Title :

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

Author(s) :

Ahmed, Muhammad Usman [Auteur]
Biologie et pharmacologie des plaquettes sanguines: hémostase, thrombose, transfusion
Kaneva, Valeria [Auteur]
Loyau, Stéphane [Auteur]
Laboratoire de Recherche Vasculaire Translationnelle [LVTS (UMR_S_1148 / U1148)]
Nechipurenko, Dmitry [Auteur]
Receveur, Nicolas [Auteur]
Biologie et Pharmacologie des Plaquettes sanguines : hémostase, thrombose, transfusion [BPPS]
Le Bris, Marion [Auteur]
Biologie et Pharmacologie des Plaquettes sanguines : hémostase, thrombose, transfusion [BPPS]
Janus-Bell, Emily [Auteur]
Biologie et Pharmacologie des Plaquettes sanguines : hémostase, thrombose, transfusion [BPPS]
Didelot, Mélusine [Auteur]
Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U 1011 [RNMCD]
Rauch, Antoine [Auteur]
Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U 1011 [RNMCD]
Susen, Sophie [Auteur]
Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U 1011 [RNMCD]
Chakfé, Nabil [Auteur]
Centre Hospitalier Universitaire [Strasbourg] [CHU Strasbourg]
Lanza, François [Auteur]
Biologie et pharmacologie des plaquettes sanguines: hémostase, thrombose, transfusion
Biologie et Pharmacologie des Plaquettes sanguines : hémostase, thrombose, transfusion [BPPS]
Gardiner, Elizabeth [Auteur]
Andrews, Robert [Auteur]
Panteleev, Mikhail [Auteur]
Gachet, Christian [Auteur]
Biologie et Pharmacologie des Plaquettes sanguines : hémostase, thrombose, transfusion [BPPS]
Jandrot-Perrus, Martine [Auteur]
Laboratoire de Recherche Vasculaire Translationnelle [LVTS (UMR_S_1148 / U1148)]
Mangin, Pierre [Auteur]
Biologie et Pharmacologie des Plaquettes sanguines : hémostase, thrombose, transfusion [BPPS]

Journal title :

Arteriosclerosis, Thrombosis, and Vascular Biology

Pages :

2127-2142

Publisher :

American Heart Association

Publication date :

2020-09

ISSN :

1079-5642

HAL domain(s) :

Sciences du Vivant [q-bio]

English abstract : [en]

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 ...
Show more >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.Show less >

Language :

Anglais

Popular science :

Non

Collections :

• Récepteurs nucléaires, Maladies Cardiovasculaires et Diabète (RNMCD) - U1011

Source :

Harvested from HAL