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The Role of Platelet Adhesion Receptor GPIbα Far Exceeds That of Its Main Ligand, von Willebrand Factor, in Arterial Thrombosis

Wolfgang Bergmeier, Crystal L. Piffath, Tobias Goerge, Stephen M. Cifuni, Zaverio M. Ruggeri, Jerry Ware and Denisa D. Wagner
Proceedings of the National Academy of Sciences of the United States of America
Vol. 103, No. 45 (Nov. 7, 2006), pp. 16900-16905
Stable URL: http://www.jstor.org/stable/30051767
Page Count: 6
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Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
The Role of Platelet Adhesion Receptor GPIbα Far Exceeds That of Its Main Ligand, von Willebrand Factor, in Arterial Thrombosis
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Abstract

GPIbα binding to von Willebrand factor (VWF) exposed at a site of vascular injury is thought to be the first step in the formation of a hemostatic plug. However, our previous studies in VWF-deficient mice demonstrated delayed but not absent arterial thrombus formation, suggesting that, under these conditions, GPIbα may bind other ligands or that a receptor other than GPIba can mediate platelet adhesion. Here, we studied thrombus formation in transgenic mice expressing GPIba in which the extracellular domain was replaced by that of the human IL-4 receptor (IL4Rα/GPIbα-tg mice). Platelet adhesion to ferric chloride-treated mesenteric arterioles in IL4Rα/GPIbα-tg mice was virtually absent in contrast to avid adhesion in WT mice. As a consequence, arterial thrombus formation was inhibited completely in the mutant mice. Our studies further show that, when infused into WT recipient mice, IL4Rcα/ GPIbα-tg platelets or WT platelets lacking the 45-kDa N-terminal domain of GPIbα failed to incorporate into growing arterial thrombi, even if the platelets were activated before infusion. Surprisingly, platelets lacking β3 integrins, which are unable to form thrombi on their own, incorporated efficiently into WT thrombi. Our studies provide in vivo evidence that GPlba absolutely is required for recruitment of platelets to both exposed subendothelium and thrombi under arterial flow conditions. Thus, GPlbα contributes to arterial thrombosis by important adhesion mechanisms independent of the binding to VWF.

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