Life of a Red Blood Cell

1. Life of a Red Blood Cell • Erythroid precursors undergo 4-5 divisions in marrow, extrude nucleus, become reticulocytes, enter peripheral blood, and survive ~100-120 days • Must withstand severe mechanical & metabolic stress, deform to pass thru capillaries half their size, resist shearing force across heart valves, survive stasis-induced acidemia & substrate depletion, avoid removal by macrophages

2. Normal Red Blood Cell • Discoid shape with 7-8 micron diameter • Can squeeze thru 3 micron capillary • As it ages, it loses water & surface area, impairing deformability • These changes are detected by the RES and trigger removal of the aged RBCs by macrophages

3. Anemia • Initial evaluation: MCV • If MCV >100: megaloblastic or not? • If MCV <80: iron deficient or not? • MCV 80-100: reticulocytosis or not? • Increased retics: Hemolysis or posthemorrhage • Decreased retics: Renal dz, liver dz, hypothyroid, anemia of chronic dz, myelodysplasia, leukemia, myeloma, etc.

4. Hemolytic Anemia • Inadequate number of RBCs caused by premature destruction of RBCs • Severity depends on rate of destruction and the marrow capacity to increase erythroid production (normal marrow can increase production 5 to 8 fold)

5. Classification of Hemolytic Anemia • Site of RBC destruction-Extravascular or Intravascular • Cause of destruction- extracorpuscular (abnormal elements in vascular bed that “attack” RBCs) or intracorpuscular (erythrocyte defects- membrane abnormalities, metabolic disturbances, disorders of hemoglobin)

6. Pathways of RBC Destruction • Extravascular: RBCs phagocytized by RE cells; RBC membrane broken down; Hemoglobin broken into CO (lung), bilirubin (conjugation and excretion by liver), and iron (binds to transferrin, returns to marrow) • Intravascular: Free hemoglobin binds to haptoglobin or hemopexin or is converted to methemalbumin. These proteins are cleared by the liver where the heme is broken down to recover iron & produce bilirubin.

7. Hemolytic Anemias • Intrinsic RBC causes • Membranopathies: hereditary spherocytosis • Enzymopathies: G6PD • Hemoglobinopathies: Sickle cell disease • Extrinsic causes • Immune mediated: Autoimmune (drug, virus, lymphoid malignance) vs Alloimmune (transfusion reaction) • Microangiopathic (TTP) • Infection (Malaria) • Chemical agents (spider venom)

8. Diagnosis of Hemolysis • Symptoms depend on degree of anemia (ie, rate of destruction) • Clinical features: anemia, jaundice, reticulocytosis, high MCV & RDW, elevated indirect bili, elevated LDH, low haptoglobin, positive DAT (AIHA) • Acute intravascular hemolysis: fever, chills, low back pain, hemoglobinuria • Smear: polychromatophilia, spherocytosis & autoagglutination

14. Acute Intravascular Hemolysis • Causes: Blood transfusion, thermal burns, snake bites, infections (clostridia, malaria, Bartonella, Mycoplasma), mechanical heart valves, PNH • Hemoglobinemia- pink or red plasma • Hemoglobinuria: brown or red after spinning down RBCs • Urine hemosiderin: urine hemoglobin reabsorbed by renal tubular cells; detect by staining sediment • Low haptoglobin: binds free hemoglobin • Methemalbumin: appears after depletion of haptoglobin

15. Intravascular hemolysis events • Acute intravascular hemolysis • Immediate drop in Haptoglobin; rises at 2 days; normal at 4 days • Hemoglobinemia detectable 6-12 hrs after event • Hemoglobinuria detectable 12-24 hrs • Hemosiderinuria detectable 3-12 days • Methemalbumin detectable 1-12 days

16. Acute Extravascular Hemolysis • Sudden fall in hemoglobin level with no evidence of bleeding or intravascular hemolysis (no hemoglobinemia or hemoglobinuria) • Clinical setting usually points to cause

17. Causes of Extravascular Hemolysis • Bacterial & Viral infections • Drug- induced • Autoimmune • Hemoglobinopathies • Membrane Structural Defects • “Environmental” Disorders- Malignancy associated DIC, TTP, Eclampsia

