Platelet integrin αIIbβ3 plays a key role in a venous thrombogenesis mouse model

Brian D. Adair, Conroy O. Field, José L. Alonso, Jian-Ping Xiong, Shi-Xian Deng, Hyun Sook Ahn, Eivgeni Mashin, Clary B. Clish, Johannes Agthoven, Mark Yeager, Youzhong Guo, David A. Tess, Donald W. Landry, Mortimer Poncz and M. Amin Arnaout ()
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Brian D. Adair: Division of Nephrology, Massachusetts General Hospital and Harvard Medical School
Conroy O. Field: The Children’s Hospital of Philadelphia
José L. Alonso: Division of Nephrology, Massachusetts General Hospital and Harvard Medical School
Jian-Ping Xiong: Division of Nephrology, Massachusetts General Hospital and Harvard Medical School
Shi-Xian Deng: New York-Presbyterian Hospital-Columbia and Cornell
Hyun Sook Ahn: The Children’s Hospital of Philadelphia
Eivgeni Mashin: Broad Institute
Clary B. Clish: Broad Institute
Johannes Agthoven: Division of Nephrology, Massachusetts General Hospital and Harvard Medical School
Mark Yeager: University of Miami
Youzhong Guo: VCU School of Pharmacy
David A. Tess: Pfizer Inc
Donald W. Landry: New York-Presbyterian Hospital-Columbia and Cornell
Mortimer Poncz: The Children’s Hospital of Philadelphia
M. Amin Arnaout: Division of Nephrology, Massachusetts General Hospital and Harvard Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Venous thrombosis (VT) is a common vascular disease associated with reduced survival and a high recurrence rate. VT is initiated by the accumulation of platelets and neutrophils at sites of endothelial cell activation. A role for platelet αIIbβ3 in VT is not established, a task complicated by the increased bleeding risk caused by partial agonists such as tirofiban. Here, we show that m-tirofiban, a modified version of tirofiban, does not agonize αIIbβ3 based on lack of neoepitope expression and the cryo-EM structure of m-tirofiban/full-length αIIbβ3 complex. m-tirofiban abolishes agonist-induced platelet aggregation while preserving clot retraction ex vivo and, unlike tirofiban, it suppresses venous thrombogenesis in a mouse model without increasing bleeding. These findings establish a key role for αIIbβ3 in VT initiation and suggest that m-tirofiban and compounds with a similar structurally-defined mechanism of action merit consideration as potential thromboprophylaxis agents in patients at high risk for VT and hemorrhage.

Date: 2024
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DOI: 10.1038/s41467-024-52869-3

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