anemia may coexist or progress to clonal disorders, such as paroxysmal nocturnal hemoglobinuria (PNH), myelodysplastic syndrome (MDS), or acute myeloid leukemia.

Fanconi’s Anemia:

• Fanconi’s anemia is inherited as an autosomal recessive disorder.
• It is associated with skeletal (short stature), renal (ectopic kidney, horse-shoe kidney), and central nervous system (hydrocephalus) abnormalities. It usually presents between 5 and 10 years of age. Progressive pancytopenia, predisposition to hematologic malignancies (MDS < acute myeloid leukemia), and solid tumors (squamous cell carcinomas of head and neck and anogenital region) are found.

Aplastic Anemia Investigations:

Diagnosis is made with:

• Pancytopenia
• Absence Of Reticulocytes
• Hypocellular or aplastic bone marrow with increased fat spaces.
• Hemoglobin is decreased.
• PCV is decreased.
• Reticulocytopenia (varies from 0.5 to 1%) is a characteristic feature.
• Peripheral blood shows pancytopenia.
• Bone marrow study: Marked hypocellularity with replacement of more than 70% of the marrow cells by fat.
• Hematopoiesis: Paucity of all erythroid, myeloid, and megakaryocytic precursors. Initial stages may show focal areas of hematopoiesis.
• Lymphocytes and plasma cells are prominent. Bone marrow iron stores are usually increased.
• Serum iron and transferrin saturation: Increased
• Ferrokinetic studies: Delayed clearance of radioactive iron from the blood and increased uptake by the liver.

Severe aplastic anemia:

The presence of two of the following four features is needed to diagnose severe aplasia:

• Neutrophil Count Of <0.5 × 109/L
• Platelet Count Of <20 × 109/L
• Reticulocyte Count Of <40 × 109/L,
• Marrow cellularity <25%.

Severe aplastic anemia Treatment/Management:

Removal of the causative factor/agent wherever possible.

Providing supportive care while awaiting bone marrow recovery:

• Prevention and treatment of infections
• Treatment of hemorrhage
• Treatment of anemia by red cell transfusion
• Growth factors: Granulocyte colony-stimulating factor (G-CSF), Thrombopoietin (TPO) receptor agonists
• Bone marrow (stem cell) transplantation is the treatment of choice for patients under 40 years of age who have an HLA-identical sibling donor. Patients over the age of 40 years have a high risk of graft-versus-host disease.
• Eltrombopag, horse ATG, cyclosporine, and prednisone in combination produce a hematological response rate of 60–80%. These agents destroy activated suppressor cells.
• Androgens (e.g., oxymetholone) are sometimes useful in patients not responding to immunosuppression and those with moderately severe aplastic anemia.
• Steroids have little role in severe aplastic anemia but are useful for serum sickness induced by ALG. However, steroids used in children with congenital pure red cell aplasia (Diamond-Blackfan syndrome) and in some adults with pure red cell aplasia are associated with a thymoma.
• Anti-IL-2 receptor antibody (daclizumab) and arsenic trioxide (ATO) plus cyclosporine have been tried.

Acquired Pure Red Cell Aplasia (PRCA) may develop for unknown reasons, but more commonly it develops in association with specific types of malignancy, infection, or drugs. Most commonly, acquired PRCA develops as a complication of a neoplastic process such as a thymoma B- or T-cell chronic lymphocytic leukemia, non-Hodgkin’s lymphoma, or an autoimmune disorder such as rheumatoid arthritis or SLE.

Pancytopenia:

Question 46. Write short essay/note on the causes of pancytopenia. Answer:

Pancytopenia Definition: Combination of anemia, leukopenia, and thrombocytopenia.

Causes of Pancytopenia:

Disorders Of White Blood Cell:

Non-Neoplastic Disorders Of Wbc Leukocytosis:

Question 47. Write short note on leukocytosis. Answer:

An increase in the total number ofleukocytes in the blood more than 11,000/cu mm (11 × 109/L). It is usually due to increase in the neutrophils but may also be due to increased lymphocytes (or rarely monocytes and eosinophils).

Disorders Of White Blood Cell Causes: Common causes of leukocytosis

Common causes of leukocytosis:

• Viral infections (e.g., infectious mononucleosis)
• Chronic: Chronic lymphocytic leukemia and chronic myeloid leukemia
• Leukemoid reactions

Leukopenia:

Total leukocyte count is less than 4,000/cu mm (4 × 109/L).

Leukopenia Causes: Common causes of leukopenia

Common causes of leukopenia:

• Typhoid and paratyphoid
• Aplastic anemia
• Megaloblastic anemia
• Hypersplenism
• Drugs including cytotoxic drugs
• Rarely leukemia

Neutrophilia:

Neutrophilia is an absolute neutrophil count of more than 8,000/cu mm (8 × 109/L). Differential count shows more than 70% neutrophils and is usually accompanied by leukocytosis (15−30 × 109/L).

Causes of neutrophilia:

Major causes of neutrophilia:

Pathological:

• Localized: Pyogenic microorganisms causing infections, e.g., pneumonias, pyogenic meningitis, cellulitis, diphtheria, abscess, and tonsillitis
• Generalized: Septicemia, acute rheumatic fever
• Acute inflammatory processes: Inflammatory conditions (acute appendicitis), vasculitis
• Tissue necrosis: Burns, myocardial infarction, gangrene, neoplasms (tumor necrosis)
• Acute stress or hypoxic states: Following hemorrhage, hemolysis and surgery
• Myeloproliferative neoplasms: Chronic myeloid leukemia, polycythemia vera
• Metabolic: Uremia, acidosis, gout
• Miscellaneous: Eclampsia, steroid therapy

Physiological:

• Exercise (shift from marginating pool to circulating pool), newborns, extremes of temperature, pain, emotional stress and during obstetric labor

Neutropenia and Agranulocytosis:

Question 48. Write short note on neutropenia/agranulocytosis and its causes. Mention the drugs that cause agranulocytosis. Answer:

Reduction in the absolute neutrophil count (total WBC × % segmented neutrophils and band forms) below 1.5 × 109/L (1,500/cu mm). Agranulocytosis is the term used when the neutrophil count decreases below 0.5 × 109/L. These patients are highly susceptible to bacterial and fungal infections.

Neutropenia and Agranulocytosis Etiology:

The causes of neutropenia are presented:

Eosinophilia:

Question 49. Define eosinophilia and mention the causes of eosinophilia. Answer:

Eosinophilia is an absolute eosinophil count of more than 450/cu mm (0.45 × 109/L). Causes of eosinophilia are presented.

Lymphocytosis:

Question 50. Write short note on lymphocytosis and its causes. Answer:

Lymphocytosis is lymphocyte count more than 4,000/cu mm (4 × 109/L) in adults and more than 8,000/cu mm (8 × 109/L) in a child. The common causes of lymphocytosis are given.

Conditions associated with alterations in numbers of blood basophils are presented in Table:

Acute Leukemias:

Question 51. Define leukemia. Answer:

Acute Leukemias Defiition:

Leukemia is defined as a group of malignant stem cell neoplasms characterized by:

• Failure of cell maturation and proliferating of leukocyte precursors (blast/immature cells) which fill the bone marrow
• Abnormal numbers and forms of immature white blood cells which ultimately spill over into the peripheral blood.

Classifiation of Leukemias:

Question 52. Write short essay/note on classification of leukemias. Answer:

1. General/traditional classification: According to the light microscopic appearance of the cell and the speed of evolution

2. Revised French-American-British (FAB) classification of acute leukemias

• According to FAB, the marrow should show a blast count of 30% or more.
• It includes parameters which affect morphology, cytochemistry, immunophenotyping, cytogenetics, and molecular genetics.

3. WHO classification (2016) of acute myeloid and lymphoid leukemia

• WHO classification of acute leukemia incorporates parameters, namely morphology, cytochemistry, cytogenetic, molecular genetics (which are related to prognosis), and clinical features.
• The number of blasts necessary for the diagnosis is more than 20% in bone marrow when compared to 30% in FAB classification.

Etiology of Leukemias:

Question 53. Discuss the etiology of leukemias. Answer:

Leukemias Risk Factors:

In the majority of acute leukemias, the cause is not known. Numerous risk factors may cause mutations in the genes involved in regulating cell proliferation and differentiation.

These genes include oncogenes and tumor suppressor genes. Sophisticated molecular techniques such as fluorescent in situ hybridization (FISH) and gene array technology have led to the understanding of leukemia at the molecular level.

Environmental factors:

• Atomic bombing: Survivors of atomic bomb explosions in Hiroshima and Nagasaki, who had high incidence of AML and CML (chronic myeloid leukemia).
• Therapeutic radiation: Increased risk of AML (secondary leukemia) in patients with malignancies/neoplasms treated by radiation.
• X-ray exposure to fetus during pregnancy.
• Secondary AML can develop after exposure to chemotherapy drugs.
• Alkylating agents such as cyclophosphamide can lead to AML that develops after a median duration of 5-7 years, is usually preceded by myelodysplastic syndrome, and is associated with chromosome 5 or 7 abnormalities.
• Topoisomerase inhibitors such as anthracyclines lead to AML after a median duration of 1−3 years and are associated with MLL gene abnormalities.
• Benzene used in paint industry, plastic glues, etc. It causes chromosomal abnormalities resulting in a higher incidence of acute leukemia, myelodysplastic syndrome, and aplastic anemia.
• Retroviruses: Human T-cell leukemia virus (HTLV-1) is associated with adult T-cell leukemia/lymphoma.
• Immunological: Immune deficiency states (e.g., hypogammaglobulinemia).

Genetic disorders:

A few genetic disorders may be associated with acute leukemias, e.g., Down’s syndrome (ALL or AML), Fanconi’s anemia (AML), ataxia telangiectasia (ALL, NHL), and Klinefelter syndrome.

Acquired disorders:

• Acquired stem cell disorders such as PNH and aplastic anemia may transform into acute leukemia.
• Myelodysplastic syndrome (MDS): AML may develop de novo or secondary to MDS.

Acute leukemias Clinical Features:

Question 54. Discuss the clinical features, investigations, diagnosis, and management of acute leukemias. Answer:

• Though ALL and AML are distinct (immunophenotypically and genotypically), they usually have similar clinical features. A patient usually presents with nonspecific “flu-like” symptoms.
• Bone marrow failure: It is due to replacement of normal marrow hematopoietic cells by leukemic blast cells.
• It causes shortness of breath on effort, excessive tiredness/fatigue, and weakness.
• It results in life-threatening infections by bacteria or opportunistic fungi, Pseudomonas and commensals. Fever is due to septicemia.
• The infection may develop in the oral cavity, skin, lungs, kidneys, urinary bladder, and colon. The common presentations include respiratory infections (pneumonia), cellulitis, or sepsis.
• It presents as bleeding manifestations in the form of petechiae, atraumatic ecchymosis, gum bleeding, epistaxis, urinary tract, and fundal hemorrhages.
• Intracranial bleeding is a serious and fatal complication, usually associated with headache, fundal hemorrhages, and focal neurological deficits.
• Bone pain (more common in ALL) and sternal tenderness.
• Cerebral leukostasis may cause headache, confusion, and visual disturbances.
• Pulmonary leukostasis can cause dyspnea at rest, tachypnea, chest pain, pulmonary infarction, and acute respiratory distress syndrome.
• Coagulopathy: Both disseminated intravascular coagulation (DIC) and primary fibrinolysis may lead to hemorrhagic diathesis. DIC is observed in AML-M3 (promyelocytic leukemia).
• Gingival hypertrophy and infiltration of skin (leukemia cutis/chloroma)
• Hepatosplenomegaly
• Generalized lymphadenopathy

• Leukemic meningitis is rare. It presents as headache and nausea. As the disease progresses, papilledema, cranial nerve palsies, seizures, and altered consciousness develop. CSF characteristically shows leukemic blast cells, elevated proteins, and reduced glucose levels.
• Chloromas are localized, solid, soft-tissue tumor masses known as myeloblastomas, granulocytic sarcomas, or chloromas.
• Metabolic abnormalities: Hyperuricemia, elevated serum liver transaminases, and serum LDH are found in patients with acute leukemia.

Acute myeloidleukemia Investigations:

Question 55. Write short essay on laboratory diagnosis of acute myeloidleukemia. What are Auer rods? Answer:

Confimation of Diagnosis:

• Hemoglobin is low.
• Total leukocyte count: Markedly raised, but usually less than 100 × 109/L (range 1 × 109/L to 500 × 109/L). Leukopenia is common in AML.
• Platelet count: It is markedly decreased.
• It shows numerous blast cells, and types of blasts can be identified morphologically and confirmed with immunophenotyping.
• Auer rods are seen as rod-shaped red inclusion in the cytoplasm of myeloblast.
• It shows severe normochromic anemia.
• Bone marrow aspirate: Hypercellular with reduced erythropoiesis and reduced megakaryocytes. Blast cells >20% (often approaching 100%) and type of blast is confirmed by flow cytometry, immunophenotyping (FISH), cytogenetic, and molecular genetics.

Flow cytometry:

Question 56. Write short note on flow cytometry in leukemias. Answer:

• Flow cytometric immunophenotyping is useful in diagnosing the lineage in acute leukemia by the expression of lineagespecific CD markers.
• Flow cytometry allows the detection of 1 leukemic cell among 10,000 normal cells (0.01%).
• Therapeutic application—targeted therapy (e.g., Rituximab if anti-CD20 positive, Alemtuzumab if anti-CD52 positive), purging malignant cells from autografts before transplantation

• Chest X-ray: Mediastinal widening is often seen in T lymphoblastic leukemia.
• CSF examination: This is done to rule out occult CNS involvement.

For Planning Therapy:

• Biochemical parameters: Serum urate, liver function tests, renal function tests, coagulation studies, serum LDH, etc.
• Cardiac function: ECG and direct tests of left ventricular function (e.g., echocardiogram or MUGA scan)

Question 57. Discuss the management of acute leukemias. Answer:

Acute leukemias Management:

Principles of Management:

At initial presentation, acute leukemia may be:

• Probably curable (childhood acute lymphoblastic leukemia)
• Possibly curable (de novo low-risk AML)
• Probably incurable (AML with adverse cytogenetic features in the elderly, secondary AML, recurrent acute leukemia).

Type of Therapy:

• Palliative therapy: It is directed toward symptomatic benefit by means of medications and transfusions with or without chemotherapy.
• Curative intent: The goal is to cure the patient and involves chemotherapy +/- stem cell transplant.

Active therapy:

The first and major decision to be taken is whether to give specific therapy or supportive therapy.

Supportive care/therapy:

It forms the basis of treatment for both curative and palliative therapy.

• Treatment of anemia with repeated transfusion of packed red cells to avoid symptoms of anemia (hemoglobin >10 g/dL)
• Prevention or control of bleeding due to thrombocytopenia with platelet transfusions
• Prophylactically: Education about handwashing and isolation facilities. Use of selected antibiotics and antifungal agents, barrier nursing
• Therapeutically: Management of fever by identifying the microorganism and giving appropriate antimicrobial treatment in bacterial, fungal, protozoal, and viral infections
• Continuous monitoring of liver, kidney, and hemostatic functions
• Maintenance of fluid and electrolyte balance: In patients receiving chemotherapy, rapid lysis of leukemic cells may produce tumor lysis syndrome characterized by hyperuricemia, hyperkalemia, hypocalcemia, and hyperphosphatemia leading to renal injury, arrythmias, and seizures and is potentially life-threatening. It can be prevented by close attention to hydration, urine alkalinization, and prophylactic allopurinol before starting chemotherapy.
• Treatment of hyperleukocytosis: Reduction in leukocyte counts can be achieved by using chemotherapy or hydroxyurea, and leukapheresis (removal of circulating cells and re-infusion of leukocyte-poor plasma).
• Psychological support.

Bone marrow transplantation has to be considered in the following conditions:

• Acute myeloblastic leukemia (Intermediate and poor risk) in first remission in patients below 60 years of age
• Acute lymphoblastic leukemia (ALL) (high risk) in first, second, or subsequent remission

The specific therapy is intended to return the peripheral blood and bone marrow to normal (complete remission—CR).

The survival outcomes of acute leukemia are variable; they could be in excess of 90% in situations such as APML and childhood ALL to as low as 10% in recurrent acute leukemia and high-risk AML.

Question 58. Discuss the management of acute lymphocytic leukemias. Enumerate the drugs used in acute lymphocytic leukemia. Answer:

Acute Lymphocytic Leukemia:

Specific therapy involves:

• Goal of induction therapy: To induce morphologic remission and to restore normal hematopoiesis in the bone marrow with less than 5% blasts.
• Remission induction consists of combination chemotherapy including vincristine, prednisolone (dexamethasone), asparaginase (crisantaspase), and usually an anthracycline antibiotic, e.g., doxorubicin. It induces complete morphologic response within 4–6 weeks.

• Aim: To eliminate disease in the CNS and to reduce systemic minimal residual leukemic burden
• CNS-directed therapy: Triple intrathecal chemotherapy (cytarabine/methotrexate/hydrocortisone) or 1,800 cGy cranial radiation
• Postremission therapy, similar to induction phase, reduces chances of relapse.
• Remission maintenance to prevent relapse and affect cure. It involves administering drugs for 2 years or more and consists of daily6-mercaptopurine and weekly methotrexate.

Question 59. Discuss the management of acute myeloid leukemias. Answer:

Acute myeloid leukemia:

Initial therapeutic goal is to quickly induce complete remission (CR) and further therapy to prolong survival and achieve cure. Curative therapy is given to the majority of adults below the age of 60 years (without any significant comorbidity). Specific therapy (Table 8.29) of the newly diagnosed patient with AML is usually divided into two phases:

• Consolidation phase (postremission) therapy.
• Moderately intensive combination chemotherapy that includes an anthracycline (e.g., daunorubicin or idarubicin) and cytosine arabinoside (cytarabine) ± etoposide.
• “High risk” patients (include patients <70 years with high-risk karyotype) may only be treated with curative intent if an HLA-identified sibling is available for stem cell transplantation.
• Low-risk patients in AML; patients with t(8;21) or inv(16) (i.e., low risk karyotype) do not benefit from allogeneic stem cell transplantation during their first complete remission.
• Patients with high-risk karyotypes should have stem cell transplantation because they respond poorly to conventional chemotherapy.

Acute promyelocytic leukemia (M3):

• It is an uncommon variant of AML associated with severe coagulation complications.
• It has favorable prognosis.
• Induction therapy is with all-trans-retinoic acid and anthracyclines or a combination of ATA with arsenic trioxide.
• Allogeneic transplantation: It is necessary if the leukemia is not eliminated at the molecular level, only in relapsed/refractory cases.
• In relapsed cases, arsenic trioxide (induces apoptosis via activation of the caspase cascade) has been also found to be effective.

Alternative chemotherapy:

• It is used to curb excessive leukocyte proliferation and not for achieving remission.
• Hydroxyurea up to 4 g daily and L asparaginase 10,000 units are used to reduce leukocyte count without inducing

Poor Prognostic Factors in AML and ALL:

Diffrences Between Acute Lymphoblastic Leukemia and Acute Myeloblastic Leukemia:

Question 60. How do you differentiate acute lymphoblastic leukemia from acute myeloblastic leukemia? Answer:

Subleukemic Leukemia/Aleukemic Leukemia:

Question 61. Write short note on subleukemic leukemia. Answer:

• In acute leukemia, the immature neoplastic leukemic “blast” cells proliferate and accumulate but fail to mature. The blasts diffusely replace the normal bone marrow, and a variable number of these accumulate in the peripheral blood.
• Acute leukemia should be diagnosed when the blast cells constitute more than 20% of the nucleated cells in the marrow (normally blast cells < 5%) with an increase in total leukocyte count.
• Subleukemic/aleukemic leukemia is characterized by a total leukocyte count which is normal or lower than 4 × 109/L, and peripheral blood shows very few abnormal blasts. It is observed in a small percentage of patients with acute leukemia.
• Diagnosis is confirmed from the bone marrow examination which shows replacement by leukemic cells.

Leukemoid Reaction:

Question 62. Write short note on leukemoid reaction (including its definition). Answer:

• Extreme neutrophilia is sometimes associated with the presence of immature white cells and is called leukemoid reaction.
• A leukemoid reaction is a benign leukocytic proliferation characterized by a total leukocyte count of more than 50 × 10 9/L with many immature white cells (such as metamyelocytes, myelocytes, and promyelocytes and even a few myeloblasts) in the peripheral smear.
• Leukemoid reaction is the response of the normal healthy bone marrow to various stresses.
• Causes: Include infections (including tuberculosis), acute hemorrhage, hematological and nonhematological malignancies, and various toxic states.
• Bone marrow is normal with accelerated leukopoiesis.
• LAP source is increased.
• Philadelphia chromosome is negative.
• There is no absolute eosinophilia or basophilia (versus CML).
• Treatment of underlying disorder corrects the blood picture.
• Types of leukemoid reactions
• It should be differentiated from chronic myelocytic leukemia

Types of leukemoid reactions:

Hairy Cell Leukemia:

Question 63. Discuss the clinical features, investigations, and management of hairy cell leukemia. Answer:

Hairy Cell Leukemia Clinical Features:

• Hairy cell leukemia (HCL) is an uncommon chronic malignant disorder of mature B-cells with characteristic fine cytoplasmic projections.
• The term hairy cell leukemia is derived from the appearance of fine hairlike cell membrane projections on the leukemic cells, under the phase-contrast microscope.
• Hairy cell leukemia affects middle-aged to elderly men, with a male-to-female ratio of 5:1.
• Massive splenomegaly is the most common finding, hepatomegaly is less common, and lymphadenopathy is distinctly rare.
• Pancytopenia is due to marrow failure and splenic sequestration and is found in more than 50% of cases.
• Infections: About one-third of patients present with infections, especially with atypical mycobacteria, which may b due to monocytopenia. Infections are the most common cause of death.
• Risk of secondary malignancies such as Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, and thyroid cancer is there.
• Total leukocyte count: It is normal or low. Majority of patients have pancytopenia.
• Peripheral smear: It shows the characteristic hairy cells. These are the medium-sized malignant B lymphocytes with filamentous hairy structures on the surface of the cell. They have a reniform nucleus and abundant pale blue cytoplasm. Cytochemically, these hairy cells stain positively for tartrate-resistant acid phosphatase (TRAP).
• Bone marrow: Aspirate yields a dry tap and biopsy shows fibrosis with infiltration by mononuclear cells and hairy cells (fied-egg or honeycomb appearance).
• LAP score is very high. Flow cytometry reveals CD11c, 25, 103, 123 positivity.

Hairy Cell Leukemia Treatment:

• Symptomatic splenomegaly
• Constitutional symptoms (e.g., fever, night sweats, and fatigue).
• Treatment of infections with antibiotics.
• Chemotherapy: The purine analogs 2-chloroadenosine acetate (2-CDA) (cladribine) and pentostatin are highly effective with just one cycle of treatment. Rituximab is used in patients who do not respond to the above drugs. Pentostatin, interferon alfa, and splenectomy are other treatment options available.
• Contraindicated drugs: Corticosteroids and myelotoxic drugs

Hairy Cell Leukemia Prognosis: Follows an indolent course and prognosis is excellent.

Chronic Myeloid Leukemia:

Question 64. Define chronic myeloid leukemia. Write a short note on Philadelphia chromosome and its significance. Answer:

Chronic Myeloid Leukemia Definition: Chronic myeloid leukemia (CML) is one of the myeloproliferative neoplasms (MPN) of pluripotent hematopoietic stem cell characterized by overproduction of cells of the myeloid series (results in marked splenomegaly and leukocytosis) and the presence of the Philadelphia chromosome.

Molecular Pathogenesis:

• Acquired chromosomal abnormality of hematopoietic stem cells
• Balanced reciprocal translocation between the long arms of chromosomes 9 and 22 (t 9,22) increases the length of chromosome 9 and shortening of 2The shortened chromosome 22 is known as Philadelphia chromosome (Ph).
• Translocation results in fusion of the breakpoint cluster region (BCR) gene on chromosome 22q with the ABL1 (named after the Abelson murine leukemia virus) gene located on chromosome 9q.
• It produces a new hybrid oncogene, namely BCR-ABL1 fusion gene. The products of this gene are oncoproteins which have uncontrolled kinase activity and trigger the excessive proliferation and reduced apoptosis of CML cells.
• Significance: Apart from CML, Philadelphia (Ph) chromosome can be found in ALL (25–30% in adult and 2–10% in pediatric cases) and occasionally in AML. In patients with Ph positive/negative and BCR-ABL1 positive, the survival rate and therapeutic response are better than those with both Ph- and BCR-ABL1-negative patients.

Natural Course of CML:

Question 65. Discuss the natural course and clinical features of chronic myeloid leukemia. Answer:

It has three phases:

• Chronic stable phase: Most of the CML are diagnosed in this phase and lasts for about 3–5 years if untreated.
• Accelerated phase: It is more aggressive and lasts for few months.
• Blast crisis phase: It resembles acute (myeloid or lymphoid) leukemia and has poor prognosis.

Clinical Features in Chronic Stable Phase of CML

Question 66. Discuss the clinical features in chronic stable phase. Answer:

• Age: It usually occurs between 40 and 60 years of age.
• Onset: It is insidious.

