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Normocytic Anemia

Normocytic Anemia. David Lee, MD, FRCPC. normocytic anemia. Is there increased red cell production?. check reticulocyte count. increased. normal or decreased. Is there evidence of: - renal failure anemia of renal failure - endocrine failure anemia of endocrine failure

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Normocytic Anemia

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  1. Normocytic Anemia David Lee, MD, FRCPC

  2. normocytic anemia Is there increased red cell production? check reticulocyte count increased normal or decreased Is there evidence of: - renal failure anemia of renal failure - endocrine failure anemia of endocrine failure - chronic inflammation anemia of chronic disease Is there evidence of hemolysis? yes no consider bone marrow failure hemolytic anemia recent bleed bone marrow investigation Approach to normocytic anemia

  3. normocytic anemia Is there increased red cell production? check reticulocyte count increased normal or decreased Is there evidence of: - renal failure anemia of renal failure - endocrine failure anemia of endocrine failure - chronic inflammation anemia of chronic disease Is there evidence of hemolysis? yes no consider bone marrow failure hemolytic anemia recent bleed bone marrow investigation Approach to normocytic anemia

  4. consequences target tissue macrophages retention of iron in macrophages erythropoietin production kidney bone marrow response to erythropoietin Pathophysiology of anemia of chronic disease chronic infection, autoimmune disease, malignancy, etc Inflammatory stimulus T-cell & monocyte activation Cytokines interferon- TNF- IL-1, IL-6, IL-10

  5. Iron cycle

  6. Anemia of chronic disease • normocytic or microcytic • usually mild to moderate anemia • diagnosis is based on: • characteristic pattern of iron tests • presence of an inflammatory disorder • no evidence of other causes of anemia

  7. Iron studies in IDA and ACD

  8. Anemia of chronic disease • Treatment • treat the underlying cause • erythropoietin can be effective, but is expensive • Iron therapy has no role in the treatment of ACD

  9. Anemia of chronic renal failure • Mechanism: • mainly due to reduced production of erythropoietin by diseased kidneys • also contributing: iron or folate deficiency, chronic inflammation, shortened red cell survival • Treatment • erythropoietin, darbopoietin • dialysis

  10. Anemia of endocrine failure • Uncommon but correctable • hypothyroidism • hypogonadism • pan-hypopituitarism

  11. normocytic anemia Is there increased red cell production? check reticulocyte count increased normal or decreased Is there evidence of: - renal failure anemia of renal failure - endocrine failure anemia of endocrine failure - chronic inflammation anemia of chronic disease Is there evidence of hemolysis? yes no consider bone marrow failure hemolytic anemia recent bleed bone marrow investigation Approach to normocytic anemia

  12. Bone marrow failure • to be covered in a subsequent lecture

  13. consider bone marrow failure bone marrow investigation Approach to normocytic anemia normocytic anemia Is there increased red cell production? check reticulocyte count increased normal or decreased Is there evidence of: - renal failure anemia of renal failure - endocrine failure anemia of endocrine failure - chronic inflammation anemia of chronic disease Is there evidence of hemolysis? yes no hemolytic anemia recent bleed

  14. Hemolytic anemia • Anemia due to increased rate of RBC destruction • anemia occurs when destruction > production

  15. Normal red cell turnover • normal RBC survival of ~ 120 days • macrophages of the reticuloendothelial (RE) system removes RBC’s • usually no release of free hemoglobin into circulation (“extravascular”)

  16. Is there hemolysis? Look for 3 lines of laboratory evidence: 1. Damaged red cells on the blood film • spherocytes (immune hemolysis, HS) • red cell fragments (microangiopathic anemias) 2. Marrow response to hemolysis • polychromasia on blood film • reticulocytosis • erythroid hyperplasia in marrow 3. Biochemical evidence of RBC destruction • increased unconjugated bilirubin • from heme breakdown • increased lactate dehydrogenase • released from erythrocytes • decreased/absent haptoglobin • due to release of free hemoglobin into plasma

  17. Clinical manifestations • Those of anemia, plus • jaundice • hemoglobinuria (if free hemoglobin) • if chronic: cholelithiasis, splenomegaly

  18. What is the cause of the hemolysis?(also see page 7 of notes)

  19. free Hb (a2b2tetramers) Hb dimers haptoglobin kidneys liver haptoglobin- hemoglobin complex metHb binds to hemopexin & albumin globin ferriheme (Fe3+) The fate of intravascular hemoglobin

