Differential Role of Glycoprotein VI in Mouse and Human Thrombus Progression and Stability

Introduction Platelet glycoprotein (GP) VI is a promising, safe, antithrombotic target as its absence or blockade prevents in vitro thrombus formation and experimental thrombosis in various animal models without impacting the tail-bleeding time.[ 1 ] In addition, patients with a mutation in the GPVI gene exhibit only a mild bleeding diathesis,[ 2 ] further suggesting that GPVI does not play a critical role in hemostasis. GPVI is the main platelet activation receptor for collagen and viewed as being important in the initiation of thrombus formation.[ 1 ] In addition to collagen, GPVI interacts physically or functionally with other adhesive proteins including laminins, fibrin, and fibrinogen.[ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ] We have shown that human GPVI activates platelets on immobilized fibrinogen and that this process is key for the progression and stability of human thrombi.[ 7 ] [ 8 ] In sharp contrast, we observed that mouse GPVI does not promote such an activation, as platelets deposited on fibrinogen do not fully spread.[ 7 ] In this study, we investigated the consequence of absence of GPVI/fibrinogen-mediated platelet activation in mice on the regulation of thrombosis in comparison to the human system. It is important to appreciate species difference between humans and mice as the latter represent the most broadly used animal model to study experimental thrombosis and that a significant part of our current understanding of the molecular mechanism of thrombosis relies on experiments performed with these animals. Authors' Contributions E.J.-B., M.U.A., and N.R. acquired, analyzed, and interpreted the data, and wrote the manuscript; C.M. acquired and analyzed the data; B.N. provided essential tools and contributed to the writing of the manuscript; C.G. and E.E.G. contributed to the writing of the manuscript; M.J.-P. and P.H.M. conceived and designed the research, interpreted the data, wrote the manuscript, and handled funding and supervision. * These authors contributed equally to this work. Publication History Publication Date: 29 October 2020 (online)