| Autor: |
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, Arnaout MA |
| Jazyk: |
angličtina |
| Zdroj: |
BioRxiv : the preprint server for biology [bioRxiv] 2024 Jul 16. Date of Electronic Publication: 2024 Jul 16. |
| DOI: |
10.1101/2024.07.11.602533 |
| Abstrakt: |
Venous thrombosis (VT) is a common vascular disease associated with reduced survival and a high recurrence rate. Previous studies have shown that the accumulation of platelets and neutrophils at sites of endothelial cell activation is a primary event in VT, but a role for platelet αIIbβ3 in the initiation of venous thrombosis has not been established. This task has been complicated by the increased bleeding linked to partial agonism of current αIIbβ3 inhibitory drugs such as tirofiban (Aggrastat ® ). Here, we show that m-tirofiban, an engineered version of tirofiban, is not a partial agonist of αIIbβ3. This is based on its cryo-EM structure in complex with human full-length αIIbβ3 and its inability to increase expression of an activation-sensitive epitope on platelet αIIbβ3. m-tirofiban abolished agonist-induced platelet aggregation ex vivo at concentrations that preserved clot retraction and markedly suppressed the accumulation of platelets, neutrophils, and fibrin on thrombin-activated endothelium in real-time using intravital microscopy in a mouse model of venous thrombogenesis. Unlike tirofiban, however, m-tirofiban did not increase bleeding at the thrombosis-inhibitory dose. These findings establish a key role for αIIbβ3 in the initiation of VT, provide a guiding principle for designing potentially safer inhibitors for other integrins, and suggest that pure antagonists of αIIbβ3 like m-tirofiban merit further consideration as potential thromboprophylaxis agents in patients at high-risk for VT and hemorrhage. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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