Chronic Stable Phase of CML Symptoms:

Many patients are asymptomatic during the early stage of CML and may be diagnosed during routine peripheral blood examination.

• Nonspecific symptoms: Fatigue, weakness, weight loss, anorexia.
• Symptoms due to massive splenomegaly: Fullness of abdomen (abdominal distension, postprandial fullness), reflux esophagitis, dyspnea, and dragging discomfort in the left hypochondrium due to splenomegaly (caused by leukemic infiltration and extramedullary hematopoiesis). Splenomegaly is moderate to severe and is a characteristic feature in majority (80–90%) of patients.
• Symptoms of hypermetabolic state: Due to rapid turnover of cells, it may result in symptoms such as fatigue, weakness, fever, sweating, heat intolerance weight loss, and anorexia.
• Priapism: It is painful penile erection due to leukostasis (associated with marked leukocytosis or thrombocytosis).
• Bleeding tendencies occur late in the disease.

Chronic Stable Phase of CML Signs:

• Pallor due to anemia.
• Splenomegaly: Moderate to massive, nontender splenomegaly. It is due to leukemia infiltration and extramedullary hematopoiesis. Presence of tender spleen and splenic friction rub indicate splenic infarction.
• Mild hepatomegaly as a result of leukemic infiltration may develop in 60–70% of cases.
• Sternal tenderness and bone pain: They are due to hypercellularity of marrow and irritation of periosteum.

Chronic myeloid leukemia Investigations:

Question 67. Discuss the investigations/laboratory investigations/diagnosis of chronic myeloid leukemia. Answer:

• Hemoglobin is usually less than 11 g/dL.
• Total leukocyte count is markedly raised, almost always more than 20,000/µL, often exceeding 1,00,000/µL. In untreated patients, the leukocyte count progressively increases.

Peripheral Smear:

• RBC shows a moderate degree ofnormocytic normochromic anemia.
• Shift to left (shift to immaturity) with granulocytes at all stages of development (neutrophils, metamyelocytes, myelocytes, promyelocytes, and occasional myeloblasts). Predominant cells are neutrophils and myelocytes in an untreated patient. Blasts are usually less than 10% of the circulating white blood cells.
• There is increase in basophils (<20%) and eosinophils.
• Platelets: Count may be normal, increased, or decreased. Automated analyzers may give falsely elevated platelet counts due to disruption of granulocytes.

Bone Marrow Study:

• It is markedly hypercellular due to marked hyperplasia of all granulocytic elements.
• About 20–30% of the patients may develop bone marrow fibrosis in late stages.

Philadelphia Chromosome (Ph):

• It is positive in more than 95% of cases, in all three phases. In Ph-negative cases, evidence of translocation can be demonstrated by cytogenetics, reverse transcription-polymerase chain reaction (RT-PCR), and fluorescence in situ hybridization (FISH).
• BCR-ABL1 fusion gene can be demonstrated in peripheral blood or bone marrow.

Decreased NAP/LAP Score:

It is usually below 20 (normal score ranges from 40 to 100) in majority of patients. This is helpful in differentiating CML from leukemoid reaction.

Biochemical Findings:

• Serum LDH and uric acid are increased.
• Serum alkaline phosphatase is increased.
• Serum vitamin B 12 is markedly elevated due to production of binding protein (transcobalamin) by the granulocyte series.
• Marked thrombocytosis may raise serum potassium spuriously as platelets release potassium during clotting.
• Blood sugar may be falsely decreased due to glucose uptake and metabolism by leukocytes.

Question 68. Write short essay/note on the treatment and complications of chronic myeloid leukemia. Enumerate the drugs used in chemotherapy. (or) Write short note on Imatinib. Answer:

Treatment of CML:

Goal of therapy in CML

Chemotherapy: 

Tyrosine kinase inhibitors (TKIs):

• Imatinib mesylate is the first-line treatment for the chronic phase of CML.
• second-generation tyrosine kinase inhibitors (such as dasatinib, bosutinib, or nilotinib),
• allogeneic bone marrow transplantation, or
• classical cytotoxic drugs such as hydroxycarbamide (hydroxyurea) or interferon-α or melphalan, and busulfan
• Omacetaxine/homoharringtonine (plant alkaloid).

Imatinib mesylate:

• Imatinib mesylate is a tyrosine kinase inhibitor (TKI) which provides targeted therapy, i.e., high specificity blocks the enzymatic action of the BCR-ABL fusion, providing a broader therapeutic window with less toxicity.
• In all newly diagnosed CML, imatinib (400 mg/d) is more effective and has replaced IFN-α and cytarabine. It reduces the uncontrolled proliferation of white cells, producing apoptosis of cancer cells.
• In chronic stable disease, it can produce complete hematological response in >95% of cases and complete cytogenetic response (disappearance of the Ph chromosome and BCR-ABL transcripts in the blood) in >76% at 18 months of therapy. Imatinib can be continued indefinitely.
• Side effects of imatinib: Nausea, headaches, fluid retention, muscle cramps, diarrhea, skin rash, and myelosuppression (causing cytopenias).

Ponatinib is the only approved TKI capable of inhibiting BCR-ABL with the gatekeeper T315I kinase domain mutation, known to be the cause for 20% of resistant or relapsed CML cases.

Recombinant interferon-α:

• Recombinant interferon-α (rINF-α) was considered first-line treatment before the invention of imatinib.
• It was given alone or combined with the chemotherapy agent cytosine arabinoside, and induced remission and controlled chronic stable phase of CML in about 70% of cases. But it has no role as a single agent in most patients.
• It should be considered in patients not responding to imatinib.
• It is not effective in accelerated phase or blast crisis phase.
• Dosage: 3–9 mega units/day intramuscularly or subcutaneously.
• Reduces cellularity of the bone marrow.
• Reduces the number of Philadelphia-positive tumor cells in 20% of patients.
• Total eradication of Philadelphia chromosome in ~5% of patients.
• Reduces platelet count when it is very high.
• Side effects: Flu-like syndrome, weight loss, fatigue, nausea, vomiting, and headache

Hydroxyurea:

It is used to reduce white blood cell counts while awaiting confirmation of a suspected diagnosis of CML in a patient with significant leukocytosis (e.g., >100 x109 white cells/L) or in patients with systemic symptoms or with symptomatic splenomegaly.

Splenectomy:

• It is indicated to relieve the symptoms due to massive splenomegaly and in repeated splenic infarctions.

Stem cell transplantation (SCT):

• Patients under the age of 60 years who have a suitable donor
• Those who do not respond to second-line TKI and those who present with accelerated phase or blast crisis
• Best results are obtained if SCT is done in early chronic stable phase and can cure about 70% of cases.
• It can result in permanent disappearance of the Ph-positive clone.
• Disadvantages: These include risk of complications and death due to graft-versus-host disease (GVHD) and opportunistic infections.

Monitoring:

• Bone marrow biopsy: It is done at 6-month intervals to determine the cytogenetic response.
• Quantitative RT-PCR (qPCR): It should be done from peripheral blood at 3–6-month intervals once cytogenetic response has been achieved.

Prognostic Scores in CML:

• Sokal score: Age, spleen size, platelet count, blast cell counts
• Euro score: Age, spleen, platelet, blast cell counts, basophil counts, eosinophil counts
• EUTOS score/Hasford: Basophils and spleen size.

Accelerated Phase of Chronic Myeloid Leukemia:

Chronic myeloid leukemia may transform to a more aggressive blastic phase with or without going through an accelerated phase after 1–5 years of onset. It lasts for a few months.

Features of Accelerated Phase:

• Increasing anemia
• Increasing white blood cell count with an increase in circulating immature cells unresponsive to therapy
• Blasts 10–19% are seen in the blood or bone marrow
• Increase in the size of spleen
• Increase in basophil count (<20%)
• Persistent thrombocytopenia or persistent thrombocytosis unresponsive to therapy
• Hydroxyurea is the most effective drug in accelerated phase.

Features of Blast Crisis:

• Refractory to treatment
• Abrupt increase in the size of spleen
• Bone pain and sternal tenderness
• Anemia and bleeding tendencies
• Generalized lymphadenopathy may appear.
• Peripheral smear and bone marrow showing >30% cells simulating acute leukemia
• Basophils may increase to 20%.
• Thrombocytopenia may result in bleeding episodes.

Blast Crisis Phase of Chronic Myeloid Leukemia:

• Blast crisis phase of CML represents the transformation of CML into an acute leukemia.
• This final phase lasts for a few weeks to months and has a poor prognosis.
• Myeloid blast crisis that occurs in 70% when the disease transforms into acute myeloblastic leukemia.
• Lymphoid blast crisis that occurs in 30% when the disease transforms into acute lymphoblastic leukemia.

Treatment of blast crisis is the same as that for acute myeloblastic or lymphoblastic leukemia. Complications of chronic myelogenous leukemia are enlisted

Complications of chronic myelogenous leukemia:

• Fatigue due to anemia
• Excess bleeding due to thrombocytopenia
• Bone pain or joint pain due to expansion of bone marrow
• Enlarged spleen
• Vulnerable to infection due to impaired immune system

Chronic Lymphocytic Leukemia:

Question 69. Discuss the types, clinical features, investigation, clinical staging, and management of chronic lymphocytic leukemia. Answer:

Chronic Lymphocytic Leukemia Defiition:

Chronic lymphocytic leukemia (CLL) is a tumor of immature small round lymphocytes characterized by the accumulation of neoplastic mature-looking lymphocytes in the peripheral blood, bone marrow, and lymphoid organs (spleen and lymph nodes).

Chronic Lymphocytic Leukemia Types:

• B-cell origin: More than 95% of the cases of CLL express the pan B-cell markers CD19 and CD20 and also present is the aberrant expression of T-cell antigen CD5 (found only in a small subset of normal B-cells).
• T-cell origin: It constitutes less than 5%.
• It is the most common form of chronic leukemia.
• Age: Most of the patients at the time of diagnosis are over 50 years of age.
• Sex: It is more common in males than in females with a ratio of 2:1.
• Asymptomatic: It is found in about 25% of patients and is detected either because of nonspecific symptoms or routine blood examination for some other diseases.
• Nonspecific symptoms: This includes fatigue, loss of weight, and anorexia.
• Painless generalized lymphadenopathy: Initially, the cervical lymph nodes are enlarged and in later stages there may be generalized lymphadenopathy. Involved nodes are rubbery, discrete, nontender, small, and mobile.
• Splenomegaly and hepatomegaly: Mild degree is observed in very few cases.
• Presenting symptoms may be:
• Slowly developing anemia: Due to immune hemolysis and bone marrow infiltration
• Recurrent infections: Develop due to hypogammaglobulinemia. Streptococcus pneumonia, Staphylococcus, and Haemophilus influenzae cause most of the infections. Herpes zoster is also common.
• Bleeding manifestations: They are uncommon.

Transformation:

CLL may transform to:

• Prolymphocytic transformation with appearance of “prolymphocytes” in the peripheral blood (>10%).
• Transformation to diffuse large B-cell lymphoma (Richter syndrome).
• Monoclonal B-cell lymphocytosis (MBL): WHO criteria for monoclonal B-cell lymphocytosis (MBL) are the presence of monoclonal B-cell populations in the peripheral blood (PB) of up to 5 × 109/L either with the phenotype of chronic lymphocytic leukemia (CLL), atypical CLL, or non-CLL (CD52) B cells in the absence of other lymphomatous features. It has been found that MBL precedes almost all cases of CLL/SLL. In 2016, the WHO subdivided MBL into “low count” MBL (characterized by PB CLL count of <0.5 × 109/L) and “high count” MBL. The distinction is important because low-count MBL does not require routine follow-up whereas high-count MBL requires routine/yearly follow-up.

Chronic Lymphocytic Leukemia Investigations:

• Hemoglobin: Usually below 13 g/dL and as the disease progresses, it may decrease below 10 g/dL. This is due to marrow failure, but associated autoimmune hemolysis may also be contributory, when present.
• Total leukocyte count is increased and varies from 20 × 109/L to 50 × 109/L.
• Platelet count may be normal or low.
• Mild-to-moderate normocytic normochromic anemia.
• Lymphocytosis is the characteristic feature and constitutes more than 50% of the white cells, and absolute lymphocyte count should be more than 5,000 × 109/L.
• Lymphocytes are of mature type in majority of the cases.
• Smudge cells or basket cells are disintegrated lymphocytes and are due to the rupture of neoplastic lymphocytes while making the peripheral smear due to its fragile nature.
• Platelets: Normal or reduced in number (autoimmune thrombocytopenia).
• Bone marrow: It is involved in all cases of CLL and its infiltration by mature lymphocytes results in hypercellular marrow.
• Direct Coombs test: About 15–20% of patients manifest autoimmune hemolytic anemia and have positive direct Coombs test.
• Lymph node biopsy shows well-differentiated, small, noncleaved lymphocytes.
• Immunoglobulins: They are low or normal.
• Serum folic acid levels are low.

Clinical Staging:

Binet staging and Rai staging of CLL are presented in Tables respectively.

Lymphoid enlargement includes cervical, axillary, and inguinal lymph nodes.

Chronic Lymphocytic Leukemia Treatment:

Absolute indications for treatment: When any of the following features is present:

• Anemia or thrombocytopenia that can be attributed to CLL
• Recurrent fever, extreme fatigue, night sweats, and weight loss
• Bulky or progressive lymphadenopathy; massive or progressive splenomegaly with discomfort
• Autoimmune cytopenias not responsive to corticosteroids
• Symptomatic or functional extranodal involvement (e.g., skin, kidney, lung, spine)
• Progressive disease manifests by doubling of the lymphocyte count in 6 months

Treatment options based on Binet staging:

Regimen—single-agent fludarabine or combination therapy with fludarabine, cyclophosphamide, and rituximab (FCR)

Chlorambucil: Two regimens

• Continuous low-dose therapy: 5 mg/day orally
• Complications: Development of myelodysplasia and acute myeloid leukemia

Fludarabine: It is a purine nucleoside analog that is drug of choice in young patients.

• Dose: 25–30 mg/m 2 IV/day for 5 days every 4 weeks
• Complications: Autoimmune hemolytic anemia, opportunistic infections (e.g., Legionella pneumophila, Pneumocystis jiroveci, Listeria monocytogenes, and Cytomegalovirus)

Cladribine: It is also a purine nucleoside analog, an alternative to fludarabine.

• 0.2 mg/kg continuous infusion daily for 7 days every 4 weeks or
• 0.14 mg/kg over 2 hours daily for 5 days every 4 weeks

Pentostatin: It is a purine nucleoside analog that can be used instead of fludarabine or cladribine.

Rituximab and alemtuzumab: They are monoclonal antibodies against CD20 and CD52, respectively.

• Side effects: Fever, chills, nausea, headache, myalgias

Alkylating agents: Cyclophosphamide, bendamustine.

Newer drugs:

• Anti CD20 antibodies: Ofatumumab, obinutuzumab
• BCL2 inhibitor: Venetoclax
• Bruton tyrosine kinase (BTK) inhibitors: Ibrutinib, acalabrutinib
• Phosphoinositide 3’-kinase (PI3K) inhibitors: Idelalisib, duvelisib Chimeric antigen receptor (CAR)—T-cell therapy is an investigational therapy.

Myeloproliferative Neoplasms:

Question 70. Define and write short essay/note on myeloproliferative diseases (disorders) or myeloproliferative neoplasms and enumerate myeloproliferative neoplasms. Answer:

Myeloproliferative Neoplasms Defiition:

Myeloproliferative neoplasms (MPN) (old synonym myeloproliferative disorder/diseases) are clonal hematopoietic stem cell disorders which are characterized by proliferation of one or more of the myeloid lineages (erythroid, granulocytic, megakaryocytic, and mast cells).

It is seen usually in adults with a peak in the 5th to 7th decade. Splenomegaly and hepatomegaly occur commonly due to sequestration of excess hematopoietic cells or proliferation of abnormal hematopoietic cells.

WHO Classifiation (2016) of Myeloproliferative Neoplasm:

WHO classification of MPN.

Mastocytosis is no longer listed under the broad heading of MPN in WHO (2016) classifiation.

WHO classification of myeloproliferative neoplasm:

• Chronic myelogenous leukemia, BCR-ABL1 positive
• Chronic neutrophilic leukemia
• Polycythemia vera (PV)
• Essential thrombocythemia (ET)
• Primary myelofibrosis (PMF)
• Chronic eosinophilic leukemia not otherwise specified
• Myeloproliferative neoplasm, unclassifiable

Polycythemia:

Question 71. Write short essay/note on polycythemia and its classification. Answer:

Polycythemia Defiition:

Polycythemia, or erythrocytosis, refers to an increase in the number of RBCs above normal in the circulating blood, usually with a corresponding increase in hemoglobin and PCV level. PCV is a more reliable indicator of polycythemia than is hemoglobin.

Classifiation and Causes of Polycythemia:

Question 72. Write short note on causes of secondary polycythemia. Answer:

Pathophysiological classifiation of polycythemia:

• Reduced plasma volume with normal red cell mass (hemoconcentration) due to dehydration—low fluid intake, vomiting, diarrhea, sweating, acidosis
• Gaisböck syndrome (spurious polycythemia)

Absolute (increased red cell mass)

Primary (low erythropoietin level):

• Polycythemia vera (erythremia)

Secondary (high erythropoietin level)—erythrocytosis

Compensatory:

• Lung disease (e.g., COPD—chronic obstructive pulmonary disease)
• Living in high-altitude
• Cyanotic congenital heart disease (Tetralogy of Fallot, Eisenmenger’s complex)
• Chronic carbon monoxide poisoning
• Sleep apnea syndrome

As a consequence of local hypoxia: Renal artery stenosis, end-stage renal disease, hydronephrosis, renal cysts (polycystic kidney disease), postrenal transplant erythrocytosis Paraneoplastic: Erythropoietin secreting tumors—renal cell carcinoma  hepatocellular carcinoma, cerebellar hemangioblastoma, uterine leiomyoma, pheochromocytoma

Clinical Features of Polycythemia:

• Usually appears insidiously, in late middle age (median age at onset: 60 years).
• Most symptoms are due to the increased red cell mass and hematocrit.
• Plethora and cyanosis due to stagnation and deoxygenation of blood in peripheral vessels are early findings. Headache, dizziness, and visual problems result from vascular disturbances in the brain and retina.
• Increased incidence of thrombotic episodes and bleeding.
• Secondary polycythemia, in addition shows manifestations of the underlying disease.

Polycythemia Vera:

Question 73. Discuss the clinical features, diagnosis, and management of polycythemia vera. Answer:

Polycythemia Vera Defiition:

• Polycythemia vera (PV) is an acquired myeloproliferative neoplasm arising from malignant transformation of hematopoietic stem cell.
• It is characterized by trilineage (erythroid, granulocytic, and megakaryocytic) hyperplasia in the bone marrow.
• It leads to uncontrolled production of red cells, granulocytes and platelets (panmyelosis) and leads to erythrocytosis (polycythemia) and or granulocytosis and thrombocytosis.

Polycythemia Vera Etiology:

The etiology of PV is not known. PV is partly due to a failure of apoptosis as a result of deregulation of the Bcl-xgene (antiapoptotic gene), in addition a mutation in the tyrosine kinase JAK 2 V617F (which causes the substitution of phenylalanine for valine at position 617) has been found; this stimulates low-grade erythropoiesis.

• Onset is insidious.
• Age and gender: Late middle age (median age at onset is 60 years) and more common in males.
• Plethora (excessive fullness of blood) and deep dusky cyanosis due to stagnation and deoxygenation of blood in peripheral vessels are early findings.
• Headache, dizziness, vertigo, a sense of fullness in the head, rushing in the ears, visual problems, tinnitus, tiredness, syncope, and even chorea result from vascular disturbances in the brain and retina.
• Severe itching (pruritus) after a hot bath or when the patient is warm is frequent and may be disabling.
• Thrombotic episodes: For example, deep venous thrombosis, myocardial infarction, thrombosis of hepatic veins (producing Budd-Chiari syndrome).
• Bleeding manifestations include epistaxis, bleeding from peptic ulcer, bruising, and intramuscular hemorrhages.
• Peptic ulcer is seen in few patients and is five times more frequent than general population.
• Hyperuricemia: May result in urate stones, gout, and uric acid nephropathy.

Polycythemia Vera Physical fidings:

• Injection of the conjunctivae, deep red palate, dusky red hands, and retinal venous engorgement.
• Splenomegaly is very common (~70%) and is useful in distinguishing PV from secondary polycythemia.
• Hepatomegaly occurs in ~50%.

Polycythemia Vera Diagnosis:

• Hemoglobin increased ranging from 14 to 28 g/dL.
• PCV (hematocrit) increased to about 60%. However, in many patients, the plasma volume is also increased giving rise to near normal hematocrit. Hence, it is important to determine the red cell mass.
• Red cell count: Increased and usually about 6 million/mm3 (6 × 1012/L)
• Increased red cell volume and blood viscosity: Isotope dilution using the patient’s51 Cr-tagged red cells (>36 mL/kg in males and 32 mL/kg in females).
• Total white cell count (~70%) and platelet count (~50%) usually increased.
• Absolute basophil count: Increased to >100/µL in majority of patients.
• Arterial oxygen saturation (PO2) is normal and is useful for differentiating it from secondary polycythemia.
• Erythropoietin (EPO) levels are decreased in urine and serum, in contrast to secondary polycythemia.
• Bone marrow shows either erythroid hyperplasia or hyperplasia of all elements (trilineage hyperplasia) and depletion of iron stores.
• Leukocyte alkaline phosphatase (LAP): Increased in majority of patients.
• Serum vitamin B 12 and vitamin B 12 -binding protein transcobalamin I (TC I) levels: Increased (not routinely measured)
• Serum uric acid: Increased indicating increased cell turnover.
• Abnormal liver function tests.
• In ~95% patients with polycythemia vera, and in ~50% of essential thrombocytosis (ET) and primary myelofibrosis.
• Janus kinases belong to tyrosine kinase family located on chromosome 9.
• JAK2 is used by the EPO, thrombopoietin, and granulocyte colony stimulating factor (G-CSF) receptors to transmit signals and are involved in hematopoiesis.
• JAK2 inhibitors are used for managing these patients.

WHO Diagnostic Criteria for Polycythemia Vera:

WHO Diagnostic Criteria for Polycythemia Vera have been shown in Table:

Polycythemia Vera Clinical Course:

The clinical course tends to proceed as a series of phases.

• Proliferative phase: Erythroid proliferation with increased red cell mass.
• Spent phase: Excessive proliferation of erythroid cells ceases, resulting in stable or decreased erythrocyte mass
• Progression to myelofibrosis
• Acute myelogenous leukemia in 2–5% of cases.

Complications of PV:

Complications of polycythemia vera (PV):

• Thrombotic and bleeding episodes
• Peptic ulcer
• Hyperuricemia (gout)
• Sudden increase in splenic size
• Acute nonlymphocytic leukemia
• Myelofibrosis and myeloid metaplasia
• Erythromelalgia (thrombocytosis, involving the lower extremities with erythema, warmth, and pain and occasionally digital infarction)

Polycythemia Vera Treatment:

PV generally has a very slow course.

Aim of treatment: To maintain a normal blood count, PCV below 0.45 L/L and the platelet count below 400 x 109/L and to prevent the complications (mainly thrombosis and hemorrhage).

• Venesection: Repeated venesection (phlebotomy) is the treatment of choice and relieves many of the symptoms of PV.
• Continuous or intermittent treatment with hydroxycarbamide (hydroxyurea) is the treatment of choice in patients above 40 years.
• It controls thrombocytosis and generally safer than alkylating agents (e.g., busulfan) and 32P (Phosphorus) which carry an increased risk of acute leukemia
• In younger patients, interferon-α is used
• Radioactive 32P: One dose may give control for up to1½ years, but carries an increased risk to acute leukemia. In elderly patients (>70 years), 32P or low-dose intermittent busulphan may be more convenient
• Low-dose aspirin: May be used to reduce thrombotic episodes
• Anagrelide (inhibits platelet aggregation): May be used if thrombotic features develop despite above treatment.
• Itching should be treated with antihistamines. If do not relieve, hydroxyurea, interferon-α and psoralens with UV light in ‘A’ range (PUVA) may be helpful
• Asymptomatic hyperuricemia does not require treatment

Question 74. How will you differentiate primary polycythemia (polycythemia vera) from secondary polycythemia with hypoxia [(e.g., chronic obstructive pulmonary disease (COPD)]? Answer:

Differences between polycythemia vera and secondary polycythemia have been shown in Table:

Primary Myelofibrosis:

Question 75. Discuss the clinical features, investigations, and management of primary myelofibrosis (agnogenic myeloid metaplasia, myelofibrosis with myeloid metaplasia). Answer:

Primary Myelofibrosis Defiition:

Primary myelofibrosis is a clonal MPN characterized by increased fibrosis within the marrow, which replaces hematopoietic cells leading to cytopenias, splenomegaly, and extensive extramedullary hematopoiesis. The extramedullary hematopoiesis is seen in the spleen, liver and at times in lymph nodes, kidneys, and adrenals.

• It can arise from PV or ET.

Primary Myelofibrosis Clinical Features:

• Usually found above 60 years of age.
• A significant number of cases develop acute myeloid leukemia.

