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Acquired Hemolytic Anemia
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Etiologies of Acquired hemolytic anemia
Infection
Mechanical destruction
Toxins
Autoimmune
Malaria Enterotoxic E coli (HUS) Clostridium
Oxidative process Hyperbaric oxygen Nitrate / Chlorate Dapsone /
Cisplatin
Non-oxidative process Lead poisoning
Direct Injury
Ag-Ab mediated (Non-RBC Ag)
Ag-Ab mediated (RBC Ag)
Toxin mediated
March Hemoglobinuria Prosthetic valves
Post-blood transfusion Paroxysmal Cold hemoglobinuria Cold
agglutinin Disease Warm antibody type Paroxysmal Nocturnal
hemoglobinuris
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Autoimmune hemolytic anemia (AIHA)
RBC Coated Ag
Ab
Macrophage
Fc Receptor
Extra-vascular Hemolysis
Complement
Intra-vascular Hemolysis
Phagocytosis Fragmentation Cytotoxicity
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Warm Ab Immunohemolytic Anemia
The most common form (48% to 70%) of immune hemolytic anemia
50% of cases are idiopathic (primary)
Most causative antibodies are of the immunoglobulin G (IgG)
class
Antibodies often against Rh blood group antigens
Antigens- penicillin and cephalosporins & Quinidine,
-methyldopa
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Hemolysis is mainly extravascular
Takes place by splenic macrophages
Partial phagocytosis results in loss of membrane and formation
of spherocytes
which are later removed by spleen
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Warm AIHA
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Warm AIHA
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Warm AIHA
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Cold agglutinin Disease (CAD)
Antibody mediated RBC lysis at cold temperature
Antibody to I antigen (Usually IgM which effectively binds
complement)
Hemolysis both extravascular and intravascular
Ag-Ab reaction leads to B-cell proliferation in high
concentrations
Associated with Waldenstrom macroglobinemia
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Cold AIHA
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Anti-Globulin (Coombs) Testing Direct antiglobulin testing
Indirect antiglobulin testing
Patients RBCs
Patients serum
Anti-C3d
Anti-IgG
+
RBCs
+
Anti-IgG
+
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Paroxysmal cold hemoglobinuria (PCH)
Post viral infection
Donath-Landsteiner antibody
Antibody binds to RBC at low temperature
Antibody is specific to P antigen
RBC lysis mediated by complement at normal temperatures
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AIHA : Clinical features
Anemia (Abrupt, acute or chronic)
Jaundice
Hemoglobinuria (Intravascular hemolysis)
Splenomegaly
May be isolated AIHA
May be part of generalized autoimmune phenomenon
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AIHA : Situations
Abrupt onset
Mismatched blood transfusion
Acute onset
Paroxysmal cold hemoglobinuria (PCH)
Chronic
Paroxysmal nocturnal hemoglobinuria (PNH)
Cold agglutinin disease (Raynauds phenomenon)
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Paroxysmal nocturnal hemoglobinuria
Only hemolytic anemia caused by an acquired intrinsic defect in
the cell membrane
results from acquired (somatic) mutations in
phosphatidylinositol complementation glycan A (PIGA) - essential
for the synthesis of the GPI anchor (X linked)
complement mediated lysis of Red cells, white cells, and
platelets
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Paroxysmal nocturnal hemoglobinuria
Three GPI-linked proteins mutated / deficient in PNH
decay-accelerating factor (DAF) or CD55;
membrane inhibitor of reactive lysis, or CD59; (is the most
important in PNH)
C8 binding protein
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Paroxysmal Nocturnal hemoglobinuria
Paroxysmal passage of red urine (Hb-uria)
Recurrent abdominal pain (venous thrombosis)
May lead to hepatic venous occlusion (Hepatomegaly, ascitis Budd
Chiari Syndrome)
Secondary thrombocytopenia, BM aplasia, and
hemorrhage,leukemia
Diagnosis:sucrose lysis test,acidified hams test,flow
cytometry
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PNH Pathogenesis RBCs normally inhibit MAC and C3 convertase
(mediated by CD59 / CD 55 Ag)
C3 convertase
C3 C3b
+
CD 59
CD 55
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C3b C3 convertase C3b Complex
C5 C5b
Membrane Attack Complex
Complement activation
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In PNH CD59/CD55 deficient cells undergo intravascular
hemolysis
C3 convertase
C3 C3b
+
C3b C3 convertase C3b Complex
C5 C5b
Membrane Attack Complex
Complement activation
Excess C3b formation MAC mediated RBC lysis Intravascular
hemolysis
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PNH - Pathogenesis
Mechanism of thrombosis unknown. Probable activation of CD59
deficient platelets
Associated T-cell activation damages hematopoietic B cells.
CD59 deficient stem cells escape T-cell mediated damage
Targeted therapy with Eculizumab (monoclonal Ab against C5)
prevents hemolysis
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Eculizumab prevents Hemolysis by preventing MAC generation
C3 convertase
C3 C3b
+
C3b C3 convertase C3b Complex
C5 C5b
Complement activation
Eculizumab
