Distinct antithrombotic consequences of platelet glycoprotein Ibα and VI deficiency in a mouse model of arterial thrombosis

Authors

  • S. KONSTANTINIDES,

    1. The Roon Center for Arteriosclerosis and Thrombosis, Division of Experimental Hemostasis and Thrombosis, Department of Molecular and Experimental Medicine, and the Division of Vascular Biology, Department of Cell Biology, The Scripps Research Institute, La Jolla, CA, USA
    2. Department of Cardiology and Pulmonary Medicine, Georg August University, Göettingen, Germany
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    • 1

      These authors contributed equally to the work.

  • J. WARE,

    1. The Roon Center for Arteriosclerosis and Thrombosis, Division of Experimental Hemostasis and Thrombosis, Department of Molecular and Experimental Medicine, and the Division of Vascular Biology, Department of Cell Biology, The Scripps Research Institute, La Jolla, CA, USA
    2. Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
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    • 1

      These authors contributed equally to the work.

  • P. MARCHESE,

    1. The Roon Center for Arteriosclerosis and Thrombosis, Division of Experimental Hemostasis and Thrombosis, Department of Molecular and Experimental Medicine, and the Division of Vascular Biology, Department of Cell Biology, The Scripps Research Institute, La Jolla, CA, USA
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  • F. ALMUS-JACOBS,

    1. The Roon Center for Arteriosclerosis and Thrombosis, Division of Experimental Hemostasis and Thrombosis, Department of Molecular and Experimental Medicine, and the Division of Vascular Biology, Department of Cell Biology, The Scripps Research Institute, La Jolla, CA, USA
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  • D. J. LOSKUTOFF,

    1. The Roon Center for Arteriosclerosis and Thrombosis, Division of Experimental Hemostasis and Thrombosis, Department of Molecular and Experimental Medicine, and the Division of Vascular Biology, Department of Cell Biology, The Scripps Research Institute, La Jolla, CA, USA
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  • Z. M. RUGGERI

    1. The Roon Center for Arteriosclerosis and Thrombosis, Division of Experimental Hemostasis and Thrombosis, Department of Molecular and Experimental Medicine, and the Division of Vascular Biology, Department of Cell Biology, The Scripps Research Institute, La Jolla, CA, USA
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Zaverio M. Ruggeri, The Scripps Research Institute – MEM 175, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Tel.: +1 858 784 8950; fax: +1 858 784 2026; e-mail: ruggeri@scripps.edu

Abstract

Summary. Background: Collagen and von Willebrand factor (VWF) are considered essential to initiate platelet deposition at sites of vascular injury, but their respective roles remain to be elucidated. Methods: We used a model of carotid artery thrombosis induced by a ferric chloride injury to compare the time to first occlusion and occlusion rate at 25 min postinjury in mice lacking the collagen receptor, glycoprotein (GP) VI, or the ligand-binding domain of the VWF receptor, GP Ibα. Results: In normal mice used as controls (n = 12), a complete obstruction of blood flow developed within 8.05 ± 0.47 min (mean ± SEM), and the occlusion rate was 100%. The results were variable in 26 GP VI−/− mice. The artery never occluded in eight mice, but the time to first occlusion in the remaining 18 (8.36 ± 0.27 min) was not different from normal (P = 0.556). Nonetheless, the occlusion rate was 42%, because in seven mice the occluded artery reopened and stayed patent at 25 min. In contrast, the artery never occluded in 12 mice lacking GP Ibα. In ex vivo perfusion experiments, GP VI−/− platelets failed to form thrombi onto collagen type I fibrils, but formed thrombi of normal size when exposed to endothelial or fibroblast extracellular matrix. Conclusions: Absence of GP Ibα function has a more profound antithrombotic effect in vivo than absence of the GP VI-dependent pathway of collagen-induced adhesion/activation. Components of the extracellular matrix may elicit a thrombogenic response in the absence of GP VI but not GP Ibα.

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