Primary Myelofibrosis Symptoms:

• Symptoms due to progressive anemia: Fatigue, weakness, and anorexia.
• Symptoms due to massive splenomegaly: Abdominal distension, postprandial fullness, reflux esophagitis, dyspnea, and dragging discomfort in the left hypochondrium.
• Symptoms resulting from hypermetabolic state: Fever, fatigue, weight loss, night sweats, and heat intolerance.
• Bleeding tendencies due to thrombocytopenia develops at late stages.
• Death usually occurs due to portal hypertension and infections.
• Median survival is about 5 years.

Primary Myelofibrosis Signs:

• Massive splenomegaly and hepatomegaly.
• Anemia, lymphadenopathy, bleeding manifestations, ascites, cardiac failure, and jaundice.
• Hyperuricemia and secondary gout due to a high rate of cell turnover.
• Extramedullary hematopoiesis: May produce paraspinal masses with spinal cord compression, ascites, and effusions (pleural and pericardial).

Primary Myelofibrosis Investigations:

• Hemoglobin level: Normal in the early stages, but markedly reduced in the late stages.
• Total leukocyte count: Normal/increased (early stages)/decreased (late stages).
• Platelet count: Increased in early stages and decreased in the late stages.
• Moderate-to-severe degree of normochromic normocytic anemia accompanied by leukoerythroblastic blood picture (precursors of granulocytes and nucleated RBCs being present simultaneously).
• Many tear drop-shaped red cells (dacryocytes) probably due to damage in the fibrotic marrow.
• Basophilic stippling.
• Giant platelets with vacuoles.
• Cellularity: Early stages (cellular phase), it is often hypercellular and in later stages (hypocellular phase), it becomes hypocellular and diffusely fibrotic.
• Megakaryocytes are large, dysplastic, and abnormally clustered.
• LAP score: Raised
• Philadelphia chromosome: Negative.
• JAK2 V617F mutation occurs in ~50% patients. CALR mutation is also present.
• Serum vitamin B 12 : Moderately increased.
• Radiological examination shows increased bone density of vertebrate and proximal ends of long bones.

Primary Myelofibrosis Treatment:

No specific therapy exists for primary myelofibrosis

• Correct other causes of anemia like gastrointestinal blood loss and folic acid deficiency (folic acid 5 mg daily)
• Packed red cell transfusions
• Neither recombinant erythropoietin nor androgens (such as danazol) is consistently effective in controlling anemia but can be tried in some patients
• Glucocorticoids (prednisolone) may control constitutional symptoms and autoimmune complications
• Combination with low-dose thalidomide (50–100 mg/day) with prednisolone can control anemia and splenomegaly in a significant number of patients
• Patients with cellular bone marrow and marked leukocytosis: Busulphan 2 mg daily
• With hypersplenism
• If splenomegaly impairs alimentation and should be performed before cachexia sets in
• Splenic irradiation: To reduce splenic size is reserved for patients, who cannot undergo splenectomy. Patients often develop severe cytopenias
• Hydroxyurea is useful to control splenomegaly, but can produce myelosuppression that may exacerbate underlying anemia.
• Treatment of extramedullary hematopoiesis: By low-dose irradiation
• Curative treatment: Allogeneic bone marrow transplantation is the only curative treatment. It should be performed in younger patients as most patients in IMF are above 60 years of age
• Allopurinol can control hyperuricemia
• Etanercept (TNF-α antagonist) used in patients with severe constitutional features
• JAK2 inhibitors ruxolitinib is used in clinical practice

Primary Myelofibrosis Prognosis:

Median survival varies from 27 to 135 months and depends on prognostic factors

Shows poor prognostic factors:

• Age >65 years
• Presence of blasts in peripheral blood
• Hemoglobin level <10 g/dL
• Presence of constitutional symptoms
• Total WBC count >25,000/mm 3

Myelophthisis:

Question 76. Write short note on myelophthisis and its causes. Answer:

Fibrosis of the bone marrow can occur as a primary hematologic disease is known as primary myelofibrosis (myeloid metaplasia), and as a secondary reactive process, known as myelophthisis (secondary myelofibrosis).

Causes of myelophthisis (other causes of myelofibrosis) are presented. These causes may also produce splenomegaly.

Causes of secondary myelofibrosis.

How will you differentiate chronic myeloid leukemia from myelofibrosis?

Differences between chronic myeloid leukemia from myelofibrosis have been table:

Myelodysplastic Syndromes:

Question 77. Describe the etiology, classification, clinical features, diagnosis and treatment of myelodysplastic syndrome (MDS). Answer:

Myelodysplastic Syndromes Defiition :

• Myelodysplastic syndromes are a heterogeneous group of acquired clonal stem cell disorders characterized by:
• Progressive cytopenias (low blood cell counts)
• Dysplasia in one or more major cell lines (erythroid, myeloid and megakaryocytic forms)
• Ineffective hematopoiesis
• Increased risk of development of AML
• A subtype of myeloid neoplasms.

Myelodysplastic Syndromes Etiology:

• In primary MDS the exact cause is not known, however genetic factors may play a role.
• Causes of secondary/t-MDS: Exposure to radiation, benzene, postchemotherapy (particularly alkylating agents and topoisomerase inhibitors), viruses, cigarette smoking, and PNH.
• Median age is 65 years.

WHO (2016) Classifiation of MDS:

The revised WHO (2016) diagnosis and classification of MDS introduce refinements in morphologic interpretation, cytopenias assessment, and genetic information. Cytopenia is necessary for diagnosis of any MDS and in WHO (2008) classifications, MDS nomenclature included references to “cytopenia” or to specific types of cytopenia (e.g., refractory anemia). Present WHO (2016) classification depends mainly on the degree of dysplasia and blast percentages and specific cytopenias have only minor impact. Hence, the terminology for adult MDS has replaced the terms such as “refractory anemia” and “refractory cytopenia” with “myelodysplastic syndrome” followed by the appropriate modifiers: Single versus multilineage dysplasia, ring sideroblasts, excess blasts, or the del (5q) cytogenetic abnormality.

Myelodysplastic Syndromes Clinical Features:

• Usually found in patients above 60 years and slightly more common in males.
• Detected incidentally on routine blood examination in about 50% of patients.

• Symptoms are due to cytopenias which may be single-lineage cytopenia, bicytopenia, or pancytopenia.
• Weakness (anemia)
• Infections (leukopenia)
• Hemorrhage (thrombocytopenia).
• Extramedullary hematopoiesis may cause hepatomegaly and splenomegaly but is uncommon.
• About 10–40% progresses to AML because of which MDS was referred to as preleukemic syndrome.

Myelodysplastic Syndromes Diagnosis:

• Minimal morphologic criterion for the diagnosis of an MDS: Dysplasia in at least 10% of cells of any one of the myeloid lineages.
• Complete blood count: May give clues to this diagnosis.
• RBC: Mild-to-moderate degree of macrocytic or dimorphic anemia with evidence of dyspoiesis.
• WBC count may be normal or low. Neutropenia with few blasts. Number of blasts determines the type of MDS. The cytoplasm of neutrophils is hypogranular or agranular. The nuclei of neutrophils may show hyposegmentation with only two nuclear lobes (Pseudo-Pelger-Hüet cells), hypersegmentation or ringed neutrophils.
• Platelets: Variable thrombocytopenia, presence of large hypogranular or giant platelets is seen.
• NAP score is moderately or severely decreased.
• Bone marrow: The most characteristic features are varying degree of dyspoietic (disordered) differentiation affecting all nonlymphoid lineages (erythroid, granulocytic, monocytic, and megakaryocytic) associated with cytopenias.
• Cytogenic study of the marrow: Most important for establishing the diagnosis. Chromosome abnormalities of chromosome 5 or 7 are frequent.

Myelodysplastic Syndromes Treatment:

• Packed red cell transfusion for anemia
• Platelet transfusions for bleeding due to thrombocytopenia
• Antibiotic therapy for infections
• Iron chelators to reduce iron overload from multiple transfusions
• EPO and G-CSF may be useful in some patients, to ameliorate symptoms
• Others: Use of thalidomide, lenalidomide (a derivative of thalidomide), 5-azacitidine and decitabine. 5-azacytidine and decitabine (hypomethylating agents) may reduce requirements of blood transfusion and to retard the progression of MDS to AML. Lenalidomide is found useful in the 5q-syndrome
• Allogeneic hematopoietic stem cell transplantation: Curative. However, it may be performed in less than 5–10% of patients because MDS is most common during seventh or eighth decade of life

Plasma Cell Neoplasms:

Question 78. Write short essay/note on plasma cell neoplasms/disorders. Answer:

Classification of plasma cell proliferative disorders has been shown in Table:

Multiple Myeloma:

Question 79. Discuss the immunopathology, pathology, clinical features, investigations, diagnosis, and treatment of multiple myeloma. Answer:

• Multiple myeloma is a malignant plasma cell neoplasm derived from a single clone plasma cells of the bone marrow and produces multiple, lytic bone lesions.
• Plasma cells are derived from B lymphocytes.
• Normal plasma cells secrete equal quantities of heavy and light chains. But the neoplastic plasma cells frequently synthesize excess of light (L) or heavy (H) chains along with complete Igs.
• Rarely, only light chains or heavy chains are produced.
• The excess of free light chains are small with low molecular weight and therefore excreted in the urine. They are known as Bence-Jones proteins.
• IgD (uncommon)
• IgE (uncommon)
• Light chain disease (20%).
• In nonsecretory myeloma, there is no M-protein in the blood or urine but bone marrow shows plasmacytosis.
• The cause of multiple myeloma is unclear. Exposure to radiation, benzene, and other organic solvents, herbicides, and insecticides may play a role. Multiple myeloma has been reported in familial clusters of two or more first-degree relatives and in identical twins.

Multiple Myeloma Clinical Features:

• Insidious in onset.
• Age and gender: Peak incidence is seen during 6th to 7th decade, and males are more affected than females.
• Some patients may be asymptomatic, and is accidentally detected during the preclinical phase.

Mnemonic to remember common symptoms of multiple myeloma:

CRAB: C = Calcium (elevated), R = Renal failure, A = Anemia, B = Bone lesions.

Osteosclerotic Myeloma (POEMS Syndrome):

This syndrome is characterized by polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS).

The major clinical features are a chronic inflammatory-demyelinating polyneuropathy with predominantly motor disability and sclerotic skeletal lesions.

Diagnosis of Multiple Myeloma:

Question 80. Write short essay/note on diagnosis and management of multiple myeloma. Answer:

Requires at least two of the following:

• Monoclonal immunoglobulin (M protein) or light chains in the blood (>3 g/dL) and/or urine
• Infiltration of bone marrow with (clonal) plasma cells (≥10%) or plasmacytoma
• Hypercalcemia: Serum (ionized) >5.5 mEg/L
• Renal insufficiency creatinine clearance <40 mL/min, calcium >2.75 mmol/L, or >0.25 mmol/L than the ULN
• Anemia (hemoglobin or 2 g/dL below the LLN)
• Lytic bone lesions and/or osteoporosis
• Free light chain ratio between involved to uninvolved light chains >100
• Presence of >1 bone lesion on magnetic resonance imaging (MRI)
• Bone marrow plasma cell percentage >60

Smoldering (asymptomatic) multiple myeloma:

• Smoldering multiple myeloma is defined by the presence of serum M-protein level greater than 3 g/dL and/or 10% or more plasma cells in bone marrow and patients are asymptomatic.
• This entity lies in between multiple myeloma and monoclonal gammopathy of uncertain significance. Patients with smoldering multiple myeloma carry a much higher risk of progression to myeloma or related malignancy compared to monoclonal gammopathy of uncertain significance (MGUS).

Investigations in Multiple Myeloma:

• Usually shows anemia, leukopenia, thrombocytopenia, and raised erythrocyte sedimentation rate (ESR).
• Peripheral blood smear: May show rouleaux formation due to increased immunoglobulins.
• Bone marrow examination is important. Normal bone marrow contains 2–10% plasma cells. In myeloma, the bone marrow is hypercellular as a result of increased number of plasma cells and myeloma cells (neoplastic plasma cells). Increased number of myeloma cells, more than 30% of the cellularity is diagnostic.
• Urine: Bence-Jones proteins may be present
• Serum β2 microglobulin: It is a useful prognostic marker and high values signify poor prognosis.
• Hypercalcemia is due to extensive osteolytic lesions and osteoporosis and there are also increased levels of serum phosphate.
• Serum alkaline phosphatase: Usually normal in the absence of complications.
• Blood urea and serum creatinine raised in 20% of cases and along with electrolytes are used to assess renal function.
• Serum proteins: Total serum protein level is increased, albumin is decreased and globulins are markedly increased.
• Serum uric acid: Raised.
• Serum immunoglobulin estimation reveals a reduction of normal immunoglobulins below normal levels.
• Electrophoretic studies on serum and urine: Electrophoretic studies reveal raised levels of immunoglobulins in the blood and/or light chains (Bence-Jones proteins) in the urine. The monoclonal immunoglobulin (M-protein) is identified as abnormal protein “spikes” in serum or urine electrophoresis. The type of immunoglobulin can be determined by immunofixation. The most common M-protein is IgG type, followed by IgA.
• Reveals generalized osteoporosis.
• Radiographs of flat bones: Such as skull, vertebral bodies, ribs, and pelvis show the characteristic punched-out osteolytic lesions.
• Collapse of multiple vertebrate is a common finding.
• MRI and positron emission tomography (PET): May detect bone involvement when skeletal survey is normal.

Multiple Myeloma Treatment:

General measures:

• High fluid intake of about 3 L/day to treat renal impairment and hypercalcemia
• Prompt treatment of infections with antibiotics
• Treatment of anemia may require blood transfusion and erythropoietin often helps
• Analgesics to be given for relief of bone pain
• Allopurinol 300 mg daily should be given to reduce/prevent hyperuricemia and urate nephropathy
• Hyperviscosity syndrome is managed by plasmapheresis
• Bisphosphonates (e.g., zoledronate, pamidronate, clodronate) which inhibit osteoclast activity. Long-term treatment with this, reduce skeletal events such as pathological fracture, cord compression, and bone pain. An important complication of bisphosphonates is osteonecrosis of jaw
• Orthopedic assistance and physiotherapy can significantly improve the quality of life
• Renal failure: Treated by rehydration and oral prednisolone.

Autologous stem cell transplantation:

• Young patients (<65 years) without renal failure: Standard treatment is first-line high-dose chemotherapy for myeloablation (melphalan 200 mg/m 2 intravenously) to maximum response and then an autologous stem-cell transplantation

Chemotherapy:

Regimen used:

• Bortezomib, lenalidomide, dexamethasone (VRd)
• Daratumumab, lenalidomide, dexamethasone (DRd)
• Bortezomib, cyclophosphamide, dexamethasone (VCd)
• Bortezomib, thalidomide, dexamethasone (VTd)
• Carfilzomib, lenalidomide, dexamethasone (KRd)

Older patients:

• Thalidomide combined with the alkylating agent (melphalan or cyclophosphamide or chlorambucil) and prednisolone.
• Thalidomide is teratogenic. Recent studies have suggested that combination with thalidomide, results in improved response rates and overall survival, albeit with increased toxicity.
• Bortezomib is a proteasome inhibitor, which is used for upfront and relapsed is combined with doxorubicin and dexamethasone
• Lenalidomide in combination with steroids has been tried Younger patients (<65 years)
• Bortezomib, cyclophosphamide and dexamethasone. OR Newer drugs include carfilzomib, Ixazomib, pomalidomide, daratumumab, and elotuzumab
• Orally active cyclophosphamide, thalidomide, and dexamethasone-based induction (CTD) followed by a highdose melphalan autograft

Radiotherapy:

• Effective for local problems like severe bone pain, pathological fractures, and tumorous lesions As an emergency treatment of spinal cord compression complicating extradural plasmacytomas

Median survival:

• Patients with advanced myeloma: 7–8 months
• With good supportive care and chemotherapy: 3–5 years.
• Asymptomatic stage I patients are generally not given chemotherapy
• Young patients with intensive therapy may live longer

Renal Involvement in Multiple Myeloma:

Question 81. Write short note on the cause of renal failure of multiple myeloma. Answer:

• Renal involvement is observed in 50% of myeloma patients.
• Renal failure develops in ~25% of patients with multiple myeloma.
• Tubular damage from excretion of light chains (Bence-Jones proteinuria).
• Hypercalcemia resulting in nephrocalcinosis and renal damage.
• Amyloid deposition in the glomeruli (renal amyloidosis).
• Hyperuricemia producing in urate nephropathy.
• Recurrent urinary tract infections.
• Infiltration of the kidney by myeloma cells.

Poor Prognostic Factors in Multiple Myeloma:

Question 82. Write short note on the indications of poor prognosis in multiple myeloma. Answer:

Poor prognostic factors in multiple myeloma:

Radiographic Features in Multiple Myeloma:

Question 83. Write short note on the role of radiographic examination in the diagnosis of multiple myeloma. Answer:

Radiographic features in multiple myeloma:

Monoclonal Gammopathy of Uncertain Signifiance:

Question 84. Write short essay/note on monoclonal gammopathy of uncertain significance (MGUS). Answer:

Monoclonal Gammopathy Definition: MGUS is defined as presence of serum M-protein concentration lower than 3 g/dL, bone marrow clonal plasma cells <10% plasma cells, and no end organ damage no hypercalcemia, no renal impairment, no anemia, or no osteolytic lesions] or no evidence of other B-cell neoplasms.

• MGUS is one of the most common plasma cell dyscrasias, occurring in about 3–5% of general population above the age of 50 years.
• Size of M-component (risk of progression with an M-protein value of 1.5 g/dL almost twice that of a patient with an M-protein value of 0.5 g/dL)
• Type of M-component (IgM and IgA increased risk compared to IgG), and
• Abnormal free light chain ratio (kappa; lambda ratio-normal being 0.26–1.65).
• Follow-up: Patients should be followed with serum protein electrophoresis at 6 months and, if stable, can be followed every 1–2 years.
• No treatment is indicated.

Differences between multiple myeloma and monoclonal gammopathy of undetermined significance have been shown in Table:

Solitary Plasmacytoma:

Question 85. Write short essay/note on solitary plasmacytoma of bone. Answer:

• Solitary plasmacytoma (osseous plasmacytoma) is a solitary tumor occurring in the bone consisting of collection of monoclonal plasma cells.
• Comprises 3–5% of plasma cell neoplasms.
• Sites: Common sites are bones with active hematopoiesis and usually occur in the same sites as in multiple myeloma (vertebrae, ribs, skull, pelvis, femur, clavicle, and scapula).
• Clinical features: Localized bone pain or pathological fracture. Vertebral lesions may produce neurologic symptoms secondary to spinal cord or root compression.
• M-protein in serum or urine observed 24–72% of patients by immune fixation
• MRI is useful to rule out occult systemic disease.
• Treatment: Local control is achieved by radiotherapy. Up to two-thirds of patients develop systemic disease.
• Prognosis: Median survival is 7–12 years.

Solitary Extraosseous Plasmacytoma:

Question 86. Write short essay/note on solitary extraosseous plasmacytoma. Answer:

• Extraosseous (extramedullary) plasmacytoma are localized plasma cell neoplasms that arise in tissues other than bone.
• Comprises 3–5% of all plasma cell neoplasms.
• Upper respiratory tract (80%): Oropharynx, nasopharynx, sinuses, and larynx.
• Other sites: GI tract, lymph nodes, bladder, central nervous system (CNS), breast, thyroid, testis, parotid, and skin.
• Only about 20% of patients have M protein (most commonly IgA).
• Diagnosis: Requires exclusion of occult systemic disease by extensive radiographic imaging.
• Treatment: Eradicated with local radiation therapy.
• About 15% of patients subsequently develop multiple myeloma.
• About 70% of patients remain disease free at 10 years.

Plasma Cell Leukemia:

Question 87. Write short essay/note on plasma cell leukemia. Answer:

• Plasma cell leukemia (PCL) is the term used when the peripheral blood has more than 20% plasma cells with an absolute plasma cell count of 2000/μL or greater.
• Primary plasma cell leukemia: It develops without any preceding evidence of multiple myeloma. It is diagnosed in the leukemic phase (60%). It develops in younger individuals and presents with hepatosplenomegaly and lymphadenopathy, a higher platelet count, few bone lesions, mild serum M-protein component, and longer survival rate when compared to those with secondary plasma cell leukemia.
• Secondary: When leukemic transformation develops in a patient with multiple myeloma (40%).
• It is an aggressive disease associated with a high tumor burden and extramedullary dissemination.

Waldenstorm Macroglobulinemia:

Question 88. Write short essay/note on Waldenstrom macroglobulinemia. Answer:

• Waldenstrom macroglobulinemia is a syndrome characterized by IgM monoclonal gammopathy sufficient to cause a hyperviscosity of the blood and bone marrow infiltration.
• Most commonly occurs in association with lymphoplasmacytic lymphoma. The tumor cells undergo terminal differentiation to plasma cells and secrete monoclonal IgM.
• It occurs in older adults (median age 60 years).

Waldenstorm Macroglobulinemia Clinical Features:

May be asymptomatic.

• Usual presenting complaints are nonspecific and include weakness, fatigue, and weight loss. Symptoms develop due to:
• Tumor infiltration: Most patients present with weakness and fatigue due to anemia caused by marrow infiltration. Other features include fever, night sweats, weight loss, lymphadenopathy, hepatomegaly, and splenomegaly.
• Monoclonal protein: About 10% of patients have autoimmune hemolysis caused by cold agglutinins (monoclonal IgM bind to red cells at temperatures of less than 37°C). IgM may be associated with systemic amyloidosis. IgM-secreted by the tumor, because of its large size, at high concentrations increases the viscosity of the blood, giving rise to hyperviscosity syndrome.
• Visual impairment associated with venous congestion (e.g., blurring or loss of vision)
• Neurologic problems (e.g., dizziness, headache, vertigo, nystagmus, hearing loss, ataxia, paresthesias, diplopia)
• Cryoglobulinemia produces symptoms such as Raynaud phenomenon and cold urticaria
• Tumor cells can infiltrate organs and result in hepatomegaly, splenomegaly, and lymphadenopathy in about 20% patients.

Waldenstorm Macroglobulinemia Treatment:

• It is a chemotherapy- and immunotherapy-sensitive disease controllable with currently available therapies.
• No specific treatment needed for patients who do not have systemic symptoms.
• Single agent therapy with rituximab alone is used in symptomatic patients with modest hematologic compromise, IgM-related neuropathy, or hemolytic anemia unresponsive to corticosteroids.
• Combination chemotherapy and rituximab (antiCD20): Patients with severe constitutional symptoms, profound hematologic compromise, bulky disease, or hyperviscosity syndrome should be treated with the dexamethasone, rituximab and cyclophosphamide Or bortezomib, dexamethasone, and rituximab or bendamustine rituximab.
• Plasmapheresis: Most of IgM secreted by tumor cells is intravascular. Patient with symptoms due to high IgM levels (such as hyperviscosity and hemolysis) should first undergo plasmapheresis which helps in alleviating these symptoms.

Waldenstorm Macroglobulinemia Diagnosis:

• Demonstration of monoclonal IgM: By serum electrophoresis, sample may require warming to 37°C, to avoid interference of cold agglutinins. Immunofixation is required to characterize monoclonal protein.
• Bone marrow aspirate and biopsy: It shows more than 10% lymphoplasmacytic cells (CD20+).

Prognosis: Transformation to large-cell lymphoma occurs but is uncommon. Median survival is 4 years.

Hodgkin Lymphoma:

Question 89. Discuss the pathological classification, clinical features, clinical staging, investigations, diagnosis, and treatment/management of Hodgkin’s lymphoma. Answer:

• Hodgkin lymphoma (HL) is a malignant lymphoma characterized by a heterogeneous cellularity comprising of minority (1–3%) of specific neoplastic cells in a “characteristic background” of reactive non-neoplastic cells (majority) of various types.
• Cell of origin: The neoplastic Reed-Sternberg cells are derived from germinal center or immediate post-germinal center B-cells indicating that most HLs are unusual tumors of B-cell origin.
• Age: Bimodal age incidence
• One pack in young adults (15–35 years)
• Other peak in older adults (45–75 years)
• The neoplastic cells in HL are Reed-Sternberg cells and its variants.
• Reed-Sternberg cells in classical forms of HL are CD15+ and CD30+.
• Reed-Sternberg cells in lymphocyte predominance HL are CD15- ve and CD30-ve.

Hodgkin Lymphoma Etiology:

• EBV: Young adults, who have had previous EBV infection (infectious mononucleosis), have an increased risk of developing HL and the EBV genome is frequently identified in the Reed-Sternberg cells.
• Genetic factors may play a role because HLA subtypes, particularly HLA-B18, are higher in patients with HL.
• Immune status: HL seems to be more frequent in immunocompromised patients or those with autoimmune diseases, such as rheumatoid arthritis.
• Classifiation of Hodgkin Lymphoma:
• Rye classification: According to this HL was divided into four types and the prognosis varies depending upon the histological type. The nodular sclerosing type is the most common.

WHO classification of Hodgkin lymphoma:

It is the presently followed classification.

