Publications · February 22, 2018

Immobilized fibrinogen activates human platelets through glycoprotein VI

Immobilized fibrinogen activates human platelets through glycoprotein VI

In Haematologica 2018 Volume 103(5):898-907, published on Feb, 22nd 2018

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Authors

Pierre H Mangin, Marie-Blanche Onselaer,  Nicolas Receveur, Nicolas Le Lay,  Alexander T Hardy, Clare Wilson, Ximena Sanchez, Stéphane Loyau, Arnaud Dupuis, Amir K Babar, Jeanette LC Miller, Helen Philippou, Craig E Hughes, Andrew B Herr, Robert AS Ariëns, Diego Mezzano, Martine Jandrot-Perrus, Christian Gachet and Steve P. Watson

Abstract

Glycoprotein VI, a major platelet activation receptor for collagen and fibrin, is considered a particularly promising, safe antithrombotic target. In this study, we show that human glycoprotein VI signals upon platelet adhesion to fibrinogen. Full spreading of human platelets on fibrinogen was abolished in platelets from glycoprotein VIdeficient patients suggesting that fibrinogen activates platelets through glycoprotein VI. While mouse platelets failed to spread on fibrinogen, human-glycoprotein VI-transgenic mouse platelets showed full spreading and increased Ca2+ signaling through the tyrosine kinase Syk. Direct binding of fibrinogen to human glycoprotein VI was shown by surface plasmon resonance and by increased adhesion to fibrinogen of human glycoprotein VI-transfected RBL-2H3 cells relative to mock-transfected cells. Blockade of human glycoprotein VI with the Fab of the monoclonal antibody 9O12 impaired platelet aggregation on preformed platelet aggregates in flowing blood independent of collagen and fibrin exposure. These results demonstrate that human glycoprotein VI binds to immobilized fibrinogen and show that this contributes to platelet spreading and platelet aggregation under flow.

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