HEMOLYTIC ANEMIA OUTSIDE THE RED CELL WITHIN THE RED CELL 1. Membrane defects - HS - HE - Hereditary pyropoikilocytosis - Hereditary stomatocytosis 2. Enzyme defects -G6PD -Pyruvate kinase 3. Hemoglobin defects - SCA - Thalassemias - Unstable hemoglobin AUTO-IMMUNE 1. Warm 2. Cold 3. Transfusion reactions 4. Drug associated NON-IMMUNE 1. Hypersplenism 2. Fragmentation syndromes - grafts / valves / AS - HTN / Pre-eclampsia - March hemoglobinuria - MAHA - TTP/HUS - DIC - hemangioma 2. Infections/Toxins (Malaria, Babeosis, Bartonella, Clostridium welchii, snakes, spiders) 3. Drugs 4. Liver dz (Spur cell) 5. PNH

HEMOLYTIC ANEMIA Intravascular Causes in Yellow OUTSIDE THE RED CELL WITHIN THE RED CELL 1. Membrane defects - HS - HE - Hereditary pyropoikilocytosis - Hereditary stomatocytosis 2. Enzyme defects -G6PD -Pyruvate kinase 3. Hemoglobin defects - SCA - Thalassemias - Unstable hemoglobin AUTO-IMMUNE 1. Warm 2. Cold 3. Transfusion reactions 4. Drug associated NON-IMMUNE 1. Hypersplenism 2. Fragmentation syndromes - grafts / valves / AS - HTN / Pre-eclampsia - March hemoglobinuria - MAHA - TTP/HUS - DIC - hemangioma 2. Infections/Toxins (Malaria, Babeosis, Bartonella, Clostridium welchii, snakes, spiders) 3. Drugs 4. Liver dz (Spur cell) 5. PNH

Alf Alving, Scientist, U.S. Army (mid 1950s)

Extravascular Hemolysis RBC RES HBG Extravascular Hemolysis Fe Transferrin Storage and recycled in marrow CO Lung Biliverdin Uncojugated bilirubin Conjugation Bile

HBG TAKEN UP BY RENAL TUBULAR CELLS Intravascular Hemolysis RBC LYSIS HBG HAPTOGLOBIN REMOVED BY LIVER HBG TAKEN UP BY RENAL TUBULAR CELLS HEMOSIDERIN CELLS SLOUGHED IN URINE 1 WEEK LATER HEMOGLOBINEMIA HEMOGLOBINURIA

Classic Presentation 1. New onset pallor and anemia 2. Splenomegaly 3. Jaundice 3.  Indirect bilirubin (<5) 4.  Reticulocyte percentage 5.  LDH (esp LDH-2) 6.  RBC life span 7.  Haptoglobin < 25 - 83% SENS - 96% SPEC

HEMOLYTIC ANEMIA OUTSIDE THE RED CELL WITHIN THE RED CELL 1. Membrane defects - HS - HE - Hereditary pyropoikilocytosis - Hereditary stomatocytosis 2. Enzyme defects -G6PD -Pyruvate kinase 3. Hemoglobin defects - SCA - Thalassemias - Unstable hemoglobin AUTO-IMMUNE 1. Warm 2. Cold 3. Transfusion reactions 4. Drug associated NON-IMMUNE 1. Hypersplenism 2. Fragmentation syndromes - grafts / valves / AS - HTN / Pre-eclampsia - March hemoglobinuria - MAHA - TTP/HUS - DIC - hemangioma 2. Infections/Toxins (Malaria, Babeosis, Bartonella, Clostridium welchii, snakes, spiders) 3. Drugs 4. Liver dz (Spur cell) 5. PNH

Hereditary Spherocytosis Autosomal Dominant ~1:3000 Spectrin, Ankyrin, Protein 3 Dx: osmotic frag., neg. direct Coombs Tx: Splenectomy, cholecystectomy, vaccine, folate

Hereditary Eliptocytosis Autosomal Dominant ~1:4500 Protein 4.1 Dx: >75% elliptic RBC Tx: Splenectomy