• Classical Hodgkin lymphoma (>95%)
• Nodular sclerosis (NS) classic Hodgkin lymphoma
• Mixed cellularity (MC) classic Hodgkin lymphoma (most common type in India)
• Lymphocyte-rich (LR) classic Hodgkin lymphoma
• Lymphocyte depletion (LD) classic Hodgkin lymphoma
• Nodular lymphocyte predominance (LP) Hodgkin’s lymphoma (<5%)

Hodgkin Lymphoma Clinical Manifestations:

• Most common presentation: Painless enlargement of one lymph node group (unifocal origin) usually of cervical lymph node, consistency of lymph nodes is described as “Indian rubber” consistency. Then it spreads in a predictable manner to the adjacent lymph node group (contiguous spread).
• Localized disease of the mediastinum (often young women), with cough due to mediastinal lymphadenopathy or axillary nodes, and rarely in the abdominal, pelvic or inguinal nodes.
• Generalized disease: With hepatosplenomegaly and constitutional “B” symptoms is uncommon in the beginning, but may become prominent as the disease advances.
• Rare sites: It includes Waldeyer’s ring, mesenteric, epitrochlear, and popliteal nodes.
• Involvement of extralymphatic organs: Not common and may occur in the later stages.
• Classical Pel-Ebstein fever: It occurs in a cyclical pattern, characterized by several days or weeks of fever alternating with afebrile periods. It is rarely seen.
• Alcohol-induced pain at the site of lymphadenopathy.
• Pruritus is troublesome at times.

• Nephrotic syndrome: It may develop due to immune complex deposition in the kidneys. It is associated with depressed cellmediated immunity and increases the risk of infections like herpes zoster, tuberculosis, and infections with Cryptococci/ Cytomegalovirus and Candida species.
• Symptoms due to compression of various organs by lymph node masses or infiltration of various organs may develop with mediastinal involvement. These include dysphagia, dyspnea, Horner’s syndrome, hoarseness of voice, superior vena cava syndrome, and inferior vena cava obstruction.

Clinical staging: It is currently according to the Cotswolds modification of the Ann Arbor classification.

• Lymphatic structures: It includes lymph nodes, spleen, thymus, Waldeyer’s rings, appendix and Peyer’s patches; liver, and bone marrow are excluded.
• Each stage is further divided into A or B based on the absence or presence of systemic symptoms (B symptoms), respectively.

Hodgkin Lymphoma Investigations:

• Peripheral blood: Normocytic normochromic anemia is common and in advance stage, microcytic anemia develops due to defective utilization of iron. Total leukocyte count is usually normal, but sometimes may show neutrophil leukocytosis.
• Eosinophilia is observed in ~20% of patients and thrombocytosis in some patients. Lymphopenia (indicates lymphocyte depletion) is associated with bad prognosis. In the terminal stages, there may be leukopenia and thrombocytopenia.
• Serum alkaline phosphatase: If raised usually indicate bone marrow or liver involvement.
• ESR: It may be raised
• Lymph node biopsy: Surgically or by percutaneous needle biopsy under radiological guidance will establish the diagnosis.
• Liver biopsy may be useful for diagnosis in patients with hepatomegaly.
• Staging of HL: It is important not only for predicting the prognosis but also for guiding the choice of therapy.
• Chest Radiographs
• Liver Function Tests
• Renal Function Tests
• Abdominal Ultrasound
• Bone marrow trephine and aspirate (indicated in patients with clinically advanced disease, i.e., stage III, IV, those with “B” symptoms and those who are HIV-positive) and
• CT scans of neck, chest, abdomen, and pelvis.

PET scan: It is utilized for staging as well management of HL.

Hodgkin Lymphoma Management:

Aim of treatment: Curative intent with expectation of success. Patients with localized or good-prognosis disease receive a brief course of chemotherapy followed by radiotherapy to sites of node involvement and cured HD in >90% of cases. Presently, patients with all stages of HL are treated initially with chemotherapy. Patients with more extensive disease or those with B symptoms receive a complete course of chemotherapy.

Chemotherapy: Combination chemotherapy has been shown to be highly effective.

Popular chemotherapy regimens used is as follows:

Treatment plan for adults with HL:

Early stage, “low-risk”: Moderate chemotherapy, consisting of 2–4 cycles of ABVD followed by involved field irradiation (20–30 Gy). It has a 90% cure rate.

Advanced disease (including locally advanced unfavorable early stage):

• Cyclical chemotherapy with 6–8 cycles of ABVD with involved field irradiation to sites which were initially bulky
• Stanford V for ABVD: Consists of weekly chemotherapy regimen of doxorubicin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, and prednisone) administered for 12 weeks and includes radiation therapy
• Escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and procarbazine)

Autologous bone marrow transplantation is successful in about 40% cases even after the failure of chemotherapy.

Radiation therapy:

• Extended-field radiation (EFRT): Radiation field includes not only the clinically involved nodes, but also the adjacent, clinically uninvolved sites (e.g., mantle field or inverted-Y field).
• Involved-field radiation (IFRT): Radiation field is limited to the clinically involved regions (e.g., mediastinal plus low bilateral supraclavicular field which covers the entire mediastinum)
• Involved-site radiation (ISRT): Radiation field includes only pre- and postchemotherapy tumor volumes plus a margin of healthy tissue to accommodate uncertainties in determining the prechemotherapy tumor volume
• Involved-node radiation (INRT): Radiation field includes pre- and postchemotherapy nodal volumes plus a very limited margin of healthy tissue (0.5–1 cm)

Late complications: Develop due to high cure rates achieved with modern treatment.

• Development of second malignancies: Such as acute leukemia and solid organ cancers. Acute leukemia usually develops within 10 years of use of alkylating agents in combination with radiotherapy. The risk is higher with MOPP as compared to ABVD. Solid organ cancers usually develop after 10 years of radiotherapy.
• Cardiac failure and accelerated coronary artery disease: Following radiotherapy pulmonary fibrosis and hypothyroidism.

Non-Hodgkin Lymphoma:

Question 90. Discuss the pathological classification, clinical staging, clinical features, investigations, and management of nonHodgkin lymphoma (NHL). Answer:

• Lymphomas represent solid tumors of the immune system.
• Lymphomas can be divided into two major categories: NHL and HL.
• About 80% of NHL are of B-cell origin and 20% of T-cell origin.

Non-Hodgkin Lymphoma Etiology:

Various factors associated with the development of NHL have been shown in Table:

Pathology and Classifiation:

Grading of NH:

• Size of the lymphoid cells is a guide to prognosis. NHL with small lymphoid cells (mature lymphocytes) is associated with low-grade and those with large lymphoid cells (immature lymphoid cells) are found in high-grade disease.
• Follicular lymphomas are low grade and have good prognosis, and most diffuse lymphomas are high grade and have poor prognosis.

Grading of non-Hodgkin lymphoma (NHL):

WHO classifiation of lymphoid neoplasm:

It requires immunophenotyping, cytogenetics, fluorescent in situ hybridization (FISH), and antigen receptor gene rearrangement studies.

Lymphoid neoplasm Clinical Features:

• Age: NHL can occur at any age, but the peak incidence is around 60 years.
• Painless firm, lymph node enlargement or symptoms due to lymph node mass.
• Extranodal involvement is more common in T-cell lymphoma and involves the bone marrow, gut, thyroid, lung, skin, testis, brain and more rarely, bone.
• Bone marrow involvement is more common in low-grade (50–60%) than high-grade (10%) NHL and can produce cytopenia.
• Primary extranodal lymphomas present with soft tissue masses and symptoms relevant to the site. Waldeyer’s ring and epitrochlear lymph nodes are frequently involved.
• Pressure effects: Due to NHL includes gut obstruction, ascites, superior vena cava obstruction, and spinal cord compression.
• Involvement of liver and spleen results in hepatosplenomegaly.
• Patients with lymphoblastic lymphoma often present with an anterior mediastinal mass.
• Burkitt lymphoma typically disseminates to the bone marrow and meninges and involves extranodal sites.
• It may be associated with “B” or systemic symptoms. These include weight loss, sweats, fever, and itching.
• Immunologic abnormalities: For example, autoimmune hemolytic anemia and immune thrombocytopenia.
• Paraneoplastic neurologic complications of NHL include demyelinating polyneuropathy, Guillain-Barré syndrome, autonomic dysfunction and peripheral neuropathy. Paraneoplastic syndromes associated with NHL can affect the skin (e.g., pemphigus), kidney (e.g., glomerulonephritis), and miscellaneous organ systems (e.g., vasculitis, dermatomyositis, and cholestatic jaundice).

Clinical Staging (Ann Arbor Classifiation):

• Same staging system is used for both HL and NHL.
• Ann Arbor classification is also used for the clinical staging of NHL but is more useful in HL. However, ‘B’ symptoms are not included as they are not useful in predicting prognosis.

Lymphoid neoplasm Investigations:

Investigations required for staging the disease are the same as that for HL. Laparotomy is rarely required, only when retroperitoneal nodes are involved.

• Blood counts: Usually normal, but few patients may show lymphocytosis.
• Splenomegaly with hypersplenism or autoimmune hemolytic anemia may lead to reduced hemoglobin level, reticulocytosis, and positive Coombs test.
• Bone marrow aspiration and trephine biopsy: It should be performed early, since marrow involvement is common with NHL.
• Immunophenotyping of surface antigens to distinguish T- and B-cell tumors. This may be done on blood, marrow or lymph node material. It can be performed by flow cytometry and/or immunohistochemistry utilizing a minimal antibody panel (CD45, CD20, and CD3) to identify B, T or NK subtypes.
• Immunoglobulin determination: Some lymphomas are associated with IgG or IgM paraproteins.
• Measurement of uric acid levels: Few very aggressive high-grade NHLs are associated with very high uric acid levels that can precipitate renal failure when treatment is started.
• Human immunodeficiency virus (HIV) testing.
• Serum levels of LDH, b2-macroglobulin, and serum protein electrophoresis are often needed.
• Diagnostic spinal tap: Required when a first prophylactic instillation of cytarabine and or methotrexate is indicated in high-risk patients, especially with involvement of CNS, orbit, bone marrow, testis, spine or base of the skull. It is also indicated in HIV-associated lymphoma and highly aggressive lymphoma.

Regimen for non-Hodgkin’s lymphoma:

Diffuse Large B-Cell Lymphoma (DLBCL):

• Most common lymphoma in the adult population and constitutes about 30–50% of all NHL.
• Present with painless lymphadenopathy at one or several sites. Intra-abdominal disease presents with bowel symptoms due to compression or infiltration of the GIT.
• Treatment: Refer treatment of high-grade NHL mentioned earlier.

Question 91. How do you differentiate Hodgkin’s lymphoma from non-Hodgkin’s lymphoma? Answer:

Differences between HL and NHL have been shown in Table:

Burkitt Lymphoma:

Question 92. Write short note on Burkitt lymphoma/leukemia. Answer:

• Burkitt lymphoma is a highly aggressive, often extranodal B-cell lymphoma.
• Most common childhood malignancy worldwide and majority in children, but can occur in all ages.
• Male: female ratio is 3:1.
• Often presents with extranodal involvement or as leukemia.
• Burkitt lymphoma (about 80% of cases) is associated with a specific chromosomal translocation involving myc oncogene from chromosome 8 to the immunoglobulin (Ig) heavy chain region on chromosome 14.[t(8;14)].
• Categories of Burkitt lymphoma are explained

Three categories of Burkitt lymphoma:

• Endemic (African)
• Sporadic (nonendemic) Burkitt lymphoma
• Immunodeficiency-associated (HIV) lymphomas

Burkitt Lymphoma Clinical Features:

• Endemic form: Occurs in Africa. Affects children and adolescents.
• Associated with Epstein-Barr virus infection and corresponds to the distribution of malaria. Involves extranodal sites, particularly the jaw, gastrointestinal tract and gonads. Commonly presenting as a rapidly growing jaw tumor in a young child (4–7 years). Involvement of mandible and maxillary bone leads to deformity, loosening of teeth, and extrusion of the eye with loss of vision.
• Sporadic from: It presents as an abdominal mass.
• Immunodeficiency-associated (HIV) form: It usually occurs with CD4 counts above 200/mmIt again presents with abdominal involvement.
• Abdominal involvement: It presents as mass due to bilateral involvement of kidneys adrenals, ovaries, bowel, and lymph nodes.
• Other sites of involvement: CNS (common in adults), long bones, salivary glands, thyroid, testes, heart, breast, and bone marrow.

Burkitt Lymphoma Investigations:

• Histological examination: Involved tissues show diffuse monotonous infiltrate of medium-sized (intermediate-sized) lymphoid cells, numerous mitoses, and plenty of tumor cells undergoing apoptosis. The nuclear remnants of these apoptotic cells are phagocytosed by benign macrophages creating a characteristic “starry sky” pattern (resembling stars in the sky).
• Chromosome analysis: The most common form of translocation results in the movement of the MYC-containing segment of chromosome 8 to chromosome 14q32, placing it close to the IGH gene. The genetic notation for the translocation is t(8:14) (q24; q32). As a result of translocation, MYC protein is overexpressed and results in cell proliferation and stimulates apoptosis.
• Antibodies to EB viral capsid antigen: It may be detected (in endemic type, and in many with sporadic and HIV-associated tumors).

Burkitt Lymphoma Management:

• Treatment must be initiated urgently with curative intent whenever feasible.
• Adequate hydration prior to the initiation of specific therapy to prevent the risk of tumor lysis syndrome.
• CHOP (cyclophosphamide, hydroxydoxorubicon or doxorubicin, oncovin (vincristine), prednisolone) regimen OR
• Rituximab plus EPOCH (etoposide, prednisolone, oncovin (vincristine), cyclophosphamide and doxorubicin) OR
• CODOX-M/IVAC regimen (cyclophosphamide, vincristine, doxorubicin, methotrexate/ifosfamide, etoposide, or VP-16, cytarabine)
• Prophylactic CNS therapy is essential, intrathecal methotrexate or cytosine arabinoside is given in addition to high-dose systemic administration.
• Cure rates: High as 70–80%.

Adult T-Cell Lymphoma/Leukemia:

Question 93. Write short note/essay on adult T-cell lymphoma/leukemia. Answer:

• Adult T-cell leukemia/lymphoma is a neoplasm of CD4+ T-cells and develops in adults infected by human T-cell leukemia virus type 1 (HTLV-1).
• Mode of infection of HTLV-1: Transplacental transmission, blood transfusion, or sexual contact.
• Latency period between infection and development of lymphoma is long (10–30 years).
• Acute aggressive form: It is characterized by peripheral blood lymphocytosis, lymphadenopathy, hepatosplenomegaly, skin infiltration, hypercalcemia, lytic bone lesions, and raised LDH levels in blood. Opportunistic infections are common. Peripheral smear usually reveals characteristic, neoplastic cells with multilobulated nuclei, and petal-like nuclear lobules connected by thin chromatin strands, known as “cloverleaf” or “flower” cells are found in the involved tissues and peripheral blood. Bone marrow involvement is usually not prominent.
• Lymphomatous form: Constitute ~20% of cases and is associated with generalized lymphadenopathy without leukemia.
• Chronic form: Constitute ~15% of cases and may have a lowlevel absolute lymphocytosis in the peripheral blood associated with an exfoliative skin rash.
• Smoldering form: Constitute ~5% of cases and have a normal peripheral blood lymphocyte count and a small number of circulating tumor cells and skin rashes.

Prognosis: Most cases progress rapidly and are fatal.

Adult T-Cell Lymphoma/Leukemia Treatment:

• Combination chemotherapy prolongs life but does not produce remissions.
• Combination antiretroviral drugs (zidovudine + interferon-α) may be helpful in some patients.

Mucosa-associated Lymphoid Tissue Lymphoma:

Question 94. Write short note/essay on mucosa-associated lymphoid tissue lymphoma or primary gastric lymphoma. Answer:

• It is a small-cell NHL of B-cells that is extranodal in origin.
• Gastric type of MALT lymphoma is associated with H. pylori infection. Salivary gland MALT is associated with Sjogren’s syndrome.
• Other sites: It may occur in the stomach, orbit, intestine, lung, skin, soft tissue, bladder, kidney, salivary gland, and CNS.
• Age: Mainly in elderly patients with median age of 60 years.
• It may present as a mass or produce local symptoms such as upper abdominal discomfort and dyspepsia.
• Endoscopy: Often mimic benign conditions like chronic gastritis or a peptic ulcer. Multiple biopsies are required for establishing diagnosis.
• Endoscopic ultrasound (EUS) useful for staging of gastric MALT lymphoma.
• Low-grade gastric MALT lymphoma can achieve remission in 80% of cases with eradication of the infection.
• Prognosis: Good in most cases with 5 year survival of 75%.

Primary gastric lymphoma Treatment:

• Anti H. Pylori therapy in gastric MALToma.
• Extensive disease is treated with single chemotherapy agents like chlorambucil, cyclophosphamide, fludarabine, or cladribine. Combination regimens that include rituximab are also highly effective

Mycosis Fungoides:

Question 95. Write a short note on mycosis fungoides. Answer:

• Mycosis fungoides is a rare type of cutaneous T-cell NHL composed of small to medium-sized lymphoid cells with irregular nuclear outlines.
• Insidious in onset and are derived from CD4+T cells of skin-associated lymphoid tissue.
• Age: They usually present between 55 and 60 years.
• The tumor cells show epidermotropism (predilection for the epidermis) and dermis.
• Patch stage (inflammatory premycotic phase), characterized by erythematous macules usually occurring on areas not exposed to sunlight.
• Plaque stage, with elevated scaly plaques which may be pink or red/brown and are often intensely pruritic.
• Tumor stage, with dome-shaped firm tumors which may ulcerate.
• Sézary syndrome: Patients with mycosis fungoides may develop generalized erythroderma and malignant T-cells with serpentine nuclei are found in the peripheral blood and this condition is known as Sézary’s syndrome.
• Immunophenotype: Tumor cells express pan-T-cell markers CD3, CD5 and CD2.
• Prognosis: These are indolent tumors with a median survivalrate of 8–9 years.

Mycosis Fungoides Treatment:

• Localized early-stage mycosis fungoides: Can be cured with radiotherapy, often total-skin electron beam irradiation.
• More advanced stage: Palliative treatment such as topical glucocorticoids, topical nitrogen mustard, phototherapy, psoralen with ultraviolet A (PUVA), and systemic cytotoxic therapy.

Several rare lymphoproliferative disorders other than lymphoma have distinctive clinical courses.

Generalized Lymphadenopathy:

Question 96. Discuss the differential diagnosis (causes) of generalized lymphadenopathy in an adult. (or) Assessment of the extent of lymph nodal enlargement. Answer:

• Generalized lymphadenopathy is defined as significant enlargement of more than 2 or more noncontiguous lymph node groups. Various lymph node areas are depicted.
• Sites of lymph node enlargement
• Consistency
• Mobile/Fixed
• Presence Or Absence Of Tenderness
• Draining area.

• Systemic abnormalities if any.
• Chest X-ray and CT scan of thorax: To detect lymphadenopathy in the mediastinal, hilar, and paratracheal region.
• Ultrasound scanning and CT scan of abdomen: To detect intra-abdominal lymph nodes.
• Lymph node groups: Location, lymphatic drainage, and differential diagnosis are mentioned in Table

Differential Diagnosis:

Differential diagnosis of generalized lymphadenopathy:

Generalized lymphadenopathy Cause:

• Lymphomas (Hodgkin and non-Hodgkin)
• Acute lymphoblastic leukemia
• Chronic lymphocytic leukemia
• Chronic myeloid leukemia in blast crisis
• Metastatic disease (head and neck cancers, lung and breast cancers, GIT malignancies)

Generalized lymphadenopathy Infections:

• Disseminated tuberculosis
• Human immunodeficiency virus (HIV) infection
• Secondary syphilis
• Brucellosis
• Local infections (cellulitis, pharyngitis)
• Other infections: Toxoplasmosis, cytomegalovirus infection, hepatitis B, atypical mycobacteria, histoplasmosis, coccidioidomycosis, cryptococcosis
• Systemic lupus erythematosus
• Rheumatoid arthritis
• Drugs induced (phenytoin, allopurinol, hydralazine, primidone, quinidine)
• Systemic disorders: Amyloidosis, sarcoidosis, serum sickness, hyperthyroidism, Gaucher’s disease, Kawasaki disease, Kimura disease, hemophagocytic lymphohistiocytosis
• Rare: Castleman’s disease, Kikuchi Fujimotos disease, Rosai-Dorfman disease

Castleman’s disease, or angiofollicular lymph node hyperplasia:

• Patients often present with a localized lymphoid mass, but some patients have a systemic illness with fevers, night sweats, weight loss, and fatigue.
• Frequently, the systemic symptoms of Castleman’s disease are related to excessive production of IL-6.
• Castleman’s disease in HIV-infected patients is frequently associated with HHV-8.
• Patients with disseminated and plasma cell–rich forms of Castleman’s disease may occasionally progress to lymphoma.
• Patients with localized Castleman’s disease can be treated with surgical removal or radiotherapy. Patients with systemic disease may respond to treatment with high-dose corticosteroids.

Sinus histiocytosis with massive lymphadenopathy, also known as Rosai-Dorfman disease:

• Manifests as bulky lymphadenopathy in children and young adults.
• Extranodal sites such as the skin, upper airways, gastrointestinal tract, and CNS can be involved. There is a characteristic pattern of lymphoid proliferation with a thick fibrous capsule, distention of lymphoid sinuses, accumulation of plasma cells, and proliferation of large, often atypical histiocytes.
• The disease is usually self-limited, but it has been associated with autoimmune hemolytic anemia.

Kikuchi’s disease (histiocytic necrotizing lymphadenitis):

• Disease of unknown origin that most commonly affects young women.
• Symptoms most commonly consist of painless cervical lymphadenopathy that is often accompanied by fever, flu-like symptoms, and rash.
• Sometimes associated with SLE. Treatment is symptomatic, and symptoms usually resolve within weeks or months.
• Lymph node biopsies reveal foci of necrotic histiocytes.

Kimura disease: Lymphadenopathy; peripheral eosinophilia; and elevated levels of serum immunoglobulin E (IgE).

Hemostasis:

Question 97. Discuss the mechanism of hemostasis. (or) Write short essay/note on platelets and their functions. Answer:

Components of Hemostasis:

Three major components namely:

• Platelet component
• Vascular Component (Endothelium)
• Coagulation component participate in normal hemostatic mechanism.

The first two components are involved in primary hemostasis while the last component is involved in secondary hemostasis.

Hemostasis Coagulation System:

Coagulation factors Coagulation can be activated by two pathways namely extrinsic and intrinsic. Both the pathways converge on the activation of factor X to produce factor Xa (activated X).

• It requires an exogenous trigger; hence the name extrinsic. But now it is observed that released tissue factor (a proteinphospholipid complex normally present on vascular cells and activated monocytes) from vascular injury can initiate this pathway. It converts factor VII into activated factor VII (VIIa) in presence of calcium. Activated tissue factor VII complex activates factors IX and X.

• The coagulation factors utilized in extrinsic pathway are factors VII, X, II, V, and fibrinogen.
• Prothrombin time (PT) is the laboratory test which assesses the function of the coagulation factors involved in the extrinsic pathway.
• This gets activated with exposure of prekallikrein, high-molecular weight kininogen, and factor XII (Hageman factor) to any thrombogenic (negatively charged) surfaces (including glass beads).
• Prekallikrein is converted to kallikrein and factor XII becomes activated factor XII (XIIa).
• Factor XIIa converts factor XI into XIa.
• Factor XIa activates factor IX, and factor IXa with its co-factor FVIIIa activates X to Xa.
• The coagulation factors utilized in intrinsic pathway are, in order of reaction, factors XII, pre-K, HMWK, XI, IX, VIII, X, V, II, and fibrinogen.
• The partial thromboplastin time (PTT) assesses the function of the coagulation factors utilized in the intrinsic pathway. PTT is initiated by adding negatively charged particles like ground glass.
• Above two pathways have in common factors X, V, prothrombin and fibrinogen; and this part of coagulation pathway is known as the common pathway.
• Common pathway is initiated by factor Xa. Factor Xa converts prothrombin to thrombin (Factor IIa). This is facilitated by Va.
• Factor IIa converts fibrinogen into fibrin and also activates factor XIII to XIIIa that cross links fibrin to fibrin polymers.

Mechanism of Hemostasis:

• Primary hemostatic plug: The platelet component undergoes three different events—platelet adhesion and shape change, platelet secretion (release of granule contents) and platelet aggregation.
• Exposure of tissue factor at the site of injury activates the extrinsic coagulation system.
• The process generates thrombin, which cleaves circulating fibrinogen into insoluble fibrin, creating a fibrin meshwork at the injured site.
• The platelets contract and form an irreversibly fused mass known as secondary hemostatic plug.
• The sequence of conversion of the initial temporary primary hemostatic (platelet) plug into a permanent secondary hemostatic plug is known as secondary hemostasis.

Functions of platelets:

• Maintain vascular integrity
• Spontaneously arrest bleeding through platelet plug formation
• Participate in the intrinsic coagulation system
• Promote repair and healing through release of growth factors

Coagulation Regulatory Mechanism:

Question 98. Briefly outline the natural inhibitors of coagulation. Answer:

The activated coagulation system must be limited to the site of vascular injury so as to prevent coagulation in the entire vascular system. This is achieved by three endogenous anticoagulants.

