Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis

The growth arrest-specific gene 6 product (Gas6) is a secreted protein related to the anticoagulant protein S but its role in hemostasis is unknown. Here we show that inactivation of the

Gas6 gene prevented venous and arterial thrombosis in mice, and protected against fatal collagen/epinephrine-induced thrombo embolism. Gas6−/− mice did not, however, suffer spontaneous

bleeding and had normal bleeding after tail clipping. In addition, we found that Gas6 antibodies inhibited platelet aggregation in vitro and protected mice against fatal thrombo embolism

without causing bleeding in vivo. Gas6 amplified platelet aggregation and secretion in response to known agonists. Platelet dysfunction in Gas6−/− mice resembled that of patients with

platelet signaling transduction defects. Thus, Gas6 is a platelet-response amplifier that plays a significant role in thrombosis. These findings warrant further evaluation of the possible

therapeutic use of Gas6 inhibition for prevention of thrombosis.

We thank K. Bijnens, A. Bouché, I. Cartois, E. Demarsin, M. De Mol, K. Deroover, E. Gils, B. Hermans, S. Jansen, L. Kieckens, T. Vancoetsem, A. Vandenhoeck, I. Vanlinthout, M. Vanrusselt, P.

Vanwesemael, I. Vreys and S. Wyns for technical assistance and J. Vermylen for critical reading of the manuscript. This work was supported by Sanofi Research and the Swedish Medical

Research Council (Grants 07143, 12561 and 13000) and a Senior Investigators Award from the Swedish Foundation for Strategic Research. A. Angelillo-Scherrer is a recipient of awards from the

Swiss National Foundation for Scientific Research and the Fondation Suisse pour les Bourses en Médecine et Biologie.

Anne Angelillo-Scherrer and Pablo Garcia de Frutos: A.A.S. and P.G.F. contributed equally to this study.

The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium

Anne Angelillo-Scherrer, Els Melis, Jef Arnout, Mieke Dewerchin, Marc F. Hoylaerts, Désiré Collen & Peter Carmeliet

Department of Clinical Chemistry, Lund University, Wallenberg Laboratory, Malmö University Hospital, Malmö, Sweden

Cardiovascular/Thrombosis Research Department, Sanofi∼Synthélabo, Toulouse, France

Thrombosis Research Institute, Vascular Biology Laboratory, London, UK

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