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

Fiche publication

Date publication

juillet 2020

Journal

Arteriosclerosis, thrombosis, and vascular biology

Auteurs

Membres identifiés du Cancéropôle Est :
Dr GACHET Christian

Tous les auteurs :
Ahmed MU, Kaneva V, Loyau S, Nechipurenko D, Receveur N, Le Bris M, Janus-Bell E, Didelot M, Rauch A, Susen S, Chakfé N, Lanza F, Gardiner EE, Andrews RK, Panteleev M, Gachet C, Jandrot-Perrus M, Mangin PH

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/32698684

Résumé

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 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-type plasminogen activator).