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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1640.)
© 2006 American Heart Association, Inc.

Thrombosis

Two-Phase Antithrombotic Protection After Anti-Glycoprotein VI Treatment in Mice

Valerie Schulte; H. Peter Reusch; Miroslava Pozgajová; David Varga-Szabó; Christian Gachet; Bernhard Nieswandt

From the Rudolf-Virchow-Zentrum (V.S., M.P., D.V.-S., B.N.), DFG-Forschungszentrum für Experimentelle Biomedizin der Universität Würzburg, Germany; Ruhr-Universität Bochum (V.S., H.P.R.), Klinische Pharmakologie, Bochum, Germany; INSERM U.311 (C.G.), Etablissement Français du Sang-Alsace and EFS-Alsace, Strasbourg Cedex, France; and Institut für Klinische Biochemie und Pathobiochemie (B.N.), Universität Würzburg, Germany.

Correspondence to Bernhard Nieswandt, PhD, Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Versbacher Str. 9, 97078 Würzburg, Germany. E-mail bernhard.nieswandt{at}virchow.uni-wuerzburg.de

Objective— Collagen and thrombin are the strongest physiological platelet agonists, acting through different receptors, among which glycoprotein VI (GPVI) and protease-activated receptors, respectively, are the essential ones. In mice, targeting of GPVI with the monoclonal antibody JAQ1 induces depletion of the receptor from circulating platelets, resulting in abolished collagen responses and long-lasting antithrombotic protection.

Methods and Results— Mice were treated with JAQ1, and the early effects of this treatment were analyzed. In addition to the known abolition of the collagen reactivity, this treatment also affected platelet response to thrombin but not other agonists. In platelets from JAQ1-treated mice, thrombin-induced activation of integrin IIbß3, the surface expression of P-selectin, and the procoagulant activity were decreased on days 1 and 2, then progressively recovered and returned to normal on day 5. In parallel, the mice were transiently protected from lethal tissue factor–induced pulmonary thromboembolism (100% survivors versus 40% in control group), which appeared to be based on a decreased generation and activity of intravascular thrombin.

Conclusions— Anti-GPVI treatment induces 2-phase antithrombotic protection in mice consisting of a partial and transient inhibition of thrombin responses in platelets and a prolonged and complete loss of the collagen response.

Collagen and thrombin are major platelet agonists. The collagen receptor GPVI is an attractive antithrombotic target because its inhibition/absence results in profound antithrombotic protection but no bleeding in mice. We show that mice treated with the anti-GPVI antibody JAQ1 transiently display reduced platelet responses to thrombin and protection against lethal tissue factor-induced thromboembolism.

Key Words: collagen • GPVI • platelet • receptor • thrombin • thrombosis

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