Targeting of platelet integrin α_IIbβ₃ determines systemic reaction and bleeding in murine thrombocytopenia regulated by activating and inhibitory FcγR

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 GPIbα and integrin α_IIbβ₃ were highly pathogenic, and mediated their effects via different Fc-dependent (α_IIbβ₃) and Fc-independent (GPIbα) 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 α_IIbβ₃ results in acute systemic reaction and bleeding that is regulated by activating IgG Fc receptors (FcγR) and the inhibitory FcγRII. As shown by electron microscopy, anti-α_IIbβ₃ IgG mediated initial loss of α_IIbβ₃ integrin from platelet surfaces followed by rapid accumulation of α_IIbβ₃ antibody-containing immune complex (IC)-like structures in spleen and liver in vivo. In FcRγ chain deficiency, mice resisted bleeding, but not platelet destruction, while genetic ablation of FcγRII resulted in uncontrolled systemic reaction and severe hemorrhage leading to enhanced mortality. Together, these results provide evidence that IC formation and engagement of FcγR on effector cells determines the α_IIbβ₃-specific part of the platelet pathology of the systemic reaction and bleeding in murine thrombocytopenia.