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

Author:

Shao Bojing1ORCID,Hoover Christopher12ORCID,Shi Huiping12,Kondo Yuji1,Lee Robert H.3ORCID,Chen Junmei4,Shan Xindi1,Song Jianhua1,McDaniel J. Michael1,Zhou Meixiang1,McGee Samuel1,Vanhoorelbeke Karen5ORCID,Bergmeier Wolfgang3ORCID,López José A.4,George James N.6ORCID,Xia Lijun12ORCID

Affiliation:

1. Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK;

2. Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK;

3. Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC;

4. Bloodworks Research Institute, Seattle, WA;

5. Laboratory for Thrombosis Research, Katholieke Universiteit Leuven Campus Kulak Kortrijk, Kortrijk, Belgium; and

6. Hematology-Oncology Section, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK

Abstract

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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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