Inhibitors of Coagulation:

• Antithrombin is a circulating serine protease inhibitor (serpin) which inhibits the activity of thrombin and factors IXa, Xa, XIa and XIIa. One of these is antithrombin III which gets activated by binding to heparin-like molecules on endothelial cells. The heparin used to minimize thrombosis acts by activating antithrombin III.
• Proteins C and S are vitamin K-dependent proteins that act in a complex. Thrombin generated by activation of coagulation cascade, binds with thrombomodulin present on the endothelial cell membrane, and\ activates the coagulation regulatory system called protein C system. Activated protein C (APC) binds with protein S to form APCprotein S complex. This complex inactivates factors Va and VIIIa. Impaired activity of protein C as occurs in factor V eiden produces thrombophilia.
• Tissue factor pathway inhibitor (TFPI): It is a protein which inactivates tissue factor—factor VIIa complexes and inactivates factor VIIa. Endothelial cells produce prostacyclin and nitric oxide which inhibit platelet aggregation.

Fibrinolytic System:

Question 99. Describe fibrinolytic system. Answer:

• Activation of the coagulation also initiates the fibrinolytic system so that the size of the clot is limited. Fibrinolytic system does this by removal of fibrin from the clot. Otherwise, the clot may progress and involve the entire circulation with its consequences.

Bleeding Disorders (Hemorrhagic Diatheses):

Question 100. Discuss the evaluation of a patient with bleeding disorder. Answer:

Bleeding Disorders Defiition:

Increased tendency to hemorrhage (usually with insignificant injury) are collectively called as bleeding disorders (hemorrhagic diatheses). Broad classification of bleeding disorders

Broad classification of bleeding disorders:

• Coagulation defects
• Platelet disorders
• Vessel wall abnormalities

Evaluation/Investigation of Bleeding Disorders:

Information to be obtained from the history to determine:

• Evidence includes bleeding from multiple sites, spontaneous bleeding, and excessive bleeding after injury.
• A family history of a bleeding
• Age of onset: Severe inherited defects usually become apparent in infancy, while mild inherited defects are detected later in life
• Lifelong history.
• Short duration
• Evidence of disease causing the defects. Examples, evidence of liver disease, renal failure, disseminated intravascular coagulation (DIC).
• Whether the bleeding pattern is suggestive of a vascular/platelet defect or a coagulation defect? Distinguishing features of bleeding in platelet, vascular, and coagulation disorders.

Physical Examination:

Physical examination consists of search for the following:

• Purpura, bruises, ecchymoses.
• Examination of joints, particularly knees, ankles, and elbows for hemarthrosis.
• Scars over elbows and knees in factor XIII deficiency.
• Signs of liver cell disease
• Neurological signs
• Hepatosplenomegaly and lymphadenopathy.

Question 101. Write short note on screening tests for hemostasis/bleeding disorders. Answer:

Screening tests used in bleeding disorders.

• Normal range: 4–9 minutes.
• Prolonged in platelet disorders.
• Prothrombin timeb

Question 102. Write short note on prothrombin time. Answer:

• It is measured by adding tissue factor (thromboplastin) and calcium to the patient’s plasma.
• Normal is 12–16 seconds
• Measures VII, X, V, prothrombin, and fibrinogen (classic “extrinsic” pathway)
• With abnormalities of above factors (II, V, VII, and X)
• In liver disease, DIC, vitamin K deficiency and if the patient is on oral warfarin therapy.
• Also known as the PTT and is performed by adding a surface activator (such as kaolin, micronized silica or ellagic acid) phospholipid (to mimic platelet membrane) and calcium to the patient’s plasma.
• Normal APTT is 26–37 seconds
• APTT measures XII, XI, IX, VIII, X, V, prothrombin, and fibrinogen (classic “intrinsic” pathway).
• With deficiencies of one or more of above factors (II, V, VIII, IX, X, XI and XII including hemophilia A and B, von Willebrand disease)
• DIC, heparin therapy, and presence of lupus anticoagulant and acquired factor inhibitors.
• Prolonged PT, APTT or TT due to coagulation factor deficiencies can be corrected by addition of normal plasma to the patient’s plasma.
• Failure to correct after addition of normal plasma indicates the presence of an inhibitor of coagulation.
• Factor assays: It confirms coagulation defects.

Special tests of coagulation:

To confirm the precise hemostatic defect and includes estimation of fibrinogen and FDPs. Various laboratory tests in bleeding disorders are presented in Table:

Disorders Of Platelets:

Thrombocytopenia:

Question 103. Define thrombocytopenia. Enumerate the common causes, clinical manifestations, investigations, and management of thrombocytopenia. Answer:

Thrombocytopenia Definition:

Decrease in the platelet count below the lower limit of 150,000/µL is known as thrombocytopenia. Causes of thrombocytopenia.

General Clinical Manifestations:

• Bleeding into skin: It presents as purpura, petechiae, ecchymoses.
• Bleeding into mucous membranes: It presents as epistaxis, hemorrhagic bullae in oral mucosa, genitourinary bleeding, and gastrointestinal bleeding.
• Severe thrombocytopenia produces fundal hemorrhage and intracranial bleeding.
• Approach to the differential diagnosis for petechiae/purpura.
• Platelet count: Reduced and clinical manifestations roughly correlate with the platelet count.
• Principle: It measures the ability of capillaries to withstand the increased stress.
• Sphygmomanometer cuff is tied to the upper arm above the elbow and the cuff is inflated to 80 mm Hg for 5 minutes.
• Release the pressure after 5 minutes.
• The number of petechiae present in a circle of 5 cm diameter on the flexor aspect of forearm (below the bend of the elbow) is noted.
• Normal: 0–5 petechiae.
• Vascular purpura
• Defective platelet function
• Thrombocytopenia

Bleeding time (BT): Prolonged, and it bears a close relationship to platelet count.

Bone marrow:

• Normal or increased number of megakaryocytes indicates increased platelet destruction, hypersplenism, or ineffective platelet production.
• Decreased number of megakaryocytes indicates reduced production of platelets.

Qualitative Platelets Defects:

Qualitative defects of platelet function can be hereditary/ congenital or acquired.

Classification of platelet function disorders:

1. Hereditary:

• Bernard-Soulier syndrome
• Storage pool deficiency
• Glanzmann thrombasthenia

2. Acquired:

• Drugs: Aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), dipyridamole, sulfinpyrazone
• Renal failure (uremia)
• Hematologic malignancies: Myeloproliferative and myelodysplastic disorders

Immune Thrombocytopenic Purpura Defiition:

Immune (idiopathic) thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by increased destruction of platelets by autoantibodies directed against platelet membrane GPIIb/IIIa and GPIb/IX.

Pathogenesis:

Question 104. Discuss the pathogenesis, clinical features, investigations/ diagnosis, and management of immune (idiopathic) thrombocytopenic purpura (ITP). Answer:

• ITP is an autoimmune disorder with formation of antiplatelet antibodies, directed against membrane glycoproteins most often IIb/IIIa or Ib/IX of platelets.
• The antiplatelet antibodies can be demonstrated in approximately 80% of patients and are of the IgG type.

Pathogenesis Clinical Features:

ITP can be primary or secondary:

• Acute form is more common in children
• Chronic form is characterized by the persistence of thrombocytopenia for more than 6 months and is more common in adults.

• Clinical features are not specific but are due to thrombocytopenia in general.
• Patient has no physical signs other than those due to bleeding and anemia (following menorrhagia and epistaxis), intracranial hemorrhage (ICH), overt gastrointestinal bleeding, and hematuria, are uncommon.
• Splenomegaly and lymphadenopathy are uncommon in primary ITP and in their presence one should consider the diagnoses other than ITP.
• May be associated with hemolysis (Evan’s syndrome).
• Majority of patients with acute ITP recover within 6 months.

Pathogenesis Investigations and Diagnosis:

The diagnosis of ITP is one of exclusion. It requires only isolated thrombocytopenia (i.e., without anemia or leukopenia) without another apparent cause

• Platelet count is usually markedly reduced (thrombocytopenia) and is below 80 × 109/L. Platelet count should be repeated using sodium citrate (anticoagulant) to exclude pseudothrombocytopenia caused by platelet aggregation and clumping in the presence of EDTA anticoagulant.
• Tourniquet test (Hess test): Positive
• Bleeding time (BT): Prolonged
• Bone marrow examination: Usually not performed in acute ITP, unless treatment becomes necessary on clinical grounds. It is important in chronic ITP to rule out thrombocytopenia resulting from bone marrow failure. Bone marrow shows moderate increase in number of both immature and mature forms of megakaryocytes. A decrease in the number of megakaryocytes argues against the diagnosis of ITP.
• Antiplatelet antibodies: Tests for platelet autoantibodies are not widely available but may be demonstrated in blood. However, a negative test does not exclude ITP.
• In chronic ITP, secondary causes such as HIV, hepatitis C virus infection, etc. should be excluded.

Pathogenesis Treatment:

• Children with mild acute ITP usually do not require treatment
• Adults with platelet counts >30 × 109/L usually do not require treatment. Patients with even lower platelet counts may require treatment, if they have spontaneous bruising or bleeding
• Overt hemorrhage (treated with platelet concentrates)
• Platelet counts below 20,000/mm 3
• Organ or life-threatening bleeding irrespective of the circulating platelet count
• Platelet transfusion: If platelet counts <20,000/mm 3 or bleeding manifestations
• Single-donor platelets have a shelf life of 3–5 days, and one unit will raise platelets 30,000 to 50,000/µL
• To induce remission
• To maintain remission in chronic ITP
• Postoperatively, in patients where splenectomy failed to achieve the result
• Pregnant women after the 5th month of pregnancy
• Both adults and children: Initial dose is 1–2 mg/kg of prednisolone/day. Initial dose is continued for at least 2 weeks (or if necessary 3–4 weeks), and then reduced slowly and stopped
• About 66% respond to prednisolone but relapse is common when the dose is reduced
• Second-line therapy:
• Splenectomy: Majority of patients respond well and achieve a normal platelet count
• Chronic ITP in adults who fail to responded to corticosteroids
• Patients requiring unacceptably high doses of corticosteroids to maintain a safe platelet count
• When there is severe bleeding or threatening cerebral hemorrhage (despite adequate corticosteroid therapy)
• In the first 4–5 months of pregnancy, if steroids do not induce full remission
• Spleen being the major site of platelet destruction, splenectomy prevents its destruction
• Reduces the concentration of circulating antiplatelet antibodies
• 375 mg/m 2 intravenously once a week for four consecutive weeks
• ADR- immunosuppression, progressive multifocal leukoencephalopathy

Third-line therapy:

Patients who fail to respond to splenectomy, a wide range of other therapies are available. Major drawbacks of these therapies are modest response rates and slow onset of action. The therapies include:

• High-dose corticosteroids
• Intravenous immunoglobulin (i.e., IgG): It is effective.

Indications:

• Acute situation prior to surgery and child birth, and in patients with intracranial bleed
• Patients with ITP where corticosteroid therapy and splenectomy are contraindicated
• Side effects: Nausea, vomiting, fever, and headache. Uncommonly neutropenia and hemolytic anemia
• Dose: 1–2 g/kg
• Indications: Patients who do not respond to steroids and may be tried before splenectomy
• Should be given only to Rh-positive patients
• Effective in patients with ITP but the effect is usually temporary, and nearly 50–75% patients relapse
• Dose is 75 µg/kg intravenously
• Side effects: Nausea, vomiting, fever, chills and intravascular hemolysis
• Refractory cases which fail to respond to corticosteroids and splenectomy
• Agents used are vinca alkaloids (vincristine, vinblastine), azathioprine, cyclophosphamide, cyclosporine, and combination chemotherapy, mycophenolate mofetil
• Plasmapheresis: Employed as an emergency measure to remove antibodies from the plasma
• Romiplostim, 500 μg subcutaneously once weekly
• Eltrombopag 50 mg, once-daily pill
• Serious ADRs: Thrombocytosis, thrombosis, bone marrow firosis
• Fostamatinib: A tyrosine kinase inhibitor that inhibits the spleen tyrosine kinase Syk
• Danazol is an androgen with low virilizing activity has been tried in idiopathic thrombocytopenic purpura
• Platelet transfusions are reserved for intracranial or other extreme hemorrhage, where emergency splenectomy may be justified
• Emergency treatment: Necessary in case of life-threatening bleeding. It consists of intravenous administration of methylprednisolone (30 mg/kg, maximum dose 1 g) over 20 to 30 minutes along with platelet transfusion. This is followed by intravenous immunoglobulin (1 g/kg)

Thrombocytosis:

Question 105. What are the common causes of thrombocytosis? Answer:

Thrombocytosis Defiition:

Platelet count more than 450,000/mm3 is known as thrombocytosis.

Thrombocytosis Causes:

Causes of thrombocytosis have been shown in Table:

Disorders Of Coagulation (Clotting):

Question 106. Write short note on congenital bleeding disorders Answer:

Hereditary coagulation disorders:

• von Willebrand disease
• Hemophilia A
• Hemophilia B
• Hemophilia C: Inherited deficiency of factor XI (factor 11); also called Rosenthal syndrome; an autosomal recessive disorder

Hemophilia A (Factor VIII Deficiency):

Question 107. Discuss the etiology, classification, clinical features, diagnosis, and management of hemophilia A. Answer:

• Hemophilia A is the most common hereditary X-linked recessive disease with a reduction in the amount or activity of factor VIII (antihemophilic factor). About 30% of hemophiliacs have no family history and may be due to acquired mutations.
• Males are affected and females are carriers.
• Incidence: 1 in 10,000 males.

Mode of Inheritance:

• Hemophilia A is an X-linked recessive disorder.
• Usually males are the sufferers and females are the carriers.
• She is born to an affected father and a carrier mother (25% risk).
• Females with inactivation of the X-chromosome such as Turner’s syndrome (45, XO)
• She has inactivation of normal X-chromosome due to unfavorable lyonization (rare).
• Degree of deficiency of factor VIII and severity of bleeding tends to be similar in all the affected members of the same family.
• Normal level of factor VIII in the blood is 0.50–1.50 IU/mL. Hemophilia A may be classified based on the factor VIII activity in blood.

Hemophilia A Clinical Features:

• Clinical severity depends on the level of factor VIII activity and is presented.
• Excessive bleeding: Hemophilia A is characterized by excessive bleeding, but is unusual until the child is about 6 months old.
• Post-traumatic bleeding: Bleeding following trauma is characteristically “delayed.”
• Severity of bleeding: Range from mild to severe.
• Petechiae observed in platelet and vascular disorders are not seen in hemophilia.

Bleeding into joints (hemarthrosis):

• Frequent and spontaneous hemorrhages occur into the large joints, especially knees, elbows, ankles, wrists and hips, and are known as hemarthrosis.
• Nature of bleeding: Usually spontaneous or follows minor trauma.
• Acute stage: Affected joint is swollen, hot and tender and movements severely restricted. These changes gradually subside over a period of days.
• Consequences: Recurrent bleeding into the joints will lead to crippling deformities and disuse atrophy of muscles around the joint.

Bleeding into muscles:

• Common sites: Calf and psoas muscles.
• Psoas hematomas may compress the femoral nerve resulting in sensory disturbances over thigh and weakness of quadriceps.
• Calf hematomas can result in contraction and shortening of the Achilles tendon.

Other manifestations:

• Easy bruising
• Massive bleeding following trauma (from wounds) or operative procedures (e.g., bleeding from sockets after dental extraction)
• Cerebral hemorrhage
• Hematuria and ureteric colic due to passage of blood clots.
• Bleeding time is normal.
• Clotting time is prolonged.
• Platelet count is normal.
• PT is normal.
• APTT is increased (normal 35–45 seconds) from 50 seconds to a few minutes.
• Factor VIII assay is required for the confirmation of diagnosis and to assess the Factor VIII levels and severity of disease.

Antenatal Diagnosis:

• Chorionic villous sampling (CVS): Done at 8–9 weeks of gestation, sexing the fetus, and using informative factor VIII probes. It is the preferred method.
• Amniocentesis: Sexing the fetus at 16 weeks of gestation by amniocentesis and, if fetus is male, a fetal blood sampling is done at about 19–20 weeks of gestation.

Hemophilia A Management:

• Wounds and bleeding from mucous membrane: Apply local pressure and pressure bandages or sutures. Immobilize wounds by bandages, splinting, etc.
• During acute stage: Elevate the affected part and immobilize by splinting and bandages. Pain is relieved by analgesics like acetaminophen or codeine.
• During recovery phase: Physiotherapy.
• Agents used: Factor VIII concentrate is available as plasma-derived and recombinant products. Recombinant products are the treatment of choice and are replacing the plasma-derived factor VIII concentrate.
• Route of administration: Intravenous infusion to correction of deficiency of factor VIII and to achieve normal levels.
• Early treatment of spontaneous bleeding.
• Severe or prolonged wound and tissue bleeding.
• Control of bleeding during and after surgery and trauma.
• Prophylaxis: In all patients with severe hemophilia so as to prevent recurrent bleeding into joints and subsequent joint damage (arthropathy).
• Dose of factor VIII = Desired factor level (%) × body weight (in kg) × 0.5.
• Viral hepatitis (hepatitis B virus, delta virus and hepatitis C virus).
• Infection with HIV.
• Development of factor VIII inhibitors.
• Desmopressin (DDAVP) is a synthetic vasopressin analog that causes a transient rise in factor VIII activity by 3–5 times. It is given at a dose of 0.3 µg/kg body intravenously over 15 minutes.
• Indication: Minor bleeding and minor surgery.
• Indications: To control local hemostasis/bleeding in the gums, nasal bleeding, gastrointestinal tract, during oral surgery (e.g., dental extraction) and menstruation.
• Drugs used: Epsilon (ε) aminocaproic acid (EACA) and tranexamic acid.
• Action: Inhibit the proteolytic activity of plasmin and results in inhibition of fibrinolysis.
• Tranexamic acid: 25 mg/kg three to four times a day.
• EACA: Requires a loading dose of 200 mg/kg (maximum of 10 g) followed by 100 mg/kg per dose (maximum 30 g/d) every 6 hours.
• Not indicated to control hematuria because of the risk of formation of an occlusive clot in the lumen of genitourinary tract structures.
• Thromboembolic disease.

Hemophilia A Complications:

About 15% of the patients receiving factor VIII therapy develop inhibitory antibodies that bind and inhibit factor VIII.

• Treatment for patients with factor VIII inhibitors: Immune tolerance induction (ITI) is the most effective strategy of eradication of inhibitors with steroids or other immunosuppressants. Emicizumab, a bifunctional monoclonal antibody that can substitute for factor VIII is used in these cases.
• Antibodies to AHG may occur de novo in nonhemophiliacs as part of an immunological disorder such as systemic lupus erythematosus.
• Arthropathy
• HIV and HCV infection
• Inhibitor development.

Preventive Therapy for Hemophilia:

• Gene therapy
• Concizumab-monoclonal antibody directed against tissue factor pathway inhibitor

Hemophilia B:

Question 108. Write short essay/note on hemophilia B (Christmas disease) and its management. Answer:

• Hemophilia B is caused by a deficiency of factor IX.
• Mode of inheritance: X-linked disorder
• Patients with severe disease: Present with muscle hematomas and hemarthrosis which progresses to crippling joint deformities.
• Diagnosis: Factor IX assay shows deficiency of factor.

Hemophilia B Management:

• Management is similar to hemophilia A.
• Fresh frozen plasma to treat mild-to-moderated bleeding.
• Gene therapy: It may be effective in managing severe disease.
• Desmopressin is ineffective.

Von Willebrand’S Disease:

Question 109. Discuss the etiology, clinical features, investigations, and treatment of von Willebrand’s disease. Answer:

• von Willebrand’s disease (vWD) is characterized by defective platelet function as well as factor VIII deficiency, and both are due to a deficiency or dysfunction of vWF.
• Major categories: The vWF gene is located on chromosome 12 and numerous mutations of the gene produce vWD.
• Type 1 is an autosomal dominant, relatively mild disorder.
• Type 3 is an autosomal recessive disorder and is severe.
• Type 2a is most commonly characterized by defective assembly of multimers.
• Type 2b is caused by synthesis of an abnormal vWF with increased affinity for platelets which results in thrombocytopenia.

von Willebrand Factor:

• vWF is a protein synthesized by endothelial cells and megakaryocytes.
• vWF acts as a carrier protein which binds to factor VIII and forms plasma factor VIII-vWF complex. vWF protects factor VIII and is important for its stability. It has no role in the coagulation cascade, but deficiency of vWF causes a secondary reduction of factor VIII causing coagulation defect.
• vWF is the most important cofactor for adhesion of platelets to the exposed subendothelial collagen matrix by GpIb/IX. Hence, the deficiency of vWF results in a defect of platelet function.

Von Willebrand’S Disease Clinical Features:

• Variable and ranges from mild asymptomatic conditions to a severe hemorrhagic disorder.
• The common symptoms are spontaneous bleeding from mucous membranes (e.g., epistaxis), excessive bleeding from wounds or menorrhagia. In severe cases, manifestations may be similar to hemophilia A.

Acquired causes of vWF deficiency:

• Lymphoproliferative disorders
• Congenital heart disease
• Aortic stenosis
• Left ventricular assist device or extracorporeal membrane oxygenation
• Wilms tumor hypothyroidism
• Valproic acid and other medications

Laboratory Findings:

• Bleeding time is prolonged despite a normal platelet count because of defect in platelet function.
• Tourniquet test (Hess test): Positive due to defect in platelet adhesion.
• APTT: Prolonged because vWF stabilizes factor VIII by binding to it. A deficiency of vWF gives rise to a secondary decrease in factor VIII levels.
• vWF assay: Plasma level of active vWF is decreased.
• Platelet function test: Function of vWF is assessed by ristocetin aggregation test. Ristocetin induces multivalent vWF multimers to bind platelet glycoprotein Ib-IX and results in bridging of platelets to each other. The resultant clumping (agglutination) of platelets is measured by aggregometer. The degree of ristocetin-dependent platelet agglutination is a measure of vWF activity. Defective ristocetin induced platelet aggregation is diagnostic of vWF.

Von Willebrand’S Disease Management:

Management of bleeding:

• Mild bleeding: Managed with desmopressin.
• Severe bleeding: Controlled by intravenous cryoprecipitate or plasma-derived concentrates containing vWF and factor VIII. Recombinant activated factor VII (rFVIIa,) has also been successfully used in vWD patients with severe hemorrhage refractory to vWF replacement therapy.

Vitamin K deficiency:

• Clinically, it manifests as ecchymoses, bleeding from injection sites, bruises, gum bleeding, hematemesis, melaena, or hematuria.
• Both the PT and activated partial thromboplastin time are prolonged.
• Administration of vitamin K in a dose of 5–10 mg stops bleeding within 1–2 days.
• If blood loss is severe or response to vitamin K is inadequate, transfusion of fresh blood or fresh frozen plasma is indicated.

Fibrinolysis:

Causes of excessive fibrinolysis have been shown in Table:

Microangiopathic Hemolytic States And Thrombocytopenias:

Clinical Spectrum:

Hemolytic uremic syndrome

• Thrombotic thrombocytopenic purpura (TTP)
• Systemic sclerosis
• Malignant hypertension
• Preeclampsia–eclampsia
• Antiphospholipid antibody syndrome
• Renal transplant associated
• Drug induced
• Radiation therapy associated.

Thrombotic Thrombocytopenic Purpura:

Question 110. Discuss thrombotic thrombocytopenic purpura. Answer:

Thrombotic thrombocytopenic purpura (TTP) is a severe microangiopathic hemolytic anemia (MAHA), characterized by systemic platelet aggregation, organ ischemia, profound thrombocytopenia (with increased marrow megakaryocytes), fragmentation of erythrocytes, fever, and renal failure.

Thrombotic Thrombocytopenic Purpura Etiology and Pathogenesis:

• Normally endothelial cells and megakaryocytes secrete normal vWF multimers into the plasma. These multimers spontaneously develop into unusually large multimers which are most effective in mediating platelet adhesion.
• A plasma protease enzyme called ADAMTS 13 (“vWF metalloprotease”) regulates the activity of vWF by cleaving the hemostatically active unusually large multimers into normal multimers. Thus, ADAMTS-13 regulates the size of vWF multimers and prevents platelet adhesion.
• TTP patients have an inherited or acquired deficiency of ADAMTS-1The deficiency leads to accumulation of unusually large multimers of vWF in plasma.
• These large multimers promote platelet adhesion or promote intravascular platelet aggregation and cause spontaneous activation of the coagulation cascade.
• This results in hyaline thrombi throughout the microcirculation, leading to tissue ischemia, and infarction that are characteristic of TTP.
• Secondary causes of acute TTP: These include pregnancy, oral contraceptives, SLE, infection, and drugs (ticlopidine and clopidogrel). They may or may not have associated antibodies to ADAMTS-13.

Thrombotic Thrombocytopenic Purpura Clinical Features:

The classic five symptoms of TTP are:

• MAHA with schistocytosis (at least 3 cells per 100)
• Severe Thrombocytopenia
• Transient Neurologic Symptoms Secondary To Cns Ischemia
• Renal abnormalities including hematuria and/or proteinuria.
• Platelet count markedly reduced often below 20,000/µL (thrombocytopenia).
• Peripheral blood smear shows fragmented red cells (called schistocytes) and numerous reticulocytes.
• PT, PTT, and fibrinogen concentration: Normal, because the coagulation system is not activated.
• Urine shows moderate proteinuria and both gross and microscopic hematuria.
• Serum LDH: Raised due to release from ischemic tissues.
• ADAMTS-13 activity: Reduced below 5–10% of normal.

