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

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

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

Extravascular Hemolysis

Fe

Transferrin

Storage and recycled in marrow

Biliverdin

Uncojugated bilirubin

Conjugation

Bile

CO

Lung

RBC

RES

HBG

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

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

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

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

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

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

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 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)