Selectin-like kinetics and biomechanics promote rapid platelet adhesion in flow: the GPIbα-vWF tether bond

The ability of platelets to tether to and translocate on injured vascular endothelium relies on the interaction between the platelet glycoprotein receptor Ib alpha (GPIbα) and the A1 domain of von Willebrand factor (vWF-A1). 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 flow to initiate adhesion, 2) short-lived tethering events at sites of vascular injury in vivo, and 3) a fast intrinsic dissociation rate constant, k_off⁰ (3.45 ± 0.37 s^-1). Values for k_off, also varied 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 217pN). The biological importance of rapid bond dissociation is demonstrated by kinetic characterization of the naturally occurring A1 domain mutation, I546V that results in spontaneous binding of plasma vWF to circulating platelets in flowing blood. This mutation resulted in a loss of the shear threshold phenomenon, a ∼6-fold reduction in k_off, 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.