Deletion of platelet CLEC-2 decreases GPIbα-mediated integrin αIIbβ3 activation and decreases thrombosis in TTP.

Abstract

Microvascular thrombosis in patients with thrombotic thrombocytopenic purpura (TTP) is initiated by GPIbα-mediated platelet binding to von Willebrand factor (VWF). Binding of VWF to GPIbα causes activation of the platelet surface integrin αIIbβ3. However, the mechanism of GPIbα-initiated activation of αIIbβ3 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 αIIbβ3 activation induced by the binding of VWF to GPIbα. 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 αIIbβ3 antagonist, reduced pulmonary arterial thrombosis in the TTP mouse model. Our observations demonstrate that GPIbα-mediated activation of integrin αIIbβ3 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.

• Authors: Bojing Shao, Christopher Hoover, Huiping Shi, Yuji Kondo, Robert H Lee, Junmei Chen, Xindi Shan, Jianhua Song, J Michael McDaniel, Meixiang Zhou, Samuel McGee, Karen Vanhoorelbeke, Wolfgang Bergmeier, José A López, James N George, Lijun Xia
• Journal: Blood (Blood) Vol. 139 Issue 16 Pg. 2523-2533 (04 21 2022) ISSN: 1528-0020 [Electronic] United States
• PMID: 35157766 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 by The American Society of Hematology.

Chemical References

• Lectins, C-Type
• Platelet Glycoprotein GPIIb-IIIa Complex
• von Willebrand Factor
• Aspirin

Topics

• Aspirin
• Blood Platelets (metabolism)
• Humans
• Hypertension, Pulmonary
• Lectins, C-Type (genetics, metabolism)
• Platelet Activation
• Platelet Glycoprotein GPIIb-IIIa Complex (metabolism)
• Purpura, Thrombotic Thrombocytopenic (metabolism)
• Thrombosis (etiology)
• von Willebrand Factor (metabolism)