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The ability of platelets to tether to and translocate on injured vascular endothelium relies on the interaction between the platelet glycoprotein receptor Ib α(GPIbα) and the A1 domain of von Willebrand factor (vWF-A1). To date, limited information exists on the kinetics that govern platelet interactions with vWF in hemodynamic flow. We now report that the GPIbα-vWF-A1 tether bond displays similar kinetic attributes as the selectins including: 1) the requirement for a critical level of hydrodynamic flow to initiate adhesion, 2) short-lived tethering events at sites of vascular injury in vivo, and 3) a fast intrinsic dissociation rate constant, koffo (3.45 ± 0.37 s-1). Values for koff, as determined by pause time analysis of transient capture/release events, were also found to vary exponentially (4.2 ± 0.8 s-1 to 7.3 ± 0.4 s-1) as a function of the force applied to the bond (from 36 to 217 pN). The biological importance of rapid bond dissociation in platelet adhesion is demonstrated by kinetic characterization of the A1 domain mutation, I546V that is associated with type 2B von Willebrand disease (vWD), a bleeding disorder that is due to the spontaneous binding of plasma vWF to circulating platelets. This mutation resulted in a loss of the shear threshold phenomenon, a approximately sixfold reduction in koff, but no significant alteration in the ability of the tether bond to resist shear-induced forces. Thus, flow dependent adhesion and rapid and force-dependent kinetic properties are the predominant features of the GPIbα–vWF-A1 tether bond that in part may explain the preferential binding of platelets to vWF at sites of vascular injury, the lack of spontaneous platelet aggregation in circulating blood, and a mechanism to limit thrombus formation.
Doggett, T. A., Girdhar, G., Lawshé, A., Schmidtke, D. W., Laurenzi, I. J., Diamond, S. L., & Diacovo, T. G. (2002). Selectin-Like Kinetics and Biomechanics Promote Rapid Platelet Adhesion in Flow: The GPIbalpha-vWF Tether Bond. Retrieved from https://repository.upenn.edu/cbe_papers/24
Date Posted: 20 February 2005
This document has been peer reviewed.