Thrombotic Thrombocytopenic Purpura Diagnosis:

Schistocytes and elevated serum LDH (out of proportion to the degree of hemolysis) suggest the diagnosis of TTP.

Thrombotic Thrombocytopenic Purpura Treatment:

• Daily plasma exchange (removing 40 mL/kg body weight of plasma and replacing it with equal volume of fresh frozen plasma) is the treatment of choice.
• Provides ADAMTS-13 and removes associated autoantibody in acute TTP.
• Continued for at least 2 days after remission, which is defined as stabilization of clinical symptoms and return to normal of platelet count and LDH levels along with rising hemoglobin level.
• Cryoprecipitate and fresh frozen plasma (FFP) also contain ADAMTS-13 can be used.
• Corticosteroids: Pulsed intravenous methylprednisolone is given acutely and is generally added to plasma exchange to suppress formation of antibody.
• Rituximab: It is a monoclonal antibody against CD20, suppresses antibody-producing cells. It is used in those patients who are refractory to plasma exchange and corticosteroids.
• Splenectomy: Performed in resistant cases which remove antibody-producing cells.
• Platelet concentrates are contraindicated.

Prognosis: Untreated cases have a mortality of up to 90% but with modern management it has been reduced to about 10%.

Hemolytic-Uremic Syndrome:

Question 111. Discuss the clinical features, investigations, and treatment of hemolytic-uremic syndrome (HUS). Answer:

Hemolytic-uremic syndrome is distinguished from TTP by the absence of fever and neurological symptoms, the prominence of acute renal failure (uremia), frequent affection of children, and different pathogenesis.

Hemolytic-Uremic Syndrome Etiology and Pathogenesis:

• HUS develops following damage to the endothelium by toxins, drugs or radiation. One main cause of HUS in children and the elderly is infectious gastroenteritis caused by Escherichia coli strain 0157:H7.
• E. coli produces a Shiga-like toxin which is absorbed from the inflamed gastrointestinal mucosa.
• The toxin enters circulation and damages endothelial cells of microvasculature, mainly in the renal glomerular capillaries and initiates platelet activation and thrombi formation.
• Pneumococcus associated HUS-streptococcal neuramidase exposes a novel antigen [Thomsen-Freidenreich (T) antigen] on RBCs/platelets/glomeruli
• Non-STEC, non-pneumococcal
• Factor H, factor I, factor B
• MCP (CD46) expression on PBMCs
• Factor H autoantibodies
• Direct exon sequencing of CFH, MCP, CFI, CFB, C3
• Copy number variation across CFH-CFHR locus
• Red cells get trapped in the formed thrombi, undergo fragmentation resulting in schistocytes.
• Splenic trapping of the fragmented red cells causes extravascular hemolysis.

Differences between thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are presented on Table:

Hemolytic-Uremic Syndrome Clinical Features:

Age: HUS develops most commonly in children between 1 and 5 years of age few days after an episode of bloody diarrhea. HUS can also develop in adults following certain drugs and radiation therapy that damage endothelial cells.

Classical presentation: Triad of microangiopathic hemolytic anemia, thrombocytopenia and renal failure (oliguria).

Hematuria and hypertension are also common. Despite thrombocytopenia, bleeding manifestations are rare.

Complications: Fluid overload may result in pulmonary edema and hypertensive encephalopathy.

Hemolytic-Uremic Syndrome Investigations:

• Hemoglobin levels: Decreased (anemia).
• Platelet count: Markedly reduced often below 20,000/µL (thrombocytopenia).
• LDH: Elevated.
• Blood urea and creatinine: Elevated.
• Urine: May show proteinuria and red blood cells.
• PT and aPTT: Normal
• Stool: Culture for enterohemorrhagic E. coli—positive; shiga toxin—positive.

Hemolytic-Uremic Syndrome Treatment:

• Supportive care: For the renal and hematological complications.
• Antibiotics: If shigellosis is suspected/ detected.
• Experimental: Eculizumab, monoclonal antibody to C5.

Hemolytic-Uremic Syndrome Prognosis:

With appropriate supportive care, they usually recover completely, but in more severe cases renal damage may result in death.

Disseminated Intravascular Coagulation:

Question 112. Discuss the causes, pathogenesis, clinical features, laboratory features, and management of disseminated intravascular coagulation (DIC: defibrination syndrome: consumption coagulopathy). Answer:

Disseminated intravascular coagulation is a widespread acute or chronic thrombohemorrhagic disorder in which a combination of thrombosis and hemorrhage develops as a secondary complication of a wide variety of disorders.

• DIC is a serious, often fatal, important clinical condition which needs an immediate diagnosis and management. The symptoms of DIC depend on the nature, intensity and duration of the underlying disorder.
• Signs and symptoms are related to the tissue hypoxia and infarction caused by the microvascular thrombosis; or with bleeding diathesis due to the depletion of factors and the activation of fibrinolytic mechanisms; or both.
• Bleeding is the most common clinical feature in acute DIC. It may manifest as ecchymoses, petechiae, or bleeding from mucous membranes or at the sites of venipuncture.
• Microvascular thrombi cause ischemic necrosis of the organ with resultant dysfunction of the involved organ and occur most often with chronic underlying diseases. Organ dysfunction may manifest as hepatic, renal, cardiac, or respiratory failure or neurological disturbances. It may also result in gangrene of extremities and hemorrhagic necrosis of the skin.

• Waterhouse-Friderichsen syndrome: Occult thrombosis of adrenal vein thrombosis resulting in adrenal hemorrhage.
• Trousseau sign: Migratory venous thrombosis in cancers.
• Multiorgan dysfunction syndrome (MODS): Frequent consequence of DIC and is usually due to bleeding into organs or thrombotic alteration in various organs (hepatic, cardiac, central nervous, renal, and pulmonary systems).

Laboratory Findings (Investigations) in DIC:

Question 113. Write short note on investigations to diagnose DIC. Answer:

• Peripheral smear: Presence of schistocytes.
• Platelet count: Decreased because of utilization of platelets in microthrombi.
• PT: Increased.
• APTT: Increased because of consumption and inhibition of the function of clotting factors.
• Thrombin time (TT): Increased because of decreased fibrinogen.
• Plasma fibrinogen: Decreased.
• Presence of schistocytes (fragmented RBCs) in the peripheral smear.
• FDP (fibrin degradation/split products): Secondary fibrinolysis results in generation of FDPs, which can be measured by latex agglutination.
• D-dimer test: D-dimer is formed during fibrinolysis as a result of degradation of cross-linked fibrin by plasmin.
• D-dimer levels are elevated and are specific for diagnosing DIC.
• Scoring system for DIC
• International Society of Thrombosis and Hemostasis DIC score has been shown in Table

Question 114. Write short note on management of DIC. Answer:

DIC Management:

• Control or elimination of the underlying cause (e.g., removal of a dead fetus, placenta, etc.).
• Correction of precipitating factors, e.g., acidosis, dehydration, sepsis and hypoxia.
• Platelet concentrates: 1–2 units/10 kg.
• Fresh frozen plasma: 15–20 mL/kg.
• Cryoprecipitate: 1 unit/10 kg.
• Purpura fulminans during the surgical resection of giant hemangiomas and during removal of a dead fetus.
• Acute promyelocytic leukemia.
• Antifibrinolytic drugs: For example, EACA, or tranexamic acid prevent fibrin degradation by plasmin may reduce bleeding episodes.
• However, they increase the risk of thrombosis and concomitant use of heparin is indicated.
• Antithrombin III, protein C concentrate, TFPI have been tried

Transfusion Medicine:

Question 115. Discuss blood transfusion, blood component transfusion, and indications for transfusion therapy. Answer:

Transfusion medicine comprises of blood and blood component/products transfusion. Blood cannot be synthesized artificially. So the source of blood is from a healthy human donor.

Whole Blood:

• One unit of blood collected from a donor contains 450 mL ± 10% of blood and citrate anticoagulant that also contains phosphate and dextrose.
• Whole blood provides both oxygen-carrying capacity and volume expansion. However, it is rarely used because within a few hours or days, some coagulation factors (especially factors V and VIII) and platelets decrease in quantity or lose viability.

Red Cell Concentrates (Packed Red Cells):

• Packed red cells are obtained by centrifugation/sedimentation of the whole blood. All the plasma is removed and is replaced by about 100 mL of an optimal additive solution, such as SAG-M, which contains sodium chloride, adenine, glucose, and mannitol.
• In the packed red cell unit, the hematocrit is between 55% and 65%. Since, the volume is about 330 mL; there is less risk of volume overload.
• One unit of packed red blood cells raises hemoglobin concentration by 1 g/dL.

General indications for RBC transfusion:

• Replace acute blood loss due to hemorrhage or during surgery to relieve clinical features caused by insufficient oxygen delivery
• β-thalassemia major
• Sickle cell anemia
• Severe anemia of any cause

Platelet Concentrate:

• Platelet concentrate may be obtained from a single donor or pooled plasma. Platelets can also be obtained from a single donor by platelet apheresis SDP-single donor platelets.
• Platelets have ABO antigens on their surface but do not express Rh antigen. Hence, ABO matching required. But it is advisable to transfuse Rh negative persons with platelets only from Rh negative persons. One platelet concentrate (PC) should increase the platelet count by 5,000–10,000/µL. Six units of pooled platelets or one apheresis unit should increase the platelet count by approximately 30,000/μL.

Indications for platelet concentrate transfusion:

Bleeding due to:

• Immune mediated: In patients with autoimmune thrombocytopenia, it should be reserved for patients with life-threatening bleeding.
• Chemotherapy induced
• Due to leukemia
• Abnormal platelet function
• Disseminated intravascular coagulation (DIC)
• Surgical or invasive procedures in thrombocytopenic patients

Granulocyte Concentrates:

• Indications: Severe neutropenia with definite evidence of bacterial infection.
• It is not frequently employed, because it is preferable to administer the growth factors for myelopoiesis like G-CSF/GM-CSF. But it is indicated when granulocyte count is less than 500/mm 3 (agranulocytosis), and to combat infections (in neonatal sepsis and chronic granulomatous disease).

Fresh Frozen Plasma:

• The volume is about 200 mL and contains all the coagulation factors (including vWF). Present in fresh plasma. The volume transfused depends on the clinical situation and patient size, and should be guided by laboratory assays of coagulation function. The general guide is 10–15 mL/kg per dose.
• ABO matching is essential before infusion of FFP. Rh compatibility is not required
• Heparin-induced thrombocytopenia (HIT).
• Relative contraindication: Idiopathic thrombocytopenic purpura (ITP) or post-transfusion purpura (PTP) because the survival of transfused platelets is very brief.
• Patients on anticoagulant drug therapy (Coumarin)
• Antithrombin deficiency
• Coagulopathy of liver diseases
• Vitamin K deficiency
• Microangiopathic hemolytic anemia including TTP, hemolytic uremic syndrome, and HELLP syndrome

Cryoprecipitate:

• Contains concentrated precipitate of factor VIII, XIII, vWF, and fibrinogen.
• Does not require cross-matching before transfusion.
• DIC and other conditions where the fibrinogen level is very low (hypofibrinogenemia).
• It was used for hemophilia, factor XIII deficiency, and von Willebrand disease. However, it is no longer used for these disorders because of the greater risk of virus transmission compared with virus-inactivated coagulation factor concentrates.
• Various coagulations factors and their amount in one unit of cryoprecipitate are mentioned in Table

Factor VIII and IX Concentrates:

• These are freeze-dried preparations of specific coagulation factors prepared from large pools of plasma from many donors.
• Indications: For patients with hemophilia and von Willebrand’s disease, where recombinant coagulation factor concentrates are unavailable.

Saline-washed Red Blood Cells:

Saline washing of red cells is an effective means of removing leukocytes and plasma (up to 99%). This product is largely restricted to patients with antibodies to IgA or IgE, and those requiring red cells with minimal plasma as in thalassemia and paroxysmal nocturnal hemoglobinuria.

Frozen Red Blood Cells:

Red blood cells can be freezed and stored up to 3 years by addition of glycerol as an endocellular cryoprotective agent. This procedure is used for storage of rare blood groups. Frozen red cells may be indicated for patients with history of severe allergic reactions to plasma or leukocyte factors, e.g., patients sensitized to IgA.

Irradiated Blood Products:

Cellular blood products (red cells, platelets, granulocytes) can be irradiated to a dose of 1,500 rads before transfusion in order to minimize the risk of transfusion-acquired graft-versus-host disease in immunocompromised individuals.

Immunoglobulins:

Rh Immune Globulin:

• Known or suspected inoculation of Rhmother with unknown or Rh+ fetal red cells, e.g., abortion, threatened abortion, ectopic pregnancy, amniocentesis, abdominal trauma in 2nd or 3rd trimester, postpartum if new born is Rh+.
• Following transfusion of Rh+ cellular blood products (e.g., platelets) to an Rhfemale of child bearing age or younger.
• Acute ITP resistant to steroids.

Safe Transfusion Procedures:

Question 116. Write short note on precautions to be observed in blood transfusion. Answer:

Pretransfusion Testing:

Before transfusion of any blood or its components, it is necessary to know whether they are compatible with the recipient’s blood.

• Donor blood: The tests routinely carried out on donor’s blood include ABO and Rh grouping, tests for HBsAg, anti-HCV, anti-HIV-1 and HIV-2 and serum alanine aminotransferase (ALT), malaria, and syphilis.
• Recipient blood: The recipient’s ABO and Rh grouping is also carried out.

Compatibility Testing:

These are set of procedures which include: Review of patient’s past blood bank history and records (if done earlier), ABO and Rh typing of the recipient and donor, antibody screening test of recipient’s and donor’s serum followed by cross-matching. It is sometimes referred to as cross-matching. However, cross-match is only a part of compatibility test.

Cross-matching: Cross-matching is very important before any blood transfusion. Cross-matching should be carried out to ensure that there are no antibodies in patient’s serum that will react with the donor’s cells when transfused. Full cross-matching requires about 45 minutes if no red cell antibodies are present, but may need hours if a patient has multiple antibodies.

• It is the final check of ABO compatibility between donor and recipient.
• Detects the presence of any clinically significant, unexpected antibodies in the recipient’s serum that may react with donor’s cells, thereby preventing any transfusion reaction.
• Types: Cross-matching procedure may involve major and minor cross-matching. Major cross-matching consists of mixing donor’s red cells with recipient’s (patient’s) serum; whereas minor cross-matching consists of mixing patient’s red cells with donor’s serum.

Bedside Procedures for Safe Transfusion:

• An error of patients receiving the wrong blood is important avoidable cause of mortality and morbidity in transfusion medicine.
• Most incompatible transfusions are due to failure to adhere to standard procedures for taking correctly labeled blood samples and ensuring that the correct pack of blood component is transfused into the intended recipient.
• It is always necessary to monitor the recipient during and after transfusion so that any complications can be dealt with accordingly.

Complications Of Blood Transfusion:

Question 117. Write short essay/note on the complications of blood transfusion. Answer:

Complications of blood transfusion have been shown in Table:

Immunological Complications/Reactions:

Acute Hemolytic Transfusion Reaction:

• Most serious complication of blood transfusion.
• Cause: Occurs due to transfusion of incompatible donor red cells resulting in destruction of donor cells. Usually due to ABO incompatibility.
• Clinical features:
• The initial symptoms may occur within few minutes after starting the transfusion. Patient typically develops fever with chills, pain in the lumbar region, dyspnea, pruritus, burning sensation at the site of transfusion and centrally along the vein, and chest pain.
• In an unconscious patient, more severe features like hypotension, shock, intravascular hemolysis which results in hemoglobinuria and oliguria with acute renal failure and excessive bleeding due to DIC may develop.

Blood Transfusion Diagnosis:

In majority of cases, this results from clerical errors like wrong labeling of the cross-match sample, improper checking or transfusion to the wrong recipient, confirmed by finding evidence of hemolysis (e.g., hemoglobinuria), and incompatibility between donor and recipient.

Blood Transfusion Management:

• Stop the transfusion immediately if there is any suspicion of serious transfusion reaction.
• Change the blood transfusion set and maintain the venous access using normal saline.
• Perform physical examination such as blood pressure, urine output and evidence of bleeding. Emergency treatment may be needed to maintain the blood pressure and renal function.
• Withdraw new blood samples from the opposite arm of the patient and send it to the blood transfusion laboratory along with the donor units to exclude a hemolytic transfusion reaction.
• Centrifuge one more blood sample from the recipient of transfusion and look for any free hemoglobin in the supernatant.
• Perform coagulation screening tests including partial thromboplastin time, platelet count, fibrinogen levels and fibrin-degradation products to exclude DIC. Laboratory evaluation for hemolysis includes the measurement of serum haptoglobin, lactate dehydrogenase (LDH) and indirect bilirubin levels.
• If hypotension develops, administer intravenous fluids and if required, vasopressors.
• Administer diuretic furosemide to maintain urine output.

Febrile Nonhemolytic Transfusion Reactions (FNHTR):

• Common complication of blood transfusion.
• Cause: Usually develop due to presence of leukocyte antibodies in patients who have previously been transfused or pregnant. Can also occur due to release of cytokines from donor leukocytes in platelet concentrates.
• Time of occurrence: Usually occur toward the end of infusion or within hours of completing the transfusion.
• Typical signs: Flushing and tachycardia, fever (>38°C), chills, and rigors.

Allergic Reactions—Urticaria:

• Common but rarely severe.
• Cause: Urticarial reactions are mostly result from plasma-protein incompatibility due to the presence of antibodies in the recipient’s blood to infused plasma proteins or infusion of allergens that react with IgE antibodies in the patient.

Blood Transfusion Treatment: Stop or slow the transfusion and administer 10 mg of chlorphenaramine (chlorpheniramine) intravenously.

Anaphylactic Reactions:

• These are severe reactions which develop after transfusion of only a few milliliters of the blood component.
• Severe reactions are seen in patients who have antibodies against IgA and are often deficient in IgA. The antibodies react with IgA present in the donor blood.
• Symptoms and signs: Difficulty in breathing, coughing, nausea and vomiting, hypotension, bronchospasm, loss of consciousness, respiratory arrest, and shock.
• Treatment: Stop transfusion and maintain vascular access. Immediately administer 0.5 mg epinephrine (adrenaline) IM, and 10 mg chlorpheniramine, IV glucocorticoids, and endotracheal intubation may be required in severe cases.

Transfusion Related Acute Lung Injury (TRALI):

• Cause: TRALI usually develops from the transfusion of donor plasma that contains high-titer anti-HLA antibodies that bind recipient leukocytes. This produces aggregation of leukocytes in the pulmonary vasculature and release mediators that increase capillary permeability. Such antibodies are most frequently found in females after pregnancy and are not found in plasma of males unless they have been transfused.
• Patient develops an acute respiratory distress, either during or within 6 hours of transfusing the patient. It is characterized by fever, cough, shortness of breath, and typical bilateral interstitial infiltrates on chest X-ray. The reaction occurs during or soon after transfusion and may be life-threatening.

Blood Transfusion Treatment: Supportive and patients usually recover without any sequelae.

Delayed Hemolytic Transfusion Reactions (DHTRs):

• These are not completely preventable.
• May occur in patients previously sensitized to RBC alloantigens (such as Rh, Kidd, Kell, Duffy) by previous transfusions or pregnancies.
• The antibody level is too low to be detected by pretransfusion compatibility testing.
• When the patient is transfused with antigen-positive blood, there is early production of alloantibody (usually by IgG antibodies) that binds donor RBCs, resulting in destruction of the transfused donor cells.
• Occurs 3–21 days after transfusion with the incompatible blood.
• Direct Coombs’ test (DAT): Positive, if carried out during hemolysis. Later, patient may show only positive indirect Coombs’ test.

Blood Transfusion Treatment: Usually no specific therapy is required.

Transfusion–associated Graft-versus-Host Disease (TA-GVHD):

• Rare but potentially fatal complication.
• Develops 8–10 days, and death occurs at 3–4 weeks after transfusion.
• Mechanism: Donor blood products contain mature T lymphocytes that recognize host HLA antigens as foreign and mount an immune response and attack upon recipient’s tissues. It is observed more commonly in immunocompromised recipients.
• Clinical features include fever, generalized characteristic skin rash, jaundice (with abnormalities of liver function), diarrhea, and features of pancytopenia (due to marrow failure).
• Prevention: TA-GVHD can be prevented by transfusing the irradiated blood/components in patients at risk.
• It is highly resistant to treatment with immunosuppressive therapies, including glucocorticoids, cyclosporine, antithymocyte globulin, etc.

Post-transfusion Purpura:

• It is an immune-mediated thrombocytopenia that usually occurs predominantly in parous women.
• Antibodies against human platelet antigens (HPAs) are found in the patient’s serum.
• It occurs 7–10 days after platelet transfusion.
• Thrombocytopenia is usually severe and may cause bleeding.
• Platelet transfusions are usually ineffective and can worsen the thrombocytopenia and hence should be avoided.

Alloimmunization:

• Alloimmunization usually does not cause clinical problems with the first transfusion but these may occur with subsequent transfusions. Delayed consequences of alloimmunization, include HDN (hemolytic disease of the newborn) and rejection of tissue transplants.
• Detected during pretransfusion testing and may delay finding antigen-negative cross-match-compatible products for transfusion.
• Alloimmunization may develop during pregnancy to fetal RBC antigens (i.e., D, c, E, Kell, or Duffy) inherited from the father and not shared by the mother.
• Alloimmunization to antigens on leukocytes and platelets: It can lead to refractoriness to platelet transfusions.

Blood Transfusion Treatment: Treatment with high-dose (0.4 g/kg/day for 5 days). Intravenous immunoglobulin may neutralize the effector antibodies, or plasmapheresis can be used to remove the antibodies.

Nonimmune Complications/Reactions:

Question 118. Write short note on infections transmitted by blood transfusion. Answer:

• Circulatory overload: Significant in the elderly, pregnant women, those with reduced cardiac function (e.g., cardiac failure) or renal failure resulting in acute pulmonary edema.
• Air embolism: It used to develop in olden days when transfusion was given from the glass bottle.
• This is seen in patients who receive multiple transfusions over a period of few years (e.g., thalassemia). The excess iron gets deposited in reticuloendothelial cells of spleen, bone marrow, liver, heart and endocrine glands.
• Iron overload can be prevented or reduced by giving iron chelating agents
• Thrombophlebitis: Inflammation of vein may develop in patients with indwelling catheters.
• Infectious complications: Transfusion of infected blood may transmit few diseases like AIDS, hepatitis (HBV, HCV and HDV), HTLV-I and II, malaria, and cytomegalovirus infection. This is prevented by screening the donors for these common and ominous infections.

Massive transfusion is defined as transfusion of more than 10 units of red cells or replacement of 1 blood volume in 24 hours. The use of large quantities of stored blood in massive transfusions may lead to a number of complications. Among these are dilutional coagulopathy, circulatory overload, hyperkalemia, hypoglycemia, hypothermia, and rarely, citrateinduced hypocalcemia.

Blood Groups and Diseases:

• The first established disease relationship was between carcinoma of the stomach and group A.
• Duodenal ulcer is 1.4 times more common in group O patients.
• It is also reported that group A individuals have greater levels of factor VIII than group O, and hence greater complications of bleeding are seen in group O than A.
• A relationship between the Duffy (Fy) blood group and malaria is well established. It is seen in West Africa where the frequency of Fy a-b- is about 90%; these individuals are resistant to Plasmodium vivax. Experimentally, it has been shown that antigens Fya and Fyb act as receptors for the parasite to enter the cell.
• The Kell (K) group is associated with chronic granulomatous diseases and Rh null is implicated in autoimmune hemolytic anemia.

Stem Cells:

Question 119. Define and classify stem cells. Discuss their clinical applications. Answer:

Stem Cells Defiition:

Stem cells are characterized by their ability of self-renewal and capacity to generate differentiated cell lineages.

Stem Cells Properties:

• Self-renewal capacity
• One daughter cell which gives rise to differentiated mature cells and regenerating tissues
• Other remains undifferentiated stem cells which retain the self-renewal capacity.

Stem Cells Types:

• Embryonic stem cells: During development of embryo, the blastocysts contain undifferentiated pluripotent stem cells which are called as embryonic stem cells or ES cells. These cells can form cells of all three germ cell layers.
• Normal function: To give rise to all cells of the body.
• Normal function: Tissue homeostasis.
• Use: Adult stem cells include hematopoietic stem cells (HSC) in bone marrow, peripheral blood or cord blood. They are currently the only type of stem cells commonly used to treat human diseases.
• Use: For therapeutic cloning in the treatment of human diseases.

Clinical Application:

Some diseases in which marrow transplantation has been utilized are presented:

Diseases treated with marrow transplantation:

Other Applications:

• Useful in understanding the pathology of disease and origin of cancers.
• Monitor the development of genetic disorders.
• Test the efficacy of drugs.

