HIGH YIELD HEMATOLOGY

1. HIGH YIELD HEMATOLOGY pamancio'11

2. Disclaimer: Not meant to replace formal reading of subject material! pamancio'11

3. Iron deficiency anemia and other hypoproliferativeanemias pamancio'11

4. Iron Deficiency Anemia • Transferrin – iron transport protein • 120 days- average life span of RBC • 1ml RBC= 1mg elemental iron • Male: 1mg elemental iron daily • Female (childbearing years): 1.4mg/day • Proximal small intestine: iron absorption • Hepcidin - principal iron regulatory hormone pamancio'11

5. Iron Deficiency Anemia STAGES OF IRON DEFICIENCY Marrow Iron stores are absent when the serum ferritin <15 pamancio'11

6. Iron Deficiency Anemia Laboratory iron studies • Serum iron – amt of circulating iron bound to transferrin • TIBC – indirect measure of the circulating transferrin • Serum Ferritin – iron stores • Red cell protoporphyrin – elevated in Iron deficiency anemia and lead poisoning pamancio'11

7. Iron Deficiency Anemia pamancio'11

8. Iron Deficiency Anemia • Treatment • GI distress is the most common side effect • Reticulocyte count begin to increase within 4-7 days after initiation of therapy and peak at 1 1/2 weeks pamancio'11

9. Other Hypoproliferative Anemias pamancio'11

10. Disorders of hemoglobin pamancio'11

11. Hemoglobinopathies • Adult Hemoglobin: α2β2 • Bohr effect: ability of hemoglobin to deliver more oxygen to tisssues at low pH. • Developmental Biology • 6 wks: red cells first appear • 10-11 wks: fetal hemoglobin (α2γ2) • 38 wks: adult hemoglobin pamancio'11

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13. Sickle Cell Syndrome • Mutation in the β globin gene (α2β26GluVal) • Sickled cells lose the pliability needed to traverse small capillaries  rigid, adherent cells clog small capillaries and venules causing tissue ischemia, acute pain and gradual end-organ damage • Diagnosis: Hemoglobin electrophoresis • Management: hydroxyurea, BMT pamancio'11

14. Thalassemia Syndromes • Inherited disorders of α- or β- globin synthesis • TARGET CELL • β THALASSEMIA • Hypochromia and microcytosis characterize all forms • Massive bone marrow expansion: chipmunk facies due to maxillary marrow hyperplasia and frontal bossing pamancio'11

15. α THALASSEMIA pamancio'11

16. Diagnosis: Hemoglobin Electrophoresis • Management • Splenectomy is required if the annual transfusion requirement increases by 50% • Folic acid supplementation • Vaccination • Endocrine evaluation: glucose intolerance, thyroid dsyfunction, delayed secondary sexual characteristics pamancio'11

17. Transfusional Hemosiderosis • 1 unit PRBC = 250-300mg iron (1mg/mL) • Iron Chelating Agents • Desferoxamine • Deferasirox pamancio'11

18. Megaloblasticanemia pamancio'11

19. Megaloblastic Anemias • Characterized by the presence of distinctive morphologic appaearances of the developing red cells in the bone marrow • Cause: Cobalamin or Folate Deficiency pamancio'11

20. COBALAMIN • Cobalamin solely synthesized by microorganisms • Only source of cobalamin for humans is food of animal origin • ABSORPTION: • 2 mechanisms • Passive: • Active: occurs at the ileum cobalamin released by enzymes combines with Haptocorrin Ileum: Haptocorrin digested, cobalamin release and combines with IF Cobalamin-IF passes to ileum, IF attaches to cubulin endocytosis ***IF, produced by gastric parietal cells pamancio'11

