1. Platelet integrin αIIbβ3 plays a key role in a venous thrombogenesis mouse model.
- Author
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Adair BD, Field CO, Alonso JL, Xiong JP, Deng SX, Ahn HS, Mashin E, Clish CB, van Agthoven J, Yeager M, Guo Y, Tess DA, Landry DW, Poncz M, and Arnaout MA
- Subjects
- Animals, Female, Humans, Male, Mice, Clot Retraction, Cryoelectron Microscopy, Hemorrhage, Mice, Inbred C57BL, Platelet Aggregation Inhibitors pharmacology, Blood Platelets metabolism, Blood Platelets drug effects, Disease Models, Animal, Platelet Aggregation drug effects, Platelet Glycoprotein GPIIb-IIIa Complex metabolism, Tirofiban pharmacology, Venous Thrombosis metabolism, Venous Thrombosis prevention & control
- 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., (© 2024. The Author(s).)
- Published
- 2024
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