Selectin-Like Kinetics and Biomechanics Promote Rapid Platelet Adhesion in Flow: The GPIbα-vWF Tether Bond

Abstract

The ability of platelets to tether to and translocate on injured vascular endothelium relies on the interaction between the platelet glycoprotein receptor Ib alpha (GPIb(alpha)) 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 GPIb(alpha)-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, k(0)(off) (3.45 +/- 0.37 s(-1)). Values for k(off), 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 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 GPIb(alpha)-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.

L-selectin-mediated leukocyte tethering in shear flow is controlled by multiple contacts and cytoskeletal anchorage facilitating fast rebinding events

“…Indeed, other vascular adhesion receptors specialized to capture cells share on-rates similar to that of L-selectin (31). Shear flow may also promote multicontact formation for shear-promoted platelet tethering to von Willebrand factor (32). It may also enhance formation of multivalent ␣ 4 ␤ 7 and LFA-1 integrin tethers to their respective ligands (33,34).…”

A Mathematical Model of Venous Thrombosis Initiation

“…In particular, the relative number of binding sites for coagulation proteins on monocytes and platelets is roughly equal to their relative surface areas, implying that they have similar surface densities of these binding sites. The second, which pertains to adhesion to the AECs, is that the bonds mediating this adhesion, P-selectin PSGL-1 bonds for monocytes and vWF GPIba for platelets are believed to have similar kinetics (43). The moving fluid's role in the model is to transport proteins and BBCs.…”

Platelet Storage Media Change the Expression Characteristics of the Platelet-Derived Microparticles

“…There are numerous studies related to the binding of platelets to vWF [10][11][12][13] but the studies about vWF binding virtue of PMP was not previously reported. In our study, the significantly higher binding capacity of PMP to vWF was demonstrated in the Composol medium at the fourth and seventh day of storage.…”

“…von Willebrand factor (vWF) is a multimeric plasma glycoprotein that supports platelet adhesion at sites of vascular injury [10]. vWF binds to platelets via the glycoprotein Ib and IIb/IIIa receptors.…”