21. FOLATE • ABSORPTION • Rapidly absorbed from the upper small intestine • Monoglutamates rapidly absorbed • All dietary folates are converted to 5-methylTHF within the small intestinal mucosa • Monoglutamates are actively transported across the enterocyte by a carrier-mediated mechanism • BIOCHEMICAL FUNCTION • Folates act as coenzymes in the transfer of single-carbon units ( 2 of these reactions are involved in purine and pyrrimidine synthesis necessary for DNA and RNA replication) • Folate is also a coenzyme for methionine synthesis, presursor of S-adenosylmethionine (SAM), the universal donor involved in >100 methyltransferase reactions pamancio'11

22. Megaloblastic Anemia • Clinical Features • MCV • Glossitis, angular cheilosis • General Tissue Effects • Epithelial Surfaces • Mouth, stomach, small intestine, urinary and female genital tracts • Pregnancy • Infertility • Neural tube defects • Cardiovascular • Hyperhomocystinemia  thrombosis • Malignancy • Prophylactic Folic acid in pregnancy has been found to reduce the subsequent incidence of ALL in childhood • Neurologic Manifestations • Cobalamin Deficiency may cause bilateral peripheral neuropathy or degeneration of the pyramidal tracts of the spinal cord (probably due to accumulation of S-Adenosylhomocysteine) • Psychiatric disturbance is common in folate and cobalamin deficiencies, attributed to failure of SAM synthesis, which is needed in methylation of biogenic amines (e.g. dopamine), neurotransmitters, phospholipids pamancio'11

23. Megaloblastic Anemia • Peripheral Blood: • Oval macrocytes • HYPERSEGMENTATION • Bone marrow: • Hypercellular • Accumulation of primitive cells • Erythrobalst nucleus maintains a primitive appearance despite cytoplasmic maturation • Ineffective Erythropoiesis • Elevated unconjugated bilirubin due to death of nucleated red cells in the marrow pamancio'11

24. Megaloblastic Anemia • COBALAMIN DEFICIENCY • Cobalamin deficiency is usually due to malabsorption pamancio'11

25. Megaloblastic Anemia pamancio'11

26. Megaloblastic Anemia • Treatment • Cobalamin Deficiency • Indications for starting treatment • Well-documented megaloblastic anemia • Neuropathy • Should be routinely given to all patients who had a total gastrectomy or ileal resection • Folic Deficiency • Oral doses of 5-15mg daily pamancio'11

27. Hemolyticanemias and anemia due to acute blood loss pamancio'11

28. Hemolysis mainly intravascular – HEMOGLOBINURIA • Main sign of BMA eythropoiesis response: retic ct pamancio'11

29. Inherited HemolyticAnemias • 3 essential components in the red cell • Hemoglobin • Membrane-Cytoskeleton • Hereditary Spherocytosis • Metabolic Machinery • PyruvateKinase Deficiency • G6PD pamancio'11

30. Acquired Hemolytic Anemias • Mechanical Destruction • Toxic Agents and Drugs • Infection • Autoimmune Hemolytic Anemia • Paroxysmal Nocturnal Hemoglobinuria pamancio'11

31. Inherited HemolyticAnemias • 3 essential components in the red cell • Hemoglobin • Membrane-Cytoskeleton • Hereditary Spherocytosis • Hereditary Elliptocytosis • Metabolic Machinery • PyruvateKinase Deficiency • G6PD pamancio'11

32. Membrane Cytoskeleton Complex • SPECTRIN – main cytoskeletal protein • HEREDITARY SPHEROCYTOSIS • Red cells were abormally susceptible to lysis in hypotonic media • OSMOTIC FRAGILITY – main diagnostic test • Autosomal dominant inheritance pattern • ONLY CONDITION in which HIGH MCHC is seen • Splenectomy pamancio'11

33. Membrane Cytoskeleton Complex • HEREDITARY ELLIPTOCYTOSIS • STOMATOCYTOSIS pamancio'11

34. Inherited HemolyticAnemias • 3 essential components in the red cell • Hemoglobin • Membrane-Cytoskeleton • Hereditary Spherocytosis • Hereditary Elliptocytosis • Metabolic Machinery • PyruvateKinase Deficiency • G6PD pamancio'11