Hematopoietic Stem Cell Transplantation:

Question 120. Write short essay/note on hematopoietic stem cells (HSC). (or) Write a short note on peripheral blood stem cell transplantation. (or) Write short essay/note on bone marrow transplantation and its indications. Answer:

• Bone marrow transplantation was the original term used to describe the collection and transplantation of hematopoietic stem cells.
• Hematopoietic stem cell transplantation is a preferred term, because the peripheral blood and umbilical cord blood are also used as sources of stem cells.
• Definition: Hematopoietic stem cell transplantation is defined as the process of collecting and infusing hematopoietic stem cells obtained from bone marrow (bone marrow transplantation) or peripheral blood (peripheral blood stem cell\ transplantation).
• Purpose of HSC transplantation: To repopulate or replace totally or partly recipient’s hematopoietic system. HSC are self-renewing cells which can repopulate all the cell lineages in the blood.
• Bone marrow: Obtained directly from bone marrow by multiple aspirations from the pelvic bones.
• Peripheral blood (peripheral blood stem cells).
• Umbilical cord blood.

Indications for Hematopoietic Stem Cell Transplantation:

Question 121. Write short essay/note on indications for bone marrow/stem cell transplantation. Answer:

Indications for hematopoietic stem cell transplantation:

Red blood cell disorders:

• Severe aplastic anemia
• Thalassemia major
• Fanconi anemia
• Sickle cell disease

WBC disorders:

• Acute lymphoblastic leukemia—relapse after initial chemotherapy induced remission
• Chronic myeloid leukemia, acute myeloid leukemia
• Myelodysplastic syndromes, myelofibrosis
• Lymphomas: HL, NHL

Solid tumors, e.g., germ cell tumors, neuroblastoma

Immunological disorders:

• Severe autoimmune disorders: Scleroderma, lupus erythematosus
• Immune deficiency syndromes

Categories/Types of Hematopoietic Cell Transplantation:

• Autologous (“from self ”): Stem cells obtained from the recipient (same person). The patient’s own HSCs are removed and stored in the vapor phase of liquid nitrogen until required. The source of stem cells may be bone marrow or from the blood. It does not require immunosuppression. However, there is no graft-versus-tumor effect and therefore, there is increased risk of disease relapse or progression compared to allogenic HSC transplantation.
• Allogeneic (“from different genes”): HSCs are obtained from a donor-either related (usually an HLA-identical sibling) or from a closely HLA-matched volunteer unrelated donor (VUD).
• Syngeneic (“from same genes”): HSCs are obtained from an identical twin.
• Main factor for a successful allogenic transplantation is finding of an HLA-matched donor, because it reduces the risk of graft rejection and graft-versus-host disease (GVHD).

Peripheral Blood Stem Cell Transplantation Defiition:

It is defined as transplantation of stem cells derived from the peripheral blood of a donor to a recipient (allogenic) or from the patient’s own blood (autologous).

Stem Cell Transplantation Steps:

• Hematopoietic stem cells are present in the peripheral blood but in very low concentration (<0.1% of all nucleated cells). To increase their numbers, hematopoietic growth factor (G-CSF or GM-CSF) is administered to the donor (for allogenic stem cell transplant) or to the patient during recovery from intensive chemotherapy (for autologous transplant).
• Stem cells are collected from the blood by apheresis and are infused in the recipient.
• Stem cells engraft in the recipient and is characterized by the recovery of neutrophil count to >500 mm3 for 3 consecutive days.
• Hematopoietic recovery is more rapid in peripheral hematopoietic stem cell transplantation when compared to bone marrow hematopoietic stem cell transplant.

Umbilical cord blood: It is a good source of HSC with no risk to either infant or mother. Possible contamination of cord blood with CMV and Epstein-Barr virus is also low due to poor transmission from placenta. However, the major disadvantage is that the number of HSCs that can be collected from cord blood is small and an adult might require multiple cord blood donors.

Origin and source of hematopoietic stem cells used for transplantation are presented. Comparison among bone marrow, peripheral blood and cord blood stem cells are presented in Table:

Origin and source of hematopoietic stem cells used for transplantation:

• Genotypically HLA-identical siblings
• Phenotypically HLA-identical or HLA-mismatched family members
• Unrelated volunteer donors
• Bone marrow
• Peripheral blood
• Combination of blood and marrow
• Umbilical cord blood

Conditioning Regimens:

• Necessary before HSC transplantation.
• Myeloablative regimens: Eliminates malignant cells in the marrow so that transfused HSC can populate the bone marrow and develop.
• Nonmyeloablative regimens: To induce immunosuppression in recipient so that engraftment of donor cells can take place. It is less toxic.
• Usually develop within 30 days and includes infections, nausea, vomiting, alopecia, mucositis and interstitial pneumonia.
• Veno-occlusive disease of liver characterized by jaundice, ascites, and tender hepatomegaly.
• Late complications: Infertility, ovarian failure, and secondary malignancies (AML and solid organ malignancies).

Autologous Stem Cell Transplant:

Marrow or peripheral stem cells are obtained from the patient before the high-dose therapy, frozen (cryopreserved) and then reinfused after the high-dose therapy to reconstitute marrow function.

Different steps of autologous stem cell transplantation:

• Harvesting: During harvesting, bone marrow and/or peripheral HSCs (identified as CD34+ by immunophenotyping) are collected.
• Processing of HSCs: The collected bone marrow or peripheral blood stem cells are suspended in dimethyl sulfoxide (prevents ice crystallization in the cells) and frozen in liquid nitrogen. The HSCs can survive in frozen state for at least 5 years.
• Conditioning: Before the autologous transplant, the patient is given a high-dose chemotherapy and/or radiation therapy, sometimes total body irradiation (TBI). This procedure is called conditioning, the purpose of which is to eradicate the recipient’s hematopoietic and immune system and also malignant tumor cells if any. Conditioning also makes physical space available for HSCs to engraft. In contrast to allogeneic transplantation, autologous transplantation does not require immunosuppression to prevent GVHD.

Stem cell transplant: The collected frozen bone marrow or peripheral HSCs are thawed and infused intravenously like a blood transfusion. These stem cells home from the peripheral circulation to the conditioned empty marrow space. Because of conditioning the patient is pancytopenic and requires critical care. The high-dose chemotherapy also causes breakdown of the normal mucosal barriers in the mouth and gut resulting in increased susceptibility to infections and painful ulcerations.

Post-transplant engraftment: During which the hematopoietic cells produce all the three formed elements of the blood.

Allogenic Bone Marrow Transplantation:

The HSCs are obtained from an HLA-matched or HLAmismatched family member (usually a sibling) or an unrelated donor.

Different steps of allogenic stem cell transplantation:

• Harvesting: During harvesting, collected bone marrow and/ or peripheral HSCs are mixed with mature WBCs, important being lymphocytes. Mature T lymphocytes are the principal effectors of cell-mediated immunity and both therapeutic benefit and toxicities of allogeneic HSC transplant are due to immunologic reactions between donor T-cells and recipient cells.
• Conditioning: This step is similar to autologous HSC transplant. Immunosuppression is to allow engraftment of the transplanted HSCs. The patient’s endogenous lymphocytes must be suppressed by immunosuppression so as to prevent GVHD.
• Stem cell transplant: The harvested HSCs are infused into the vein just like a blood transfusion. The stem cells travel and reside in the marrow and produce erythrocytes, granulocytes and platelets. This usually takes 3–4 weeks. Patient requires utmost care during this period similar to autologous transplant.
• Engraftment: Donor T lymphocytes help donor HSCs engraft. These T lymphocytes are mostly CD8+ and they destroy any remaining host immune cells which may reject the donor HSCs. Depletion of donor T lymphocytes before allogeneic HSC transplant significantly increases the risk of graft failure. But the greatest disadvantage due to the donor T lymphocytes is development of GVHD.

Complications of Hematopoietic Stem Cell Transplantation:

Autologous HSC transplants have fewer immunologic complications but have higher rates of relapse of the disease after transplant. Allogeneic HSC transplants have lower rates of relapse but have more immunologic complications, including GVHD, which can be fatal.

• First phase: Infections develop due to neutropenia and damage to gastrointestinal mucosal barrier induced by conditioning agents used during transplantation. Source of infection is from oral, skin and gastrointestinal flora.
• Second phase: It develops during GVHD where T-cell function gets impaired. Patients may develop opportunistic viral and fungal infections.
• Third phase: It occurs due to chronic GVHD where both B-cell and T-cell functions are impaired. Patients may develop bacterial as well as opportunistic viral and fungal infections.
• Organ toxicity: The other complications include damage to GI tract, liver, and lungs.
• Interst i tial pneumonitis: This is seen in 30–40% of patients and may be fatal in some. Toxicity of radiation and chemotherapy, GVHD and viral, and pneumocystis infections are responsible.
• Veno-occlusive disease: VOD results from injury to hepatocytes and endothelium in zone 3 of the liver acinus and obstruction of hepatic sinusoids and venules. The clinical manifestations include jaundice, ascites, and painful hepatomegaly. Tissue plasminogen activator has been used to treat VOD successfully. Severe VOD is often fatal.
• Acute GVHD: If GVHD occurs before 100 days, it is termed as acute GVHD. It often affects three primary target organs simultaneously, namely skin, gastrointestinal (GI) tract and liver. It causes exfoliative dermatitis, diarrhea, hepatitis and cholestasis. It develops due to production of cytokines by Th1 cells. HLA mismatch is one of the important risk factor for its development. Treatment includes methotrexate, cyclosporine, antithymocyte globulin, corticosteroids and monoclonal antibodies against T-cells.
• Chronic GVHD: Occurs after day 100 following transplantation and can affect the skin, GI tract, liver, eyes, lungs, and joints. GVHD is difficult to treat and in severe cases it is usually fatal. It develops due to cytokine production by Th2 cells. Treatment includes cyclosporine and corticosteroids.

• An immunocompetent graft (i.e., one containing T-cells)
• HLA mismatch (minor or major) between donor and recipient
• An immunosuppressed recipient who cannot mount an immune response to the graft

Drugs Used In Hematological Diseases:

Antiplatelet Drugs:

Question 122. Write short essay/note on antiplatelet drugs. Answer:

Cyclooxygenase Inhibitors:

• Aspirin is cheap, effective and most widely used antiplatelet agent.
• Mechanism of action: Aspirin inhibits platelet enzyme cyclooxygenase (COX-1 and COX-2) and prevents the synthesis of thromboxane AThis results in impairment of platelet secretion and aggregation.
• Duration of action: Effects of aspirin on platelet function develop within an hour and lasts for the whole life span of platelets (~7 days).
• Indications: Arthritis, secondary prevention of cardiovascular events (acute coronary syndromes, stable angina) in patients with coronary artery, cerebrovascular (transient ischemic attack), or peripheral vascular disease (intermittent claudication).
• Dose: Usual dose is 75–325 mg once daily.
• Side effects: Dyspepsia to erosive gastritis or peptic ulcers with bleeding and perforation.

Adenosine Diphosphate (ADP) Receptor Antagonists on Platelets (Thienopyridines):

• Thienopyridines are drugs that selectively inhibit ADP-induced platelet aggregation by irreversibly blocking P2Y12.
• Thienopyridines include ticlopidine, clopidogrel, and prasugrel.
• Indications: Reduces the risk of cardiovascular death, MI, and stroke in patients with atherosclerotic disease.
• Ticlopidine: 250 mg twice daily
• Clopidogrel: 75 mg once daily. Loading dose of 300 mg of clopidogrel is given when rapid ADP receptor blockade is needed such as patients undergoing coronary stenting.
• Prasugrel: A loading dose of 60 mg, prasugrel produces much more rapid, potent, and consistent inhibition of platelet function than clopidogrel loading dose. It is followed by a maintenance dose of 10 mg once daily.
• Ticlopidine: Gastrointestinal and hematologic (neutropenia, thrombocytopenia, and thrombotic thrombocytopenic purpura). These side effects usually occur within the first few months of starting treatment.
• Clopidogrel and prasugrel: Gastrointestinal and hematologic side effects are rare.

Adenosine Reuptake Inhibitors:

• Dipyridamole is a relatively weak antiplatelet agent.
• Inhibits phosphodiesterase and blocks the breakdown of cyclic AMP.
• Dose: 25–75 mg three to four times a day. Dipyridamole is more commonly used along with aspirin.
• Indications: Coronary artery disease, ischemic stroke or transient ischemic attack. Rarely used at present because of dose inconvenience and side effects.
• Due to vasodilatory effect, it can lower the blood pressure and must be used with caution in patients with coronary artery disease.
• Others: Gastrointestinal complaints, headache, dizziness and hypotension.

Glycoprotein IIb/IIIa Receptor Antagonists (Inhibitors):

• It includes three agents: Abciximab, eptifibatide, and tirofiban.
• Uses: Parenteral GPIIb/IIIa receptor antagonists are used in acute coronary syndromes, unstable angina and nonST-elevatin MI percutaneous coronary interventions.
• Side effects: Bleeding tendencies and thrombocytopenia. Eptifibatide may produce hypotension.

Anticoagulants:

Question 123. Classify anticoagulants. Write short essay/note on the commonly used anticoagulants. (or) Write short note on: Answer:

• Indication for anticoagulants
• Contraindication for anticoagulants.

Classifiation of Anticoagulants:

Classification of anticoagulants has been shown in Table:

Indications for Anticoagulant Therapy:

Question 124. Write short note on indications for long-term anticoagulation. Answer:

Indications for anticoagulant therapy have been shown in Table:

Contraindications for anticoagulant therapy:

• Bleeding disorders, heparininduced thrombocytopenia
• Severe hypertension, threatened abortion, hemorrhoids, peptic ulcers
• Subacute bacterial endocarditis, tuberculosis
• Ocular and neurosurgery, lumbar puncture
• Chronic alcoholics, cirrhosis, renal failure

Unfractionated heparin:

Question 125. Write short note on (unfractionated) heparin. Answer:

Mechanism of action: Heparin acts as anticoagulant by activating antithrombin (previously known as antithrombin III) thereby potentiating its action. The activated antithrombin inhibits clotting enzymes, particularly thrombin and factor Xa.

• Mode of administration: Heparin is given parenterally. It is usually administered SC or by continuous IV infusion.
• Continuous intravenous.
• Intermittent intravenous/subcutaneous.
• Total anticoagulation: Continuous intravenous maintenance using an infusion pump at a rate of 1,000 units/hour.
• Low-dose heparinization (e.g., prophylaxis of DVT): 5,000 units 12 hourly or 8 hourly subcutaneously.
• For prophylaxis: Fixed doses of 5,000 units SC two or three times daily.
• Duration of therapy: Variable, but usually ranges from 7 to 10 days.
• Monitoring: Heparin therapy is monitored using activated partial thromboplastin time (aPTT), which is maintained at 1.5 to 2 times the control value.
• Antidote of heparin: Protamine sulfate
• Complications of heparin therapy: Includes bleeding, heparin-induced thrombocytopenia (HIT), osteoporosis, and osteomalacia (in long-standing therapy). HIT is of two types:

Heparin-induced thrombocytopenia:

• HIT type 1: Benign form develops immediately and often resolves after heparin is discontinued and is probably due to direct plateletaggregation induced by heparin.
• HIT type 2: The heparin binds to platelet factor 4 (PF4) released from platelets and forms a complex (heparin/PF4 complex) in the circulation. The antibodies formed against these complexes activate platelets, promoting thrombosis even in the presence of marked thrombocytopenia. It develops 5–10 days after starting heparin therapy. Can occur with all types of heparin.

Treatment of HIT Type 2:

• Immediately stops all heparin administration.
• Start nonheparin anticoagulants, e.g., lepirudin—a recombinant hirudin, argatroban, danaparoid, fondaparinux and bivalirudin.
• Do not administer warfarin as it can produce gangrene of limb or necrosis of skin. Vitamin K is administered if HIT diagnosed after warfarin has already been started.
• Do not administer platelet transfusion even though there is severe thrombocytopenia.

Low-molecular weight heparins (LMWH):

• LMWH are biologically active forms of conventional heparin. The molecular weights ranging from 3,000 to 8,000 Daltons.
• Mode of action: They act as anticoagulant primarily by inhibiting activated factor X (Xa) rather than activated factor II (IIa).
• Can be administered subcutaneously once or twice/day.
• Pharmacokinetics is predictable and aPTT monitoring is not needed.
• Less immunogenic and less likely to produce thrombocytopenia.
• Many patients with DVT (deep vein thrombosis) can be treated on an outpatient basis.
• Disadvantage: Higher cost.
• Commonly available LMWH: Enoxaparin, dalteparin and tinzaparin.

Question 126. Write short essay/note on oral anticoagulants. Answer:

• Water-soluble vitamin K antagonist.
• Mode of action: Vitamin K is necessary for the synthesis of coagulation factors such as prothrombin (factor II) and factors VII, IX and X and also protein C and protein S. Warfarin type anticoagulants prevents the conversion of vitamin K to its active hydroquinone form and interferes with the synthesis of the above vitamin K-dependent coagulation factors.
• Monitoring: Warfarin therapy is monitored using the PT.
• Starting dose: Warfarin is started at a dose of 5 mg oral on the first day. Subsequent daily doses are adjusted according to PT (INR) which is maintained at 1.5–3 times the control value.
• Maintenance dose: Varies from 2.5 to 7.5 mg/day.
• Duration of therapy: Variable and may range from 3 months to lifelong.
• Side effects: These include bleeding and rarely skin necrosis.
• Antidotes of warfarin: Injections of vitamin K1, 5 mg intravenously or fresh frozen plasma or prothrombin complex concentrate.
• Severe uncontrolled hypertension
• Severe renal or liver failure
• Pre-existing hemostatic disorders
• Pregnancy: It crosses the placenta and can cause fetal abnormalities. Therefore, should not be used during pregnancy.

Reversing warfarin therapy:

Direct thrombin inhibitors:

• Source: Derived from a medicinal leach.
• Recombinant form of hirudin, e.g., lepirudin, bivalirudin, and desirudin.
• Mode of action: Acts directly on thrombin.
• Monitoring: By measuring aPTT.

Clinical indications and use of direct thrombin inhibitors is presented in Table:

Question 127. Discuss novel oral anticoagulants (NOAC s). Answer:

• Dabigatran being used for prophylaxis after hip and knee replacement. The major side effect of dabigatran is hemorrhage.
• Idarucizumab: Humanized monoclonal antibody fragment (Fab) indicated in patients treated with dabigatran when reversal of the anticoagulant effects is needed for emergency surgery or urgent procedures, or in the event of life-threatening or uncontrolled bleeding.
• Rivaroxaban and apixiban are orally administered drug, factor Xa inhibitor available orally administered direct, factor Xa inhibitor that produces its anticoagulant effect through reversible binding with the factor Xa molecule. Rivaroxaban can inhibit both free and thrombus associated factor Xa

Indirect factor Xa inhibitors:

• These include fondaparinux and idraparinux.
• Mode of action: Increases the rate of inactivation of factor Xa by antithrombin, thereby blocking production of thrombin.
• Use: HIT-type II.

Fibrinolytic or Thrombolytic Agents:

Question 128. Write short essay/note on fibrinolytic agents. (or) Write short essay/note on thrombolytics. Answer:

• Goal of therapy: To produce rapid dissolution of thrombus and restore the blood flow.
• Most fibrinolytic or thrombolytic agents are recombinant forms having plasminogen activator activity.
• Mechanism of action: They convert the proenzyme, plasminogen to active enzyme plasmin. Plasmin then degrades the fibrin of thrombi and produces soluble fibrin degradation products.
• Source: It is obtained fromb-hemolytic streptococci. It is not an enzyme and does not directly convert plasminogen to plasmin. Instead it forms a complex with plasminogen, it converts other/additional molecules of plasminogen into plasmin. Since it is obtained from bacteria, it can produce allergic reactions in about 5% of patients.
• Uses: In acute ST-elevation myocardial infarction and pulmonary embolism.
• Urokinase (UK): It is used in patients who received STK in the past 6 months and require a thrombolytic agent for MI or pulmonary embolism. It does not produce allergic reaction.
• Acylated plasminogen streptokinase activator complex (APSAC)(anistreplase).
• Recombinant tissue-type plasminogen activator (rtPA): Also known as alteplase or activase is useful in acute thrombotic strokes (within 3 hours of onset) besides acute MI and pulmonary embolism.
• Prourokinase (pro-UK) like rtPA.
• Others: Tenecteplase, desmoteplase and reteplase.
• Indications for use of fibrinolytic agents

Indication for use of fibrinolytic or thrombolytic agents:

• Acute myocardial infarction
• Massive pulmonary embolism with hypotension
• Acute ischemic stroke (thrombotic or embolic)
• Acute peripheral artery occlusion

Recombinant Human Erythropoietin (rHuEPO):

• It has same biological effects of endogenous erythropoietin and is available as erythropoietin-α and erythropoietin-b.
• Anemia associated with chronic renal failure.
• Anemia of chronic inflammation.
• Anemia (hemoglobin <10 g/dL) in cancer patients given chemotherapy.
• Zidovudine-induced anemia in HIV patients.
• Anemic patients undergoing nonvascular surgery to reduce the need for allogeneic blood transfusions.
• Side effects: Hypertension, bleeding, headache, arthralgia, nausea, edema, diarrhea, increased risk of thrombosis, pure red cell aplasia, and progression of cancers.

Darbepoietin Alpha:

• Produced by recombinant DNA technology in Chinese hamster ovary cells.
• Half-life about 3 times rHuEPO and hence needs to be given less frequently.
• Side-effects similar to rHuEPO.
• Not approved for the treatment of zidovudine-induced anemia and for blood loss during perioperative period.

Hemopoietic Growth Factors:

Question 129. Write short note on hematopoietic growth factors. Answer:

Erythropoietin:

Granulocyte Colony Stimulating Factor:

• To reduce chances of febrile neutropenia following chemotherapy: When the risk of febrile neutropenia is high (>20%) as determined by age, disease characteristics, and myelotoxicity of drugs used.
• Accelerate hemopoietic recovery after chemotherapy and autologous hemopoietic cell transplantation.
• Secondary prophylaxis: In patients with solid tumors with a previous history of the febrile neutropenia who require high-dose chemotherapy and any dose reduction may compromise treatment outcome.
• Patients with neutropenia and fever: It may be administered to those patients with high risk of infection-related complications, prolonged (>10 days), and severe neutropenia (<100/µL), hypotension, multiorgan dysfunction, or invasive fungal infections. It is not recommended in afebrile patients with neutropenia.
• Mobilizing stem cells from bone marrow: For stem cell transplantation. Both G-CSF and GM-CSF have been used.
• Disadvantage: Patients undergoing chemotherapy for breast carcinoma, if treated with G-CSF may develop acute myeloid leukemia or myelodysplastic syndrome. However, the benefit outweighs the possible risks.
• Dosage: 15 mg/kg daily by subcutaneous injection. Its pegylated form has a longer duration of action and requires to be given once a day.
• Adverse effects: Fever, bone, and joint pains.

Granulocyte-Macrophage Colony-stimulating Factor (GM-CSF):

Action: Increase in neutrophil, eosinophil, macrophage, and sometimes lymphocyte counts.

Dosage: Daily subcutaneous injection of 250 µg/m2.

Both G-CSF and GM-CSF have similar efficacy and indications (refer G-CSF above).

Thrombopoietin:

• Site of production: Liver and kidney and marrow stromal cells.
• Stimulates the survival, proliferation, and differentiation of megakaryocytes and their precursors.
• Primes mature platelets to aggregate in response to subthreshold levels of thrombin, collagen and ADP.
• In cancer patients receiving chemotherapy, it has been shown to reduce the duration of postchemotherapy thrombocytopenia.
• Thrombopoietin is undergoing clinical trials in patients with immune thrombocytopenic purpura.
• Disadvantage: Most patients produce antibodies against TPO and therefore, it is not recommended in treatment of any condition.

Question 130. Write short note on vitamin K. Answer:

• Vitamin K is a fat-soluble vitamin and requires bile for its absorption.
• Vitamin K is required by liver for the production of factors II, VII, IX and X, protein C, and protein S.

Vitamin K Treatment: Shows a dramatic response to parenteral vitamin K therapy. Vitamin K may not be effective in the presence of liver cell disease.

Dose: Daily 10 mg of injections of vitamin K.

Causes of Vitamin K Defiiency:

• Inadequate stores: As in hemorrhagic disease of the newborn (vitamin K levels are low and are due to lack of gut bacteria and low concentrations of the vitamin in breast milk) and severe malnutrition (especially when combined with antibiotic treatment).
• Defective absorption: Diseases that interfere with fat absorption, e.g., obstructive jaundice owing to the lack of intraluminal bile salts, pancreatic disease or small bowel disease.
• Oral anticoagulant drugs which are vitamin K antagonists (warfarin therapy).

Clinical manifestation: Deficiency manifests as bleeding/hemorrhagic state.

Bone Marrow Examination:

Question 131. Write short note on indications for and complications of bone marrow aspiration. Answer:

Bone marrow examination is essentially done to confirm or rule out a hematologic disorder. It also helps in evaluation of nonhematological disorders (e.g., metastasis).

Bone marrow may be obtained by:

• Aspiration: Bone marrow aspiration is a simple, easy, and safe procedure
• Trephine biopsy is indicated in conditions where the aspiration either fails to yield marrow or to confirm some of the diseases (where biopsy findings are diagnostic). Indications for bone marrow aspiration.

