Acquired Hemolytic Anemia
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
Autoimmune hemolytic anemia (AIHA)
RBC Coated Ag
Ab
Macrophage
Fc Receptor
Extra-vascular Hemolysis
Complement
Intra-vascular Hemolysis
Phagocytosis Fragmentation Cytotoxicity
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
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
Warm AIHA
Warm AIHA
Warm AIHA
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
Cold AIHA
Anti-Globulin (Coombs) Testing Direct antiglobulin testing
Indirect antiglobulin testing
Patients RBCs
Patients serum
Anti-C3d
Anti-IgG
+
RBCs
+
Anti-IgG
+
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
AIHA : Clinical features
Anemia (Abrupt, acute or chronic)
Jaundice
Hemoglobinuria (Intravascular hemolysis)
Splenomegaly
May be isolated AIHA
May be part of generalized autoimmune phenomenon
AIHA : Situations
Abrupt onset
Mismatched blood transfusion
Acute onset
Paroxysmal cold hemoglobinuria (PCH)
Chronic
Paroxysmal nocturnal hemoglobinuria (PNH)
Cold agglutinin disease (Raynauds phenomenon)
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
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
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
PNH Pathogenesis RBCs normally inhibit MAC and C3 convertase
(mediated by CD59 / CD 55 Ag)
C3 convertase
C3 C3b
+
CD 59
CD 55
-
C3b C3 convertase C3b Complex
C5 C5b
Membrane Attack Complex
Complement activation
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
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
Eculizumab prevents Hemolysis by preventing MAC generation
C3 convertase
C3 C3b
+
C3b C3 convertase C3b Complex
C5 C5b
Complement activation
Eculizumab