Hereditary Stomatocytosis Autosomal Dominant Lack of Protein 7.2 (stomatin)  Permeability to Na, K Stomatocytes, xerocytes  target cells Tx: Splenectomy

Stateville Penitentiary, near Joliet, IL (mid 1950s)

Warm Immunohemolyis Most common in adult women (CT, SLE) IgG bound to RBC activate phagocytes and complement Dx: + direct Coombs Tx: 1. Prednisone 1mg/kg ( RES, Ab production) 2. Splenectomy 3. Cyclophosphamide 4. Azathioprine 5. IV gamma globulin 6. Transfusions (cross-matching impossible)

Cold Immunohemolyis monoclonal production of cold agglutinins response to infection (M. pneumoniae, EBV) IgM mediated complement attack (no Fc) Tx: 1. Underlying cause 2. Splenectomy, Steroids, have minimal role

1931 – Nobel prize for discovery of hexose-monophosphate shunt and glycolytic pathway (Otto Meyerhof, Gustav Embden students) 1931-1944 discovery of cytochromes, flavin adenine dinucleotide, nicotinamide adenine dinucleotide. 1944 – offered 2nd Nobel prize, but prevented from accepting it by Hitler Otto Warburg (1883-1970)

TTP Ab inhibits protease that normally cleaves vWF Dx Tx 1. Intravascular hemolysis 2. Thrombocytopenia 3. Non focal neurologic findings 4.  Renal function 5. Fever Dx Negative direct Coombs Fragmented RBC, but no spherocytes Normal coagulation tests Tx Plasmapheresis, glucocorticoids, dipyridamole, dextran, ASA

HUS O157:H7 Shiga-like verotoxins that damage renal vascular endothelial cells Clinically similar to TTP, no neuro manifestations Tx Plasmapheresis, dialysis, transfusions Role of glucocorticoids, dextran, heparin uncertain

Liver disease: Spur Cell Anemia  cholesterol to phospholipid ratio Splenic traffic jam Clinically similar to TTP, no neuro manifestations Limited Treatment

PNH Somatic mut. on X-chromosome Gene makes GPI anchor Many proteins can’t attach to RBC No DAF and membrane inhibitor of reactive lysis (MIRL), RBC sensitive to complement Hypercoaguable state Dx: pancytopenia,  LAP, sucrose hemolysis, Ham’s test (lysis in acidified serum) Tx: Transfusion, glucocorticoids, Fe BM transplant usually effective

G6PD X chromosome, recessive 11% African American males  sensitivity to oxidative stress Heinz bodies, bite cells Triggers: infection, drugs, met. acidosis, moth balls, fava beans Dx: enzyme assay (fluorescent spot) after acute episode Tx: avoid triggers

DRUGS THAT CAUSE HEMOLYTIC ANEMIA OXIDANT 1. Antibiotics - nitrofurantoin - sulfa - dapsone - nalidixic acid 2. Primaquine 3. Pyridium 4. Doxorubicin 5. Methylene blue PENICILLIN TYPE (Ab + Drug-Membrane) 1. Penicillins 2. Cephalosporins 3. Synthetic penicillins IMMUNE COMPLEX (Ab-Drug + Membrane) (Most common type) 1. quinidine 2. rifampin AUTOIMMUNE (AutoAb to Rh Ag) 1. methyldopa MISCELLANEOUS 1. Vitamin K (water soluble)

Cinchona plant, Costa Rica, containing both quinine and quinidine, named for the Countess of the Spanish town of Chinchon

Hematuria, Hemoglobinuria, and Myoglobinuria

Causes of Intravascular Hemolysis 1. Transfusion reactions 2. Infections - Clostridium welchi - Malaria, Babeosis - Bartonella - Mycoplasma pneumonia 3. Fragmentation syndromes - grafts / valves / AS - HTN / Pre-eclampsia - March hemoglobinuria - TTP/HUS - DIC - hemangioma 4. G6PD deficiency with oxidant stress 5. PNH 6. Infusion of hypotonic solutions 7. Snake and Spider venoms 8. Some autoimmune hemolytic anemias (RhoD)