Pharmacological Blockade of Glycoprotein VI Promotes Thrombus Disaggregation in the Absence of Thrombin

Muhammad Usman Ahmed, Valeria Kaneva, Stéphane Loyau, Dmitry Nechipurenko, Nicolas Receveur, Marion Le Bris, Emily Janus-Bell, Mélusine Didelot, Antoine Rauch, Sophie Susen, Nabil Chakfé, François Lanza, Elizabeth E. Gardiner, Robert K. Andrews, Mikhail Panteleev, Christian Gachet, Martine Jandrot-Perrus, Pierre H. Mangin

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Objective: 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 (glycoprotein VI)-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 motif signalling molecules, src-kinases, Syk, PI3Kβ, or phospholipase C, resulted in kinetics of thrombus disaggregation similar to ACT017. The absence of ACT017-induced disaggregation of thrombi from 2 afibrinogenemic patients suggests that the role of GPVI requires interaction with fibrinogen. Finally, platelet disaggregation of fibrin-rich thrombi was also promoted by ACT017 in combination with r-tPA (recombinant tissue plasminogen activator). Conclusions: This work identifies an unrecognized role for GPVI in maintaining thrombus stability and suggests that targeting GPVI could dissolve platelet aggregates with a poor fibrin content.

Original languageEnglish (US)
Pages (from-to)2127-2142
Number of pages16
JournalArteriosclerosis, Thrombosis, and Vascular Biology
DOIs
StateAccepted/In press - 2020

Keywords

  • fibrinogen
  • hemostasis
  • platelet
  • rheology
  • thrombosis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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