Deletion of platelet CLEC-2 decreases GPIba-mediated integrin aIIbb3 activation and decreases thrombosis in TTP

Microvascular thrombosis in patients with thrombotic thrombocytopenic purpura (TTP) is initiated by GPIba-mediated platelet binding to von Willebrand factor (VWF). Binding of VWF to GPIba causes activation of the platelet surface integrin aIIbb3. However, the mechanism of GPIba-initiated activation of aIIbb3 and its clinical importance for microvascular thrombosis remain elusive. Deletion of platelet C-type lectin-like receptor 2 (CLEC-2) did not prevent VWF binding to platelets but specifically inhibited platelet aggregation induced by VWF binding in mice. Deletion of platelet CLEC-2 also inhibited aIIbb3 activation induced by the binding of VWF to GPIba. Using a mouse model of TTP, which was created by infusion of anti-mouse ADAMTS13 monoclonal antibodies followed by infusion of VWF, we found that deletion of platelet CLEC-2 decreased pulmonary arterial thrombosis and the severity of thrombocytopenia. Importantly, prophylactic oral administration of aspirin, an inhibitor of platelet activation, and therapeutic treatment of the TTP mice with eptifibatide, an integrin aIIbb3 antagonist, reduced pulmonary arterial thrombosis in the TTP mouse model. Our observations demonstrate that GPIba-mediated activation of integrin aIIbb3 has an important role in the formation of thrombosis in TTP. These observations suggest that prevention of platelet activation with aspirin may reduce the risk for thrombosis in patients with TTP.