1. 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

2. 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

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

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

5. 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

6. 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

7. 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

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

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

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

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

14. 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)

15. 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

16. 1931 – Nobel prize for discovery of hexose-monophosphate shunt and glycolytic pathway (Otto Meyerhof, Gustav Embden students)
discovery of cytochromes, flavin adenine dinucleotide, nicotinamide adenine dinucleotide.
1944 – offered 2nd Nobel prize, but prevented from accepting it by Hitler
Otto Warburg ( )

17. 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

18. 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

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

20. 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

22. 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

23. 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)

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

26. Hematuria, Hemoglobinuria, and Myoglobinuria

27. 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)