18. Infectious causes of hemolysis • 5-20% of pts with falciparum malaria have acute intravascular hemolysis (black water fever); most have mild extravascular hemolysis • Clostridial sepsis may cause severe intravascular hemolysis • Mild hemolysis occurs with mycoplasma pneumonia; often associated with high titer cold agglutinin; self limited

19. Drug-induced Hemolysis • May occur by an immune mechanism or by challenging the RBC metabolic machinery • Oxidant drugs causing hemolysis in G6PD deficiency: nitrofurantoin, sulfa drugs, dapsone, primaquine, pyridium, doxorubicin • Drugs causing immune-mediated hemolysis: penicillin, quinidine, methyldopa, streptomycin

20. G6PD Deficiency • ~10% of African-American males have X-linked A variant • The older RBCs are lost from circulation • New RBCs have normal or high G6PD levels; therefore they can usually compensate for the hemolysis even if the drug is continued

21. Drug Induced Hemolysis • Formation of antibodies specific to the drug: in high doses PCN binds RBC membrane, if pt forms Ab against PCN, the RBC are destroyed • Induction of Ab to RBC membrane antigens:methyldopa induces autoab to Rh ag • Selective binding of streptomycin to RBC membrane with formation of complement fixing antibody • All have Coombs (DAT) positive for IgG

22. Autoimmune Hemolytic Anemia • Anticipate this cause of hemolysis in infections, collagen vascular diseases, lymphoid malignancies • Generally, acute extravascular hemolysis • Spherocytes seen; no fragments; elevated LDH; suppressed haptoglobin; reticulocytes • Autoantibodies are directed against RBC components (eg, Kell antigen) • May be warm-reacting (IgG) or cold-reacting (IgM) antibody

23. Autoimmune Hemolytic Anemia • Warm reacting abs will show IgG +/- C3 • Cold reacting abs will have C3 only • RBCs sensitized to IgG only are removed in the spleen; those with complement are destroyed in the liver (Kupffer cells have C3b receptors) • Warm reacting abs often respond to steroids • Cold reacting antibodies are more often resistant to therapy and are associated with lymphoid malignancy

24. Causes of Autoimmune Hemolysis • SLE • Non-Hodgkins lymphomas, CLL • Hodgkins Disease • Myeloma • HIV • Hepatitis C • Chronic Ulcerative Colitis

25. Management of Hemolysis • The increase in RBC production requires adequate iron (intravascular hemolysis) & folate supplies (all hemolytic states) • Intravascular hemolysis- transfusion reaction- stop transfusion, IVFs to induce diuresis and mannitol (increases renal blood flow & decreases hemoglobin reabsorption)

26. Management of Extravascular Hemolysis • Acute self-limited hemolysis in G6PD pts rarely needs Rx; pt education important • Severe hemolysis may require transfusion in addition to therapy aimed at specific trigger • Iron overload becomes a problem in hemoglobinopathies • Parvovirus infection may cause aplastic episodes pts with chronic hemolytic states • Pigment gallstones occur in chronic hemolytic states • Splenectomy reduces RBC destruction in pts with hereditary spherocytosis

27. Management of Warm-Ab Autoimmune Hemolysis • Steroids block RE clearance of RBCs with IgG or C3 on surface and decrease production of IgG antibody • Prednisone 1 to 1.5 mg/kg/day is usual dose • Most respond within 2 weeks • Very slow taper required • Chemotherapy or splenectomy may help if steroids fail • Transfusions given if needed, may require “least incompatible” blood; likely will be destroyed at the same rate as the patient’s own blood

28. Management of Cold-Ab Autoimmune Hemolytic Anemia • Usually no treatment required in setting of mycoplasma or EBV infection. • Occasionally transfusion is needed. Washed RBCs have less complement and are less likely to trigger further hemolysis. • Steroids usually do not help • Chemotherapy (eg, cyclophosphamide or chlorambucil) may help • In severe cases, plasmapheresis can reduce intravascular antibody titer • May have dramatic cold sensitivity; warm infusions, avoid cold exposure