Previous work on cellular destruction induced by several clinically relevant anti-platelet
IgG antibodies suggested
antigen-specific mechanisms in the development of
immune thrombocytopenia in mice. mAb directed against mouse platelet GPIbalpha and
integrin alpha(IIb)beta(3) were highly pathogenic, and mediated their effects via different Fc-dependent (alpha(IIb)beta(3)) and Fc-independent (GPIbalpha) pathways, indicating that clearance of
IgG-bound platelets is only one event in the pathogenesis of murine
thrombocytopenia. Here, we demonstrate that in addition to
thrombocytopenia, targeting of platelet
integrin alpha(IIb)beta(3) results in acute systemic reaction and
bleeding that is regulated by activating
IgG Fc receptors (FcgammaR) and the inhibitory FcgammaRII. As shown by electron microscopy, anti-alpha(IIb)beta(3)
IgG mediated initial loss of alpha(IIb)
beta(3) integrin from platelet surfaces followed by rapid accumulation of alpha(IIb)beta(3) antibody-containing
immune complex (IC)-like structures in spleen and liver in vivo. In FcRgamma chain deficiency, mice resisted
bleeding, but not platelet destruction, while genetic ablation of FcgammaRII resulted in uncontrolled systemic reaction and severe
hemorrhage leading to enhanced mortality. Together, these results provide evidence that IC formation and engagement of FcgammaR on effector cells determines the alpha(IIb)beta(3)-specific part of the platelet pathology of the systemic reaction and
bleeding in murine
thrombocytopenia.