  20. Causes of intravascular hemolysis • Mechanical • Malfunctioning mechanical heart valve • Microangiopathic • DIC, TTP, HUS • Immunological • acute hemolytic transfusion reaction • Infection • malaria • Enzymopathy • severe G6PD deficiency

  21. Immune vs non-immune hemolysis Hemolytic anemia Immune Non-immune Congenital Acquired • Autoimmune • Alloimmune • Drug-induced • Defects of: • RBC membrane/ • skeleton • (eg. Hereditary spherocytosis) • RBC enzymes • (eg. G6PD deficiency) • Hemoglobin • Infections • sepsis • malaria • Mechanical • prosthetic heart valve • microangiopathic HA

  22. Immune hemolysis • most frequent cause of hemolysis • due to IgG or complement on red cells • tags the red cell for phagocytosis by macrophages • spherocytes form if phagocytosis is incomplete

  23. Diagnosis of immune hemolytic anemia • Direct Antiglobulin Test (DAT or direct Coomb’s test) • detects IgG or complement on patient’s red cells • positive DAT seen in almost all cases • Indirect Antiglobulin Test (IAT, indirect Coomb’s test) • detects antibody in patient’s serum against red cell antigens • Peripheral Blood Film: spherocytes

  24. Immune vs non-immune hemolysis Hemolytic anemia Immune Non-immune Congenital Acquired • Autoimmune • Alloimmune • Drug-induced • Defects of: • RBC membrane/ • skeleton • (eg. Hereditary spherocytosis) • RBC enzymes • (eg. G6PD deficiency) • Hemoglobin • Infections • sepsis • malaria • Mechanical • mech. heart valve • microangiopathic HA

  25. Autoimmune hemolysis • Most common type of immune hemolysis • primary (idiopathic) • secondary • autoimmune hemolysis secondary to: • autoimmune condition (such as SLE) • infection • lymphoma or CLL

  26. Treatment of autoimmune hemolytic anemia • treat the underlying cause, if there is one • stop suspect drugs if possible • prednisone • transfuse RBC’s, if needed

  27. Immune vs non-immune hemolysis Hemolytic anemia Immune Non-immune Congenital Acquired • Autoimmune • Alloimmune • Drug-induced • (other causes of immune hemolysis are rare) • Defects of: • RBC membrane/ • skeleton • (eg. Hereditary spherocytosis) • RBC enzymes • (eg. G6PD deficiency) • Hemoglobin • Infections • sepsis • malaria • Mechanical • prosthetic heart valve • microangiopathic HA

  28. Hereditary spherocytosis • most common inherited red cell membrane disorder • 1/5000 in northern European populations • autosomal dominant • due to mutations of RBC membrane cytoskeleton proteins

  29. Normal membrane cytoskeleton Hereditary spherocytosis loss of membrane = loss of SA = loss of deformability = increased splenic clearance

  30. Hereditary spherocytosis • Clinical features: • severity varies, usually mild to moderate anemia • splenomegaly, cholelithiasis, jaundice may occur • Laboratory features • hemolytic anemia with spherocytes • osmotic fragility test • negative DAT • Treatment • usually none required • splenectomy if severe • counsel patient and family about inheritance

  31. An approach to hemolytic anemia Hemolytic anemia Immune Non-immune Congenital Acquired • Autoimmune • Alloimmune • Drug-induced • (other causes of immune hemolysis are rare) • Defects of: • RBC membrane/ • skeleton • (eg. Hereditary spherocytosis) • RBC enzymes • (eg. G6PD deficiency) • Hemoglobin • Infections • sepsis • malaria • Mechanical • prosthetic heart valve • microangiopathic HA

  32. G6PD deficiency • Most common inherited red cell enzymopathy • up to 10% of those with African and Mediterranean descent • X-linked • hemolysis due to increased oxidative damage to red cells

  33. G6PD deficiency • severity of anemia variable • usually little or no anemia unless exposed to precipitating event or drug: • infections • sulfa, primaquine, dapsone • fava beans

  34. G6PD deficiency • Laboratory diagnosis • “bite” cells • Heinz bodies • measure G6PD level • Treatment • supportive • avoid precipitants • counsel patient/family

  35. normocytic anemia Is there increased red cell production? check reticulocyte count increased normal or decreased Is there evidence of: - renal failure anemia of renal failure - endocrine failure anemia of endocrine failure - chronic inflammation anemia of chronic disease Is there evidence of hemolysis? yes no consider bone marrow failure hemolytic anemia recent bleed bone marrow investigation Approach to normocytic anemia

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