Ligand interactions of platelet glycoprotein Ib-IX-V in thrombosis

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The transition of circulating blood platelets from a fluid-phase, non-adherent state to an adherent, activated and aggregated state (thrombus formation) is critical in the normal haemostatic response to blood vessel injury and in thrombotic diseases such as heart attack and stroke. One unique platelet receptor, the glycoprotein Ib-IX-V complex, is of particular interest, because it initiates platelet aggregate or thrombus formation at high fluid shear stress in flowing blood, including the pathological shear stress that occurs in a sclerotic coronary artery. Our published and preliminary results show how GPIb-dependent interaction of platelets with von Willebrand factor, the major adhesive ligand for GPIb-IX-V, is dependent on the level of shear stress. Using a cross-species (human to canine) homology-swap approach, where human sequence is replaced by the corresponding canine sequence within discrete structural domains, a sequence of GPIb has been identified which becomes increasingly important as hydrodynamic shear stress increases. It is proposed to further define the interactive surface of GPIb that recognizes von Willebrand factor at increasing shear, and to define the relationship between the shear-dependent alteration of GPIb conformation and its ability to interact with other pro-thrombotic or pro-inflammatory binding partners.