| First Author | Shao B | Year | 2022 |
| Journal | Blood | Volume | 139 |
| Issue | 16 | Pages | 2523-2533 |
| PubMed ID | 35157766 | Mgi Jnum | J:331859 |
| Mgi Id | MGI:7294336 | Doi | 10.1182/blood.2021012896 |
| Citation | Shao B, et al. (2022) Deletion of platelet CLEC-2 decreases GPIbalpha-mediated integrin alphaIIbbeta3 activation and decreases thrombosis in TTP. Blood 139(16):2523-2533 |
| abstractText | Microvascular thrombosis in patients with thrombotic thrombocytopenic purpura (TTP) is initiated by GPIbalpha-mediated platelet binding to von Willebrand factor (VWF). Binding of VWF to GPIbalpha causes activation of the platelet surface integrin alphaIIbbeta3. However, the mechanism of GPIbalpha-initiated activation of alphaIIbbeta3 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 alphaIIbbeta3 activation induced by the binding of VWF to GPIbalpha. 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 alphaIIbbeta3 antagonist, reduced pulmonary arterial thrombosis in the TTP mouse model. Our observations demonstrate that GPIbalpha-mediated activation of integrin alphaIIbbeta3 plays 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. |
