The role of platelet adhesion receptor GPIbα far exceeds that of its main ligand, von Willebrand factor, in arterial thrombosis

GPIb alpha 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, GPIb alpha may bind other ligands or that a receptor other than GPIb alpha can mediate platelet adhesion. Here, we studied thrombus formation in transgenic mice expressing GPIb alpha in which the extracellular domain was replaced by that of the human IL-4 receptor (IL4Ra/GPlb alpha-tg mice). Platelet adhesion to ferric chloride-treated mesenteric arterioles in IL4Ra/GPlba-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, IL4R alpha/ GPIb alpha-tg platelets or WT platelets lacking the 45-kDa N-terminal domain of GPIb alpha failed to incorporate into growing arterial thrombi, even if the platelets were activated before infusion. Surprisingly, platelets lacking beta 3 integrins, which are unable to form thrombi on their own, incorporated efficiently into WT thrombi. Our studies provide in vivo evidence that GPIba absolutely is required for recruitment of platelets to both exposed subendothelium and thrombi under arterial flow conditions. Thus, GPIb alpha contributes to arterial thrombosis by important adhesion mechanisms independent of the binding to VWF.