title: A humanized glycoprotein VI (GPVI) mouse model to assess the antithrombotic efficacies of anti-GPVI agents.
abstract: Glycoprotein VI (GPVI) has been proposed as a promising antiplatelet target, because its blockade prevents experimental thrombosis without impairing hemostasis. The objective of this study was to develop a preclinical tool to evaluate the role of human GPVI (hGPVI) in various models of thrombosis and to screen anti-GPVI compounds. A genetically modified mouse strain expressing hGPVI has been developed using a knockin strategy. The mice were viable and fertile and did not present any hematological defects. Approximately 3700 copies of human GPVI were detected at the platelet surface. Platelet aggregation, fibrinogen binding, and P-selectin exposure were normal in response to various agonists. The 9O12.2 Fab fragment directed against human GPVI bound to hGPVI platelets in vitro and ex vivo and markedly reduced collagen- and collagen-related peptide-induced responses. Injection of 9O12.2 into hGPVI animals did not prolong the tail bleeding time but provided protection against lethal thromboembolism induced by a collagen/adrenaline mixture. In addition, 9O12.2 reduced arterial thrombus growth by 44% after superficial laser injury, 43% after deep laser injury in mice pretreated with hirudin, and 48% after mechanical injury. In conclusion, we have developed a humanized mouse model that could be used in preclinical studies to evaluate the effects of anti-GPVI compounds.
authors.affiliation: Unité Mixte de Recherche Scientifique 949, Institut National de la Santé et de la Recherche Médicale, Strasbourg, France.
authors.forename: Pierre Henri
authors.initials: PH
authors.lastname: Mangin
authors.forename: ChaoJun
authors.initials: C
authors.lastname: Tang
authors.forename: Catherine
authors.initials: C
authors.lastname: Bourdon
authors.forename: Stéphane
authors.initials: S
authors.lastname: Loyau
authors.forename: Monique
authors.initials: M
authors.lastname: Freund
authors.forename: Béatrice
authors.initials: B
authors.lastname: Hechler
authors.forename: Christian
authors.initials: C
authors.lastname: Gachet
authors.forename: Martine
authors.initials: M
authors.lastname: Jandrot-Perrus
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D055879:Gene Knock-In Techniques; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000502:physiology; D013927:Thrombosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D005343:Fibrinolytic Agents; D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI