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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
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
AUTO-IMMUNE
1. Warm
2. Cold
3. Transfusion reactions
4. Drug associated
OUTSIDE THE RED CELL
HEMOLYTIC ANEMIA
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HEMOLYTIC ANEMIAIntravascular Causes in Yellow
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
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
AUTO-IMMUNE
1. Warm
2. Cold
3. Transfusion reactions
4. Drug associated
OUTSIDE THE RED CELL
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Alf Alving, Scientist, U.S. Army(mid 1950s)
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Extravascular Hemolysis
Fe
Transferrin
Storage and recycled in marrow
Biliverdin
Uncojugated bilirubin
Conjugation
Bile
CO
Lung
RBC
RES
HBG
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Intravascular Hemolysis
RBC LYSIS
HBG
HAPTOGLOBIN
REMOVED BY LIVER
HEMOGLOBINEMIA
HEMOGLOBINURIA
HBG TAKEN UP BY RENAL TUBULAR CELLS
HEMOSIDERIN
CELLS SLOUGHED IN
URINE 1 WEEK LATER
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1. New onset pallor and anemia2. Splenomegaly3. Jaundice 3. Indirect bilirubin (<5)4. Reticulocyte percentage5. LDH (esp LDH-2)6. RBC life span7. Haptoglobin
< 25
- 83% SENS
- 96% SPEC
Classic Presentation
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HEMOLYTIC ANEMIA
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
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
AUTO-IMMUNE
1. Warm
2. Cold
3. Transfusion reactions
4. Drug associated
OUTSIDE THE RED CELL
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Hereditary Spherocytosis
- Autosomal Dominant - ~1:3000- Spectrin, Ankyrin, Protein 3- Dx: osmotic frag., neg. direct Coombs- Tx: Splenectomy, cholecystectomy,
vaccine, folate
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Hereditary Eliptocytosis
- Autosomal Dominant - ~1:4500- Protein 4.1- Dx: >75% elliptic RBC- Tx: Splenectomy
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Hereditary Stomatocytosis
- Autosomal Dominant - Lack of Protein 7.2 (stomatin) Permeability to Na, K- Stomatocytes, xerocytes target
cells- Tx: Splenectomy
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Stateville Penitentiary, near Joliet, IL (mid 1950s)
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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)
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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
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Otto Warburg (1883-1970)
- 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
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TTP
- Ab inhibits protease that normally cleaves vWF- 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
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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
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Liver disease: Spur Cell Anemia
cholesterol to phospholipid ratio- Splenic traffic jam- Clinically similar to TTP, no neuro
manifestations- Limited Treatment
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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
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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
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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)
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Cinchona plant, Costa Rica, containing both quinine and
quinidine, named for the Countess of the Spanish town of
Chinchon
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Hematuria, Hemoglobinuria, and Myoglobinuria
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Causes of Intravascular Hemolysis
1. Transfusion reactions2. 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 stress5. PNH6. Infusion of hypotonic solutions7. Snake and Spider venoms8. Some autoimmune hemolytic anemias (RhoD)