Identification of critical antigen-specific mechanisms in the development of immune thrombocytopenic purpura in mice

The pathogenic effects of antiplatelet antibodies were investigated in mice , Monoclonal antibodies (mAbs) of different immunoglobulin G subclass direc ted against mouse GPIIbIIIa, GPIIIa, GPIb alpha, GPIb-IX, GPV, and CD31 wer e generated and characterized biochemically. MAbs against GPIb-IX, GPV, CD3 1, and linear epitopes on GPIIIa had mild and transient effects on platelet counts and induced no spontaneous bleeding, Anti-GPIb alpha mAbs induced p rofound irreversible thrombocytopenia(< 3% of normal) by Fc-independent mec hanisms but only had minor effects on hematocrits. In contrast, injection o f intact mAbs, but not F(ab)(2) fragments, against conformational epitopes on GPIIbIIIa, induced irreversible thrombocytopenia, acute systemic reactio ns, hypothermia, decreased hematocrits, and a paradoxical loss of surface G PIIbIIIa on platelets in vivo, the latter suggesting the formation of plate let-derived microparticles, Blockage of platelet-activating factor receptor s inhibited the acute reactions, but not thrombocytopenia, loss of GPIIbIII a, and decreases in hematocrits. Repeated injections of low doses of anti-G PIIbIIIa antibodies resulted in profound thrombocytopenia and bleeding, whe reas no acute systemic reactions were observed. These data strongly suggest that the identity of the target antigen recognized by antiplatelet antibod ies determines the mechanisms of platelet destruction and the severity of b leeding in mice, the latter depending on previously unrecognized anti-GPIIb IIIa-specific inflammatory mechanisms, (Blood, 2000;96: 2520-2527) (C) 2000 by The American Society of Hematology.