35. ENZYME ABNORMALITIES • PYRUVATE KINASE DEFICIENCY • Newborn with neonatal jaundice; jaundice persists and is usually variable with a very high reticulocytosis • Mainly supportive in management pamancio'11

36. ENZYME ABNORMALITIES • GLUCOSEE 6-PHOSPHATE DEHYDROGENASE (G6PD) DEFICIENCY • G6PD – only source of reduced NADPH which directly and via reducd glutathione, defends RBCs against oxidative stress • X-linked • Acute HA can develop as a result of • Fava beans • Infections • drugs pamancio'11

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38. Typically, hemolytic attack starts with malaise, weakness, abdominal or lumbar pain- 2-3 days: jaundice, hemoglobinuria • Peripheral smear: hemighosts, bite cells or blister cells • Supravital staining: Heinz Bodies (consisting of precipitates of denatured hemoglobin) pamancio'11

39. Acquired Hemolytic Anemias • Mechanical Destruction • Toxic Agents and Drugs • Infection • Autoimmune Hemolytic Anemia • Paroxysmal Nocturnal Hemoglobinuria pamancio'11

40. Acquired Hemolytic Anemias • Mechanical Destruction • March Hemoglobinuria • Toxic Agents and Drugs • A drug can cause hemolysis through at least 2 mechanisms: • A drug can behave as hapten and induce antibody production • A drug can trigger, perhaps through mimicry, the production of an antibody against a red cell antigen pamancio'11

41. Acquired Hemolytic Anemias • Mechanical Destruction • Toxic Agents and Drugs • Infection • Malaria – most frequent infectious cause of HA in endemic areas • E. coli o157:H7 • Clostridium perfringens • Autoimmune Hemolytic Anemia • Paroxysmal Nocturnal Hemoglobinuria pamancio'11

42. Acquired Hemolytic Anemias • Mechanical Destruction • Toxic Agents and Drugs • Infection • Autoimmune Hemolytic Anemia • Paroxysmal Nocturnal Hemoglobinuria pamancio'11

43. AUTOIMMUNE HEMOLYTIC ANEMIA • Caused by an autoantibody directed against a red cell antigen. pamancio'11

44. AUTOIMMUNE HEMOLYTIC ANEMIA • Caused by an autoantibody directed against a red cell antigen; i.e., a molecule present on the red cell surface • The autoantibody binds to the red cells • In most cases, the Fc portion of the antibody will be recognized by the Fc receptor of macrophages, and this will trigger erythrophagocytosis. pamancio'11

45. AUTOIMMUNE HEMOLYTIC ANEMIA • COOMB’S TEST or DIRECT ANTIGLOBULIN TEST • PREDNISONE 1MG/KG pamancio'11

46. PAROXYSMAL COLD HEMOGLOBINURIA • Viral infection • Self-limited • Donath-Landsteiner antibody • COLD AGGLUTININ DISEASE • IgM antibody, usually anti-I specificity • Regarded as a form of Waldensrom macroglobulinemia;ie, as a low grade mature B cell lymphoma • Immunosuppressives pamancio'11

47. Acquired Hemolytic Anemias • Mechanical Destruction • Toxic Agents and Drugs • Infection • Autoimmune Hemolytic Anemia • Paroxysmal Nocturnal Hemoglobinuria pamancio'11

48. Paroxysmal Nocturnal Hemoglobinuria • Triad: • Hemolysis • pancytopenia • risk of thrombosis • May evolve into AplasticAnemia and PNH may manifest itself in patients whopreviously have AA, rarely may evolve into AML pamancio'11

49. Paroxysmal Nocturnal Hemoglobinuria • Diagnosis: • Gold standard: Flow Cytometry: CD55 and CD59 negative • Historically: Ham’s and Sucrose Lysis Test • Management: • Folic acid 3mg/day • BMT: only from of treatment that can provide cure • Eculizumab: anti-C’5 pamancio'11

50. Table 106–6 Diseases/Clinical Situations with Predominantly Intravascular Hemolysis pamancio'11