Hematology Board Review.

1. Hematology Board Review. Soham Puvvada.

2. Objectives: • Anemia: focus on Iron Deficiency Anemia. • Myeloproliferative disorders: focus on P.Vera. • Malignant Heme: focus on CLL. • Peripheral Smear Review.

3. Anemia: deficiency in oxygen carrying capacity of blood due to decreased erythrocyte mass. • General Categories: • Production deficiency. • Maturation Defects. • Survival Defects. • Sequestration. • Blood Loss.

4. Underproduction Anemias: • Kidney Disease:Normochromic, Normocytic with low retic count. Target hgb=11-12; epo dosing: 100-150u/kg/wk. For epo to be effective, Ferritin>100ng/ml and iron sat>=20%. • Anemia of Hypometabolic States: • Hypothyroidism, Addison Disease, Hypogonadism, Panhypopituitarism (low growth hormone) • Anemia from bone marrow damage: • Aplastic anemia: treated with ATG, cyclosporine. • PNH: chronic hemolytic anemia, iron def from urinary losses, venous thrombosis, pancytopenia. • Marrow infiltrative disorders.

5. Anemia of chronic disease: • Seen in inflm conditions or chronic infections. • Most common anemia in hospitalized patients. • Hgb typically 9-11g/dl range/ • Decreased retic count, decreased response to Epo. • Iron levels: normallow • Normochromic/normocytic->hypochromic/microcytic. • Impaired iron utilization despite normal to increased stores. • Iron replacement not usually necessary • Treat underlying condition.

6. Maturation Defects • Cytoplasmic: • Impaired hgb synthesis – iron deficiency • Protoporphyin deficiency – sideroblastic anemia • Globin synthesis deficiency - thalassemias • Nuclear: DNA synthesis defects – folate,b12 • B12 def: Serum methylmalonic acid and homocysteine become elevated before b12 levels fall below the normal range. • Folate def: RBC folate levels more reliable than serum folate; may be increased with concurrent b12 def, increased serum homocysteine, normal methymalonic acid. • B12 def must be ruled out in folate def patients because supplemental folate can improve the anemia of b12 deficiency but NOT the neurologic sequelae.

7. Iron Deficiency Anemia. Increased iron requirements: • Blood loss: menstruation, GI bleeding. • Intravascular hemolysis (PNH, hemolysis secondary to prosthetic valve) • Pregnancy, lactation Inadequate iron supply: • Poor nutrition • Absorbed in proximal small bowel: gastric bypass surgery, achlorhydria, celiac disease, IBD. • Most common cause of thrombocytosis in adults.

8. Comparison of Iron Deficiency and AOCD.

9. Treatment: • Reticulocytosis in 4-7 days • Increased hemoglobin in first several weeks (4-6 classically) • Anemia usually resolves in 4-6 months (depending on etiology of iron deficiency) • Continue oral replacement for several months after anemia has resolved to replete iron stores. • Oral Iron: treatment failure sec to non-compliance, treat constipation • Parental Iron: dextran: can give total dose replacement in single dose, rate of anaphylaxis 0.6%. • Ferrlecit® (Sodium Ferric Gluconate): Usually do not give as a single dose as total replacement can cause hypotension from excess of free iron

10. MKSAP QUESTIONS: • 64 y.o man is evaluated for worsening dyspnea and gradual increase in exercise tolerance over the past 2 months associated with COPD. He had an ACS event 2 years ago and his medications include daily aspirin, bronchodilators, inhaled corticosteroids, aspirin and statin. On exam, P=90, BP=130/90, R=20/min. Labs include Hgb =9.6g/dl(96 x109 L), and MCV=78fL. Stool is positive for occult blood. Iron deficiency anemia is diagnosed. Upper endoscopy reveals chronic gastritis and the daily aspirin is stopped.

11. Which of the following is the most appropriate treatment for this patient’s anemia? • A. Blood Transfusion • B. IV Iron • C. Oral Iron • D. Erythropoetin.

12. Answer: C=Oral Iron. Response to oral iron is fast-less than 1 week. in the ICU setting, liberal transfusion strategy was associated with a high overall mortality rate. the patient’s cardiac hx is not a reason to institute blood transfusion. No indication of renal disease, and therefore no reason to do epo

13. 78 y/o woman is evaluated for increasing forgetfulness. The problem has been slowly progressive over the past 7 months. She is able to live independently and has not had difficulties with ADL. The remainder of the hx and exam are non contributory. Hgb=7.8g/dl, WBC= 3800/ul, MCV=110, Plt=127,000. LDH=565, Dbili=0.3, Tbili=4.8, B12=325pg/ml, Folate=12ng/ml, Homocysteine=2.57 mg/l, Methylmalonic acid=400nmol/L

14. Which of the following is the most likely diagnosis? • A. Folate Deficiency • B. Vitamin B12 deficiency • C Autoimmune Hemolytic Anemia • D. Myelodysplasia

15. Answer=B: Vit b12 deficiency. • B12 def: increased methylmalonic acid and homocysteine concentrations • Folate def: elevated homocysteine concentration only, MMA nl. • Supp folate will reverse anemia-not help with neuropysch s/s-B12 replacement does not always reverse neurological findings but can prevent further deterioration of mental status.

