Pharmacological Blockade of GPVI Promotes Thrombus Disaggregation in the Absence of Thrombin

Arteriosclerosis, Thrombosis, and Vascular Biology
Muhammad Usman AhmedPierre H Mangin

Abstract

Atherothrombosis occurs upon rupture of an atherosclerotic plaque and leads to the formation of a mural thrombus. Computational fluid dynamics and numerical models indicated that the mechanical stress applied to a thrombus increases dramatically as a thrombus grows, and that strong inter-platelet interactions are essential to maintain its stability. We investigated whether GPVI-mediated platelet activation helps to maintain thrombus stability by using real-time video-microscopy. Approach and Results: We showed that GPVI blockade with 2 distinct Fab fragments promoted efficient disaggregation of human thrombi preformed on collagen or on human atherosclerotic plaque material in the absence of thrombin. ACT017-induced disaggregation was achieved under arterial blood flow conditions, and its effect increased with wall shear rate. GPVI regulated platelet activation within a growing thrombus as evidenced by the loss in thrombus contraction when GPVI was blocked, and the absence of the disaggregating effect of an anti-GPVI agent when the thrombi were fully activated with soluble agonists. The GPVI-dependent thrombus stabilizing effect was further supported by the fact that inhibition of any of the 4 key immunoreceptor tyrosine-based m...Continue Reading

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Citations

Aug 28, 2020·Arteriosclerosis, Thrombosis, and Vascular Biology·Shuchi Gupta, Lawrence F Brass
Jan 15, 2021·Arteriosclerosis, Thrombosis, and Vascular Biology·Joseph E Aslan
Dec 15, 2020·Platelets·Maan H HarbiMark R Thomas
Dec 4, 2020·Arteriosclerosis, Thrombosis, and Vascular Biology·Gina PerrellaJohan W M Heemskerk
Oct 31, 2020·Thrombosis and Haemostasis·Emily Janus-BellPierre H Mangin
May 27, 2021·Expert Opinion on Drug Discovery·Marialucia Gallorini, Simone Carradori
Jun 9, 2021·Scientific Reports·G J PenningsL Kritharides
Jul 3, 2021·International Journal of Molecular Sciences·Neale HarrisonMichael G Tomlinson
Jul 30, 2021·Frontiers in Oncology·Attila BraunElmina Mammadova-Bach
Aug 17, 2021·Journal of Thrombosis and Haemostasis : JTH·Pierre H ManginUNKNOWN Subcommittee on Biorheology
Sep 10, 2021·Arteriosclerosis, Thrombosis, and Vascular Biology·Gina PerrellaJohan W M Heemskerk
Nov 13, 2021·Journal of Biomechanics·Anastasia A MasalcevaDmitry Yu Nechipurenko

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