Contraindications for bone marrow aspiration: Hemophilia and congenital hemorrhagic disorders. Complications of bone marrow aspiration and biopsy

Sites for bone marrow aspiration:

• Usual sites for bone marrow aspiration are:
• Posterior superior iliac spine
• Iliac crest
• Anterior superior iliac spine
• Spinous process of lumbar vertebra

In infants, upper end of the tibia is the ideal site for marrow aspirate

Complications of bone marrow aspiration and biopsy:

• Local infection
• Cardiac tamponade or mediastinitis

The spleen is a hematopoietic organ capable of supporting elements of the erythroid, myeloid, megakaryocytic, lymphoid, and monocyte-macrophage (i.e., reticuloendothelial).

Splenomegaly:

Question 132. Write short essay/note on splenomegaly. Answer:

Splenomegaly Definition: The “gold-standard” definition of splenomegaly is splenic weight: The normal adult spleen weighs about 50–250 g.

The weight can only be established at splenectomy or postmortem examination. The clinical finding of a palpable spleen was considered as splenic enlargement, but up to 16% of palpable spleens have been found to be of normal size on radiological assessment.

On ultrasound examination, ‘‘craniocaudal length” is commonly used to measure splenic size. This correlates with splenic volume. However, the upper limit of normal size varies from 11 to 14 cm.

Mechanisms of Splenomegaly:

Many of the mechanisms represent exaggerated forms of normal function of spleen.

Functions of spleen:

• Clearance of microorganisms and particulate antigens from the blood
• Synthesis of immunoglobulin and properdin factors
• Destruction of senescent or abnormal RBCs
• Embryonic hematopoiesis, which can be reactivated as extramedullary
• Hematopoiesis in certain diseases (e.g., primary myelofibrosis)

Diseases Associated with Splenomegaly:

Diseases associated with splenomegaly have been shown in Table:

Causes of Asymptomatic Splenomegaly:

Causes of asymptomatic splenomegaly have been shown in Table:

Causes of Massively Enlarged Spleen:

Causes of massively enlarged spleen have been shown in Table:

Question 133. Write short essay/note on causes of massive splenomegaly. Answer:

A spleen is considered as massively enlarged when its lower pole is within the pelvis or which has crossed the midline into the right lower or right upper abdominal quadrants.

Indications for Splenectomy:

• Hematological: Isolated thrombocytopenia, immune thrombocytopenic purpura (ITP), hemolytic anemia, autoimmune hemolytic anemia, warm type (AIHA), hereditary spherocytosis, thalassemia major or intermedia, neutropenia, primary myelofibrosis
• Hairy cell leukemia, splenic marginal zone lymphoma, chronic lymphocytic leukemia
• Painfully enlarged spleen
• Traumatic or atraumatic splenic rupture, blunt abdominal trauma with splenic contusion or rupture
• Splenic artery aneurysm
• Primary treatment of an isolated splenic vascular or parenchymal lesion
• Splenic abscess, acute splenic torsion with infarction due (e.g., “wandering spleen syndrome”) splenic infarction
• Splenic vein thrombosis with bleeding esophageal varices
• Splenorenal shunting for portal hypertension

Hypersplenism:

Splenomegaly is often accompanied by hypersplenism. This is a complication of splenomegaly and not a diagnosis. The specific cause of the splenomegaly must be determined.

Classical features of hypersplenism:

• Splenomegaly
• Any combination of anemia, leukopenia, and/or thrombocytopenia
• Compensatory bone marrow hyperplasia
• Improvement after splenectomy

Causes of Splenic Rupture:

• Traumatic splenic rupture: Blunt abdominal trauma
• Atraumatic splenic rupture
• Neoplasm, e.g., leukemia, lymphoma
• Infection, e.g., infectious mononucleosis, CMV, HIV, endocarditis, malaria
• Inflammatory disease/noninfectious disorders, e.g., acute and chronic pancreatitis, primary amyloidosis
• Drug and treatment related, e.g., anticoagulation, G-CSF, thrombolytic therapy, dialysis
• Mechanical causes, e.g., pregnancy-related, congestive splenomegaly
• Idiopathic (normal spleen)

Disorders Of Heme Synthesis The Porphyrias:

• The porphyrias are caused by deficiencies of enzymes involved in heme synthesis, which lead to blockade of the porphyrin pathway and subsequent accumulation of porphyrins and their precursors.
• Cause: Most of the porphyria is due to partial enzyme deficiencies. These enzyme deficiencies may be inherited as autosomal dominant, autosomal recessive, or X-linked traits, with the exception of porphyria cutanea tarda (PCT), which usually is sporadic.

Classifiation:

Due to deficiency of an enzyme involved in the synthesis of heme, there is build-up of porphyrins and metabolites in various tissues. It is classified depending on site of overproduction and accumulation of porphyrin but overlapping features are common.

It may be classified as follows:

• Hepatic (in the liver)
• Erythropoietic (in the red cell).
• Based on the clinical manifestations as acute or cutaneous.

Structure of porphyrins: It consists of four pyrrole rings. Two molecules ofδALA condense to form a pyrrole ring. Depending on the structure of the side chain, porphyrins can be divided into uroporphyrins, coproporphyrins, or protoporphyrins. Intermediates accumulated and deficient enzymes in various porphyrias are depicted.

The three most common porphyrias are PCT, acute intermittent porphyria (AIP), and erythropoietic protoporphyria (EPP).

Two broad patterns of symptoms occur in the various types of porphyria:

• Cutaneous photosensitivity
• Acute neurovisceral syndrome.

Cutaneous Photosensitivity:

• These are due to excess production and accumulation of porphyrins in the skin and occur predominantly on areas of the skin that are exposed to sunlight.
• Due to accumulation of water soluble uro- and coproporphyrins leads to blistering.
• Due to accumulation of the lipophilic protoporphyrins leads to burning sensations in the exposed skin.

• They produce pain, erythema, bullae, skin erosions, hirsutism and hyperpigmentation. Skin also becomes sensitive to damage from minimal trauma.

Acute Neurovisceral Syndrome:

This presents with acute abdominal pain and features of autonomic dysfunction (e.g., tachycardia, hypertension, and constipation). Acute motor polyneuropathy may cause qaudriparesis mimicking GB syndrome. Neuropsychiatric manifestations include insomnia, anxiety, restlessness, agitation, hallucinations, hysteria, disorientation, delirium, apathy, depression, and phobias.

Triggering factors: Porphyria can relapse and remit or follow a prolonged and unremitting course. Sometimes, it may be triggered by alcohol, fasting, or drugs such as anticonvulsants, sulphonamides, estrogen, and progesterone.

• Diagnosis and classification depends on the pattern of the porphyrins and porphyrin precursors found in blood, urine, and stool. Urine gets colored on exposure to sunlight.
• Measurement of the deficient enzymes.
• Genetic testing

Prevention:

• Avoid sunlight (sun exposure) and skin trauma.
• Use of barrier sun creams containing zinc or titanium oxide and protective clothing.
• Oralb-carotene prevents formation of free radicals and provides effective protection against solar sensitivity.
• Afamelanotide, a synthetic analogue of alpha-melanocyte-stimulating hormone (α-MSH) is useful in EPP.

Management:

Neurovisceral:

Acute: The management of acute episodes is largely supportive.

• Analgesics to be given and avoid drugs that may aggravate an attack.
• Intravenous glucose inhibits ALA synthase activity leading to reduced ALA synthesis. In some cases, it can terminate acute attacks.
• Intravenous heme (in various forms such as human hematin or heme arginate) infusion reduces ALA and PBG excretion by having a negative effect on ALA synthase N activity. It relieves pain and accelerates recovery and decreases the duration of an attack and is useful in a severe attack.
• Maintain calorie and fluid intake.
• Cyclical acute attacks in females may respond to suppression of the menstrual cycle using gonadotropin-releasing hormone analogs.

Cutaneous Photosensitivity Episodes:

Acute attack:

• Treated symptomatically.
• Venesection (reduces urinary porphyria) can be used for PCT in both acute and remission phases. A prolonged course of low-dose chloroquine is effective as it helps in excretion by forming a water-soluble complex with uroporphyrins.
• Liver transplantation may be useful for severe cases.

Pseudoporphyria:

• In certain settings, patient develops blistering and skin fragility identical to PCT with the histological features but with normal urine and serum porphyrins. Hypertrichosis, dyspigmentation, and cutaneous sclerosis do not occur. This condition is called pseudoporphyria.
• Most commonly due to medications especially NSAIDs, usually naproxen other NSAIDs and tetracycline can cause similar picture.
• Some patients on hemodialysis develop a similar PCT-like picture.

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Anaemia – Exam questions and answers

Questions about anaemia

Common anaemia exam questions for doctors and medical students 

• Congenital or acquired
• Immune-mediated or non-immune mediated
• Intravascular or extravascular

What are the common causes of a microcytic anaemia?

• Overwhelmingly the most common is iron-deficiency
• Thalassaemia
• Sideroblastic anaemia
• Lead poisoning

What are the common causes of a macrocytic anaemia?

• B12 or folate deficiency
• Myelodysplastic syndrome
• Brisk bleeding or haemolysis
• Hypothyroidism and alcohol cause macrocytosis, but not typically anaemia

What are the common causes of normocytic anaemia?

• Renal failure
• Chronic inflammation
• Bone marrow failure

What proportion of the healthy population have a positive DAT?

• Approximately 5%, so a positive DAT is not evidence of haemolytic anaemia, in the absence of other findings such as a raised bilirubin, LDH and reticulocyte count.

Now click here for how to investigate and manage anaemia

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Essays on blood: why do we actually have it?

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Disclosure statement

David Irving is employed by the Australian Red Cross Blood Service and has research collaborations with others receiving NHMRC and ARC research grants. Australian governments fund the Australian Red Cross Blood Service for the provision of blood, blood products and services to the Australian community.

University of Technology Sydney provides funding as a founding partner of The Conversation AU.

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This week we’re running a series in collaboration with the Australian Red Cross Blood Service looking at blood: what it actually does, why we need it, and what happens when something goes wrong with the fluid that gives us life. Read other articles in the series here .

Just as a village can’t grow into a city without some form of transport (road, rail or river) that provides necessary interconnections for it to flourish, living things are limited in the size they can reach unless they have some form of circulatory system to transport nutrients and remove waste.

Single celled organisms such as bacteria and fungi, and some multicellular creatures such as sponges, corals and flatworms, simply absorb the nutrients they need and get rid of their waste using a passive process known as diffusion (which is much like soaking in and draining out).

More complex animals have developed some kind of circulatory system. A variety of different systems and pumps (hearts) have developed, but they all have a few things in common. These include something to carry oxygen around their bodies, a fluid of some sort, and some “plumbing” – in humans (and a number of other species) the fluid is called blood and the plumbing is our arteries, veins and capillaries. The oxygen carrier is haemoglobin.

Depending on the organism and where it has adapted to live, its oxygen carrier can come in different forms, often giving its “blood” different colours. Spiders, crustaceans, octopuses and squid use haemocyanin, which is based on copper and gives them blue blood. This carrier works well in low oxygen environments and in the cold.

Segmented worms and some leeches use an iron based carrier called chlorocruorin, which can appear either green or red, depending on its chemical environment. Vertebrates, including humans, use haemoglobin, which makes their blood red.

A truly special case is the Antarctic icefish , which lost its haemoglobin long ago as a result of a presumably random mutation. It has adapted though, and now survives by transporting oxygen that is simply dissolved in its blood. This is possible thanks to the cold conditions it lives in.

What is our blood made of?

Human blood, and that of all creatures with backbones (Antarctic ice fish excepted), is red. The colour comes from a chemical known as haem, which contains iron. It’s the iron that is the crucial ingredient for carrying oxygen. Oxygen is needed for our cells to burn sugars, fats and proteins in a controlled way. This provides us with the energy we need to live.

Outside our bodies, we know that when iron is exposed to oxygen, it rusts. And it doesn’t easily “unrust”. But to work as an oxygen carrier in our bodies, iron needs to “rust” and “unrust” on demand - picking up oxygen where it is in plentiful supply (our lungs), and releasing it where it is required (the cells in our organs).

This on/off oxygen switch is made possible with help from complex larger molecules. The first is haem, a flat ring structure that holds an iron atom at its centre. Haem is held closely by proteins known as globin, and this combination forms haemoglobin, which is itself packaged up in red blood cells to be transported around the body.

Infographic - From animal experiments to saving lives: a history of blood transfusions

The molecular structure of haemoglobin is delicately tuned to allow it to bind oxygen in the lungs and drop it off in areas where there is less oxygen available.

Red cells are specialised parcels, lacking DNA, that are able to squeeze through the tiniest capillaries, down to four millionths of a meter (equivalent to roughly half their diameter). Their donut shape maximises their surface area to make sure they can efficiently deliver oxygen, while keeping them small enough to fit through the smallest blood vessels.

More than just the red stuff

As well as red cells, our blood contains other cells and chemicals that repair and maintain the transport system and send signals around the body.

White blood cells, also known as leukocytes, repel or destroy invaders. Some white blood cells (lymphocytes) manufacture molecules known as antibodies that tag viruses and bacteria for destruction, while others called neutrophils and macrophages (literally “big eaters”) engulf bacteria, fungi and parasites to keep our circulation clean. When neutrophils have done their job you sometimes might see them as the main component of pus.

Platelets are very small fragments of larger cells called megakaryocytes. They react to any breaches to the walls of blood vessels, gathering together and triggering reactions that form a plug (or a clot) for the damaged section. If a person doesn’t have enough platelets, they can suffer from uncontrollable bleeding.

Where does it come from?

All blood cells (red cells, white cells and platelets) develop from haematopoietic (literally meaning “blood-making”) stem cells, located in the bone marrow. It has recently been found that many platelets are made in the lungs , from megakaryocytes that have migrated there from the bone marrow.

As stem cells develop, they progressively specialise into the many different types of blood cells, making developmental choices along the way. The specialisation of cells during development is tightly controlled by a symphony of growth factors. In some types of blood cancers and serious diseases, stem cell or bone marrow transplants can be used to “reboot” the blood making system.

As our knowledge of the control of blood cell development grows, we’re making progress towards being able to reproduce this process in cells grown in the laboratory . This is still some time away from being a broadly available process, but an exciting area to watch as it develops.

Update: the sentence outlining the shape of red blood cells was incorrect and has been reworded.

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11 Effective Tricks to Lower Your Blood Pressure Instantly

• How to Lower It

Weight Management

Get enough exercise, quit smoking, reduce alcohol and caffeine consumption, eat dark chocolate, try supplements, improve sleep, reduce stress.

• Take Medication
• Can Water Help?

When to Seek Medical Help for a Hypertensive Crisis

Frequently asked questions.

The best ways to lower blood pressure rely on long-term lifestyle changes, like adopting a healthy diet and quitting smoking, supported by blood pressure medication . This can help you to achieve a healthy blood pressure, which for most adults is 120/80 millimeters of mercury (mmHg) or lower.

A high blood pressure diagnosis begins with a systolic (first number) reading of 130 or more, or a diastolic pressure (second number) of 80 or more. Unfortunately, there is no quick way to lower blood pressure without medical intervention and careful monitoring .

This article presents 11 tricks to lowering blood pressure and long-term decisions you can make to integrate these steps into your lifestyle. They include tips on reducing sodium intake, losing weight, reducing stress, and other ways to help you reach your blood pressure goals.

Kinga Krzeminska / Getty Images

Change Your Diet

People with high blood pressure are often told to eat less salt. Reducing the sodium in your diet can be difficult because many foods that you don't think of as salty actually contain a lot of sodium. You'll have to adjust your diet and monitor food labels; a dietitian can help with this.

Follow a Heart-Healthy Diet

According to one systematic review, the Dietary Approaches to Stop Hypertension (DASH) diet is the most effective dietary approach to lowering blood pressure. This diet was created and funded by the National Institute of Health’s National Heart, Lung, and Blood Institute (NHLBI), and involves limiting sodium to 2,300 milligrams a day; limiting fried, sugary, fatty, and processed foods; and eating more foods that are rich in magnesium, calcium, and potassium.

Calcium-Rich Foods

Foods high in calcium include:

• Dairy products (milk, cheese, yogurt)
• Leafy greens (kale, spinach)
• Nuts and seeds
• Canned salmon

Potassium-Rich Foods

Potassium is a key nutrient, with food sources that include:

• Fruits (bananas, oranges, cantaloupe)
• Vegetables (acorn squash, sweet potato, avocado)
• Legumes (peas and beans)
• Dairy (yogurt, milk)

Magnesium-Rich Foods

You can add magnesium to the diet by eating:

• Peanut butter and nuts (almonds, cashews)
• Meats (chicken, ground beef)
• Vegetables (avocado, broccoli, carrots, potato)
• Legumes and whole grains (rice, black beans)

There's some evidence that foods high in flavonols , including berries and apples, also can help to lower your blood pressure. Other studies support the role of dietary fiber in reducing blood pressure, with food sources including:

• Fruits (cherries, pectin-rich citrus foods, and berries)
• Whole grains (barley, wheat, oats)
• Resistant starches (rice, beans and other legumes, potatoes)

If you are overweight and have high blood pressure, losing weight could help normalize your blood pressure. According to the CDC, this is because with less body fat, your heart will undergo less stress pumping blood throughout the body.

There is strong evidence to support regular exercise and physical activity as a way to lower blood pressure.

The AHA recommends adults get 150 minutes of moderate-intensity aerobic physical activity or 75 minutes of vigorous aerobic physical activity weekly. Two days of muscle-strengthening exercises per week is also recommended.

Some ways to get this exercise include:

• Water aerobics
• Walking or hiking
• Barre, Pilates, or yoga classes
• Weight lifting
• Resistance band exercises

Smoking increases your risk of high blood pressure, heart attack , and stroke. Quitting smoking could make a big difference in your blood pressure.

Even switching to a less harmful alternative, like e-cigarettes, could benefit blood pressure. One study found that smokers who reduced or quit smoking by switching to e-cigarettes effectively lowered their blood pressure long-term.

Alcohol can raise your blood pressure. Try to reduce your alcohol consumption, especially if you're already at risk or have high blood pressure. The CDC recommends that men drink no more than two alcoholic drinks daily, and women no more than one.

Unlike alcohol, which can raise your blood pressure long-term, caffeine increases your blood pressure temporarily. Your blood pressure can be elevated for up to three hours after drinking coffee.

In order to get the most accurate blood pressure reading, avoid drinking coffee (or any caffeinated beverages) three hours before measurement. The good news is you don't have to cut out coffee entirely.

A Word From Verywell

The lifestyle modifications listed in this article—especially a healthy diet, weight loss, regular exercise, not smoking, and limiting alcohol—will not only help to manage your blood pressure but can also help to prevent type 2 diabetes, a host of cardiovascular disorders, and cancer.

Dark chocolate may help to lower blood pressure because of its flavonol content, which can relax blood vessels through vasodilation and improve blood flow.

There is still limited research evidence of dark chocolate's benefits in reducing blood pressure in humans, as the effect may not have clinical significance. However, a 2022 review of 31 studies found dark chocolate consumption may be better than cocoa drinks in delivering the amount of flavonol (notably epicatechins ) that may reduce blood pressure.

Certain dietary supplements may help to lower blood pressure, though both the American Heart Association (AHA) and American College of Cardiology (ACC) stress the importance of lasting diet and nutrition changes rather than supplements in treating hypertension.

Studies have demonstrated small improvements in blood pressure that occur in people taking calcium , potassium , and magnesium supplements, but research results can be mixed. One review of studies on vitamin D, for example, found evidence that people with adequate vitamin D intake (deficiencies are common) had a lower risk of hypertension, but it, too, called for more study.

Other supplements and alternative medicine options that may lower blood pressure include:

• Vitamin C (which may also reduce the risk of stroke)
• Coenzyme Q10
• Omega-3 fatty acids
• Folic acid (vitamin B9)

Keep in mind that any supplements you take can have side effects or contribute to drug interactions, so discuss their use with a healthcare provider.

Getting poor-quality sleep can increase your risk of high blood pressure. The American Heart Association (AHA) recommends six to eight hours of sleep per night to avoid cardiovascular (heart) issues.

If you have trouble getting enough quality sleep, consider talking to your healthcare provider. They may recommend a sleep study to see if there are other underlying causes, like sleep apnea , or lifestyle changes to encourage better sleep habits.

A stressful situation can raise your blood pressure temporarily, and chronic stress can raise your blood pressure long term. This is why stress management is one of the best ways to naturally lower blood pressure. However, "stressing less" is easier said than done.

The following stress-reduction techniques may help you lower your blood pressure:

• Deep breathing techniques
• Mindfulness meditation and other mindfulness-based techniques
• Using a planner, calendar, or to-do list for better time management
• Therapy or counseling
• Crafting, walking, or another hobby or meaningful occupation

Take Medication 

Lifestyle steps typically are supported by medication to reduce blood pressure. If you have persistent high blood pressure, your healthcare provider may recommend a medication to lower your blood pressure.

The five types of medication used to lower blood pressure include:

• Thiazide diuretics
• Calcium channel blockers
• Angiotensin-converting enzyme (ACE) inhibitors
• Angiotensin receptor blockers (ARBs)
• Beta-blockers

It is essential to follow your healthcare provider's instructions with any medication. Often, you have to take blood pressure medication at the same time each day for the best results.

Can Drinking Water Lower Blood Pressure?

Drinking enough water provides us with the optimal amount of fluids for our heart to pump without stressing it. Too little water can cause your blood pressure to lower or rise.

Being dehydrated can cause low blood pressure or orthostatic hypotension (a drop in blood pressure when changing position) due to low blood volume. Chronic dehydration, on the other hand, can lead to high blood pressure because your body reacts by constricting vessels.

Drinking a glass of water likely isn't going to immediately affect your blood pressure. However, maintaining optimal hydration can help manage your blood pressure in the long term.

Additional Drinks That Lower Blood Pressure Quickly

Some beverages also can help to lower blood pressure because they contain lycopene, potassium, or other elements associated with a health benefit for hypertension. These drinks include:

• Tomato juice
• Grapefruit juice
• Green tea (the resveratrol can help lower blood pressure)

Keep in mind that you should not use grapefruit juice with a number of other medications , including calcium channel blockers used to treat blood pressure and statin drugs to lower cholesterol.

If a person is in hypertensive crisis (a dangerous, sudden spike in blood pressure in which the systolic pressure is 180 mmHg or higher, and/or the diastolic pressure is 120 mmHg or higher), they require immediate medical attention.

Medical treatment may involve delivering hypertensive drugs intravenously (into the vein).

There are many ways to lower blood pressure, but none is quick. Changes in diet, weight loss, exercise, medication, stress reduction, quitting smoking and alcohol, and improving sleep quality can all lower your blood pressure long term.

In the short term, be sure you are measuring your blood pressure correctly. Incorrect positioning, a full bladder, or physical activity immediately before a measurement can give an artificially high reading.

There is no way to safely and rapidly lower your blood pressure on your own. In an emergency medical setting, hypertensive drugs can be delivered intravenously to reduce blood pressure quickly. If you get a high blood pressure reading at home, try retaking it after resting for five minutes and ensure you are using the correct positioning.

Blood pressure is highest in the morning because it follows your body's circadian rhythm. Your blood pressure should be lower in the afternoon and evening.

Some ways to lower blood pressure without medication include mindful meditation, time and stress management techniques, eating less salt, regular exercise, the DASH diet, losing excess weight, quitting smoking, and reducing alcohol consumption. It is also important to ensure you are measuring your blood pressure correctly to avoid artificially high readings.

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American Heart Association. What is high blood pressure?

Valenzuela PL, Carrera-Bastos P, Gálvez BG, et al. Lifestyle interventions for the prevention and treatment of hypertension .  Nat Rev Cardiol . 2021;18(4):251-275. doi:10.1038/s41569-020-00437-9

National Institute of Health (NIH).  DASH eating plan .

Dietary Guidelines for Americans.  Food sources of calcium .

U.S. Department of Agriculture. Dietary Guidelines for Americans.  Food sources of potassium.

Office of Dietary Supplements.  Magnesium .

Ottaviani JI, Britten A, Lucarelli D, Luben R, Mulligan AA, Lentjes MA, et al .  Biomarker-estimated flavan-3-ol intake is associated with lower blood pressure in cross-sectional analysis in EPIC Norfolk .  Sci Rep . 2020 Oct 21;10(1):17964. doi:10.1038/s41598-020-74863-7

Khalid W, Arshad MS, Jabeen A, Muhammad Anjum F, Qaisrani TB, Suleria HAR. Fiber-enriched botanicals: A therapeutic tool against certain metabolic ailments . Food Sci Nutr . 2022 Aug 26;10(10):3203-3218. doi:10.1002/fsn3.2920. 

Centers for Disease Control and Prevention. Know your risk for high blood pressure .

American Heart Association. American heart association recommendations for physical activity in adults and kids .

Centers for Disease Control and Prevention. Prevent high blood pressure .

Farsalinos K, Cibella F, Caponnetto P, et al. Effect of continuous smoking reduction and abstinence on blood pressure and heart rate in smokers switching to electronic cigarettes .  Intern Emerg Med . 2016;11(1):85-94. doi:10.1007/s11739-015-1361-y

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By Sarah Bence, OTR/L Bence is an occupational therapist with a range of work experience in mental healthcare settings. She is living with celiac disease and endometriosis.