16. Maturation Defects contd: thalassemia: target cells/hypochromic,microcytic. • Beta thal: • Trait-asymptomatic. • B thal intermedia: anemic, not transfusion dependent. • B thal major: cooley’s anemia: severe, growth retardation, iron overload. Hemoglobin electrophoresis: persistent elevation of hgbF, variable levels of hgbA2, and absent HgbA. • Alpha thal: • Silent carrier:1 gene absent -α/αα CBC normal • Trait: 2 genes absent-α/-α mild anemia. Electrophoresis is normal. Globin chain analysis • Hgb H disease: 3 genes absent --/-α: severe anemia, CHF • 4 genes absent: --/-- hydrops fetalis 30-40 wks gestation. .

17. Survival Defects: • Intrinsic (inherited defects) • Membrane cytoskeleton - spherocytosis, elliptocytosis • Metabolic enzymes – G6PD • Hemoglobinopathies – Sickle Cell • Extrinsic (acquired) • Antibody or complement mediated – Autoimmune hemolysis, malaria • Microangiopathy –DIC, vascular hemolysis

18. Warm Autoimmune Hemolytic Anemia • Most common type, occurs at 37°C • IgG mediated: Fc receptor mediated RBC destruction by splenic macrophages • ± complement mediated. •  retic count, microspherocytes on smear. • DAT positive. • May be caused by drugs. • Treatment: Steroids: prednisone 1mg/kg/day with taper-20% achieve remission. • Splenectomy if recurrent dz, or if steroids fail. • Also can use IVIG, Rituximab, Danazol.

19. Cold Agglutinin Disease • IgM ab recognize carbohydrate I-Ag system and cause complement fixation. • Temp below 37°C. • Intravascular hemolysis can result. • Smear shows RBC clumping and agglutination. • Therefore, spurious elevations in MCV/MCHC. • Does not respond to steroids or splenectomy • Usually anemia is mild, treat by maintaining warm envt. • If severe, alkylating agents/CD 20 ab

20. MKSAP Questions: • A 20 y/o woman is evaluated for excessive fatigue. The remainder of the history and physical exam are non contributory. Labs show Hgb of 10g/dl, MCV=60fL, RBC count=5.5 million cells/ul. The leukocyte, platelet counts and results of Hgb electrophoresis are normal. Peripheral smear is shown.

22. Which of the following is the most likely composition of her α gene alleles? • α/-, α/α • α/-, α/- • -/-, -/α • -/-, -/-

23. Answer: B-2 genes missing-α thal trait. • Choice A=alpha thal carrier • Choice C= Hgb H disease, 3 genes absent, severe anemia, CHF • Choice D=hydrops fetalis. • REMEMBER, in alpha thal trait-Hgb electrophoresis is normal.

24. 27 y/o woman with 2 year hx of SLE presents with new onset fatigue and shortness of breath for 10 days duration. Her meds include hydroxychloroquine and ibuprofen. Medical hx is otherwise non contributory. On exam, pulse=109/min, R=14/min, BP=130/80. Other than pale conjunctivae and pallor, exam normal. Hgb= 5.2 g/dl, compared with a normal value 3 months ago. Peripheral smear is notable for spherocytes, and polychromasia

25. Which of the following is the most appropriate initial treatment for the patient? • A. Oral Ferrous Sulfate • B. Corticosteroid therapy • C. Erythropoetin • D. Plasmapheresis.

26. Answer: B-corticosteroids. • The patient has warm AIHA. Polychromasia results from reticulocytosis. • First Rx-steroids. • IVIG and splenectomy are also treatment options. • Plasmapheresis is not used.

27. Anemia of Sequestration: hypersplenism usually from portal hypertension or splenic sequestration crises Anemia of Blood loss: self explanatory. when loss exceeds marrow production may result in a maturation defect (iron, b12, folate)

28. Myeloproliferative Disorders. • CML • Polycythemia Vera • Essential Thrombocythemia. • High risk of thrombosis. • Myelofibrosis with Myeloid Metaplasia • Extramedullary hematopoesis-hepatosplenomegaly/portal HTN. • “Dry tap” on bone marrow.

29. Polycythemia Vera. • Characterized by erythrocytosis. • Proliferative phase, spent phase, secondary AML • Proliferative : Pruritus, erythromelalgia, s/s of hyperviscosity, thrombosis (arterial or venous), hemorrhage, GI s/s. • Spent phase: anemia, leukopenia, myelofibrosis, hepatosplenomegaly. • Exam: may show dilated retinal veins as well as gouty arthritis.

