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

Nature Medicine volume 7, pages 215–221 (2001)Cite this article

Abstract

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.

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Figure 1: Targeting of the Gas6 gene.
Figure 5: Expression and role of Gas6 in platelets.
Figure 2: Inactivation or inhibition of Gas6 protects mice against thrombosis.
Figure 3: Effect of Gas6 deficiency or of anti-Gas6 antibodies on platelet aggregation.
Figure 4: Role of Gas6 in the formation of platelet macro-aggregates.

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Acknowledgements

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.

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Author notes

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

Authors and Affiliations

  1. 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

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

    Pablo Garcia de Frutos, Cristina Aparicio & Björn Dahlbäck

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

    Pierre Savi & Jean-Marc Herbert

  4. Thrombosis Research Institute, Vascular Biology Laboratory, London, UK

    Florea Lupu

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Correspondence to Peter Carmeliet.

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Angelillo-Scherrer, A., de Frutos, P., Aparicio, C. et al. Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis. Nat Med 7, 215–221 (2001). https://doi.org/10.1038/84667

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