Platelet physiology and thrombosis

Glycoprotein (GP) Ib alpha of the GPIb-IX-V complex and GPVI bind von Willebrand factor (vWF) and collagen, respectively, and are critical for the initial interaction of circulating platelets with the injured vessel watt under high shear conditions. These interactions act together to facilitate stable thrombus formation in vivo. Ligand binding to GPIb-IX-V of the leucine-rich repeat family or GPVI of the immunoglobulin superfamily initiates platelet activation, and inside-out activation of the platelet integrin, alpha IIb beta 3, that binds vWF or fibrinogen and mediates platelet aggregation. The binding site for GPIb alpha on vWF resides in the conserved A1 domain, encompassing the disulfide bond at Cys509-Cys695. This domain may be activated to bind platelet GPIba under shear stress by anchoring of the downstream A3 domain to collagen and conformational distortion of the intervening A2 domain. The N-terminal, 282 residues, of GPIb alpha contains the binding site for vWF-A1, as well as the conserved A-type domain of the leukocyte integrin alpha M beta 2 (alpha M I domain) and P-setectin expressed on activated platelets or endothelial cells. Endothelial P-selectin also supports surface expression of vWF multimers, enabling platelet vessel watt interaction by at Least two mechanisms. Recent evidence suggests GPVI that binds collagen, and GPIb-IX-V that binds collagen-bound vWF are physically associated on the platelet surface. This review will focus on the structure-function of primary platetet adhesion receptors, GPIb-IX-V and GPVI, and how they act together to regulate platelet thrombus formation in pathophysiotogy. (c) 2004 Elsevier Ltd. All rights reserved.