30. Diagnosis: • First r/o causes of secondary erythrocytosis. • Lab findings: • Hgb/Hct • WBC in 45% • Plts in 65% • Basophilia (seen in all MPDs) •  Uric acid (can lead to gout) and B12 •  Leukocyte alkaline phosphatase score • Low epo levels • Positive JAK2 V617F

31. Revised WHO criteria for diagnosis: • Major: • Hgb>18.5 in men/16.5 in women. • Presence of JAK2 V617F. • Minor: • Epo. • Endogenous erythroid colony formation in vitro • BMBx showing hypercellularity with prominent erythroid and megakaryocytic proliferation.

32. Treatment: • Phlebotomy, goal HCt<45% • Low Dose aspirin to decrease risk of thrombosis. • Hydroxyurea. • Interferon Alpha.

33. MKSAP questions • 50 y/o man is evaluated for recent onset of pruritus while showering. He has previously been in excellent health, eats a normal diet, never smoked, does not take meds. On exam there are ruddy facies and a palpable spleen tip. FOBT is negative. O2 sat=99% RA. Labs show a Hgb of 61.0% compared with a value of 44.5% documented 5 years ago, WBC=11,000, MCV=79fL, platelet count= 550,000/ul. Chem nl except for  serum iron concentration and serum ferritin concentration. Results of upper and lower endoscopy nl.

34. Which of the following is the most appropriate management of this patient? • A. Phlebotomy and Anagrelide. • B. Oral iron supplementation and low dose aspirin. • C. Hydroxyurea and Aspirin, 325mg/day. • D. Phlebotomy and low-dose aspirin.

35. Answer :D-phlebotomy and low dose aspirin. • Pt has P.vera:  hct,  wbc count, plt count. • Phlebotomy with goal hct≤ 45%, low dose aspirin to prevent thrombotic complications. • If pt’s plt count≥ 600,000, hydroxyurea preferable since it would lower counts of all 3 cell lines. • Anagrelide used to lower plt count-more in ET.

36. CLL • CLL and SLL are malignant monoclonal accumulation of immunologically incompetent mature B-lymphocytes in blood (>5000/mm3), bone marrow, or lymph nodes • Characteristic phenotype: CD19,CD20, CD23+ B cells and also CD5+ (Tcell assoc antigen) • Smudge cells on peripheral smear - reflect fragility of cells

37. Presentation • Often asymptomatic, identified on routine CBC. • Lymphadenopathy(80%), Hepatosplenomegaly(50%). • AIHA, ITP. • Hypogammaglobulinemia, increased susceptibility to infections. • Bone marrow failure • 5% monoclonal gammopathy • 5% develop Richter’s transformation; into high grade lymphoma-usually DLBCL.

38. Diagnosis: • Smear: smudge cells. ALC in CBC>5000. • Bone Marrow: Normo to hypercellular bone marrow with lymphocytes accounting for >30% of all nucleated cells. • Flow: low levels of surface Ig. Expression of ≥1 B cell Antigen, + CD5. • 1 point for each of below, 4-5 points 97% accurate • Weakly positive surface immunoglobulin stain • CD5 + • CD23+ • CD79b or CD22 weakly + • FMC7 negative

39. Prognosis/Treatment: • CLL with somatic mutations of IgG heavy chain region has indolent course: median survival 25 years. • CLL without such mutations-with surrogate marker ZAP 70 =much worse prognosis, median survival 8 yrs. • Treatment options mirror those for Follicular lymphoma – indolent – very successful in inducing remission, but not cure

40. MKSAP question • 32 y/o woman is evaluated in ED for acute onset of fevers, chills nausea, and weakness. Two weeks ago, she presented to her physician for a symptomatic UTI and was treated with bactrim. After 5 days of Rx, she is unable to continue the medication because of nausea, vomitting. On exam, she is acutely ill, mottled, lethargic. Hr=140/min, BP=70/30 mmhg. An indwelling foley cath is inserted, 20 cc conc. Urine obtained and sent for culture.

41. Labs show a HCt of 38%, Leukocyte count of 200/ul, and platelet count=155,000/ul. In the ICU, she is given high volume IV fluids, and IV antibiotics. The peripheral blood smear shows no circulating blasts. Which of the following is the most appropriate next step in treatment?

42. A. Prednisone • B. Cytarabine and Anthracycline chemotherapy. • C. Granulocyte Colony –Stimulating factor. • D. IVIG.

43. Answer: C-GCSF. • Sorry, couldn’t find a good CLL question. • Severe neutropenia secondary to bactrim. • Her granulocyte count should recover in 10-12 days. • GCSF will shorten the recovery period and may help with the treatment of severe infection.

44. Peripheral Smear Review:

45. schistocytes

46. Burr cells

47. Spur cells

48. Target cells

49. Hypochromic microcytic anemia

50. Spherocytes