1. Normocytic Anemia David Lee, MD, FRCPC

2. Normocytic anemia a heterogenous group of anemias normocytosis implies normal DNA metabolism and hemoglobin synthesis no common pathophysiology

3. Approach to anemia anemia check MCV MCV < 80 microcytic anemia MCV 80 - 100 normocytic anemia MCV > 100 macrocytic anemia

4. Approach to normocytic anemia Is there increased red cell production? check reticulocyte count normocytic anemia increased Is there evidence of hemolysis? hemolytic anemia yes Is there evidence of: - renal failureanemia of renal failure - endocrine failureanemia of endocrine failure - chronic inflammationanemia of chronic disease normal or decreased recent bleed no If not, then consider a primary marrow problem (MDS, MM, infiltration…) bone marrow investigation

5. Approach to normocytic anemia Is there increased red cell production? check reticulocyte count normocytic anemia increased Is there evidence of hemolysis? hemolytic anemia yes Is there evidence of: - renal failureanemia of renal failure - endocrine failureanemia of endocrine failure - chronic inflammationanemia of chronic disease normal or decreased recent bleed no If not, then consider a primary marrow problem (MDS, MM, infiltration…) bone marrow investigation

6. Anemia of chronic disease Anemia due to cytokines IL-1, TNF- , TGF-  associated with chronic inflammation –rheumatoid arthritis –systemic lupus erythematosis –inflammatory bowel disease –chronic infections: osteomyelitis, TB

7. Anemia of chronic disease Mechanisms –defective iron utilization iron is present, but cannot be utilized by erythroid precursors –impaired response to erythropoietin –?blunted increase in erythropoietin in response to anemia

8. Anemia of chronic disease usually normocytic, but 25% are microcytic usually mild to moderate anemia anemia of chronic disease is a diagnosis of exclusion bone marrow often needed to rule out other causes of anemia

9. Iron studies in IDA and ACD TestIDAACD serum ironlow TIBChighnormal or low transf. sat.low serum ferritin lownormal or increased marrow iron absentnormal or increased

10. Anemia of chronic disease Treatment –treat the underlying cause –erythropoietin can be effective, but is expensive

11. Anemia of chronic renal failure Mechanism: –mainly due to reduced production of erythropoietin by diseased kidneys –also iron or folate deficiency, chronic inflammation, shortened red cell survival Treatment –erythropoietin thrice weekly –dialysis

12. Anemia of endocrine failure Uncommon cause of anemia, but correctable –hypothyroidism –hypogonadism –pan-hypopituitarism

13. Approach to normocytic anemia Is there increased red cell production? check reticulocyte count normocytic anemia increased Is there evidence of hemolysis? hemolytic anemia yes Is there evidence of: - renal failureanemia of renal failure - endocrine failureanemia of endocrine failure - chronic inflammationanemia of chronic disease normal or decreased recent bleed no If not, then consider a primary marrow problem (MDS, MM, infiltration…) bone marrow investigation Pure red cell aplasia

14. Very rare cause of normocytic anemia immune-mediated destruction of red cell precursors in the marrow reticulocyte count is low treatment: immune suppression

15. Approach to normocytic anemia Is there increased red cell production? check reticulocyte count normocytic anemia increased Is there evidence of hemolysis? hemolytic anemia yes Is there evidence of: - renal failureanemia of renal failure - endocrine failureanemia of endocrine failure - chronic inflammationanemia of chronic disease normal or decreased recent bleed no If not, then consider a primary marrow problem (MDS, MM, infiltration…) bone marrow investigation

16. Hemolytic anemia Anemia due to increased rate of RBC destruction anemia occurs when rate of destruction exceeds production

17. Normal red cell turnover normal RBC survival of ~ 120 days macrophages of the reticuloendothelial (RE) system removes RBC’s –unclear what marks a red cell for removal –spleen is major site of RBC clearance RE system is extravascular –90% of normal RBC destruction occurs without release of hemoglobin into circulation.

18. The fate of intravascular hemoglobin free Hb     tetramers) Hb dimers haptoglobin haptoglobin- hemoglobin complex kidneys liver metHb binds to hemopexin & albumin ferriheme (Fe3+)globin

19. Extravascular vs Intravascular hemolysis ExtravascularIntravascular Test HemolysisHemolysis LD  bilirubin   haptoglobin N to absent absent hemoglobinuria absent present free Hb in plasma absent present urine hemosiderin absent present

20. Causes of intravascular hemolysis –Mechanical prosthetic heart valve, tight AS march & bongo drummer’s hemoglobinuria –Microangiopathic DIC, TTP, HUS –Immunological acute hemolytic transfusion reaction, PNH –Infection malaria Clostridium welchii sepsis –Enzymopathy severe G6PD deficiency

21. Is there hemolysis? Look for 3 lines of 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 –increased lactate dehydrogenase –decreased/absent haptoglobin

22. Approach to normocytic anemia Is there increased red cell production? check reticulocyte count normocytic anemia increased Is there evidence of hemolysis? hemolytic anemia yes Is there evidence of: - renal failureanemia of renal failure - endocrine failureanemia of endocrine failure - chronic inflammationanemia of chronic disease normal or decreased recent bleed no If not, then consider a primary marrow problem (MDS, MM, infiltration…) bone marrow investigation

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

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

25. Immune hemolysis most frequent cause of hemolysis due to IgG or complement on red cells –tags the red cell for phagocytosis –spherocytes if incomplete phagocytosis –lysis of RBC occurs if complement cascade goes to completion

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

27. Diagnosis of immune hemolytic anemia –1. Direct Antiglobulin Test (DAT or direct Coomb’s test) –detects IgG or complement on patient’s red cells –the vast majority of patients with active immune hemolysis will have a positive DAT. –2. Indirect Antiglobulin Test (IAT, indirect Coomb’s test) –detects antibody in patient’s serum against red cell antigens –A positive IAT does not necessarily mean hemolysis is occurring - It may simply mean allo-immunization due to previous exposure to “foreign” red cell antigens (past pregnancy or transfusion). –3. Peripheral Blood Film: spherocytes

28. Treatment of autoimmune hemolysis treat the underlying cause, if there is one stop suspect drugs if possible prednisone transfuse RBC’s, if needed

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

30. Hereditary spherocytosis most common inherited red cell membrane disorder 1/5000 in northern European populations autosomal dominant caused by mutations in the genes that encode RBC membrane cytoskeleton proteins.

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

32. Hereditary spherocytosis Spherocytes are cleared by the spleen more rapidly –lack of deformability means they cannot squeeze through the sieve-like slits of the spleen.

33. Hereditary spherocytosis Clinical features: –clinical severity varies –most have mild to moderate anemia –splenomegaly, cholelithiasis, jaundice may occur Laboratory features –hemolytic anemia with spherocytes –osmotic fragility test –negative DAT

34. Hereditary spherocytosis Treatment –most patients do not need treatment –splenectomy –counsel patient and family about inheritance

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

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

37. G6PD deficiency clinical severity highly variable –Most experience little or no anemia unless exposed to precipitating event or drug –precipitants: infections sulfa, primaquine, dapsone fava beans

38. G6PD deficiency Laboratory diagnosis –bite cells –Heinz bodies –measure G6PD level Treatment –supportive –avoid precipitants –counsel patient/family

39. Anemia cases

43. This is case 3 from the iron lecture