Platelet adhesion: a game of catch and release

Abstract

The interaction of circulating platelets with the vessel wall involves a process of cell catch and release, regulating cell rolling, skipping, or firm adhesion and leading to thrombus formation in flowing blood. In this regard, the interaction of platelet glycoprotein Ibalpha (GPIbalpha) with its adhesive ligand, vWF, is activated by shear force and critical for platelet adhesion to the vessel wall. In this issue of the JCI, Yago and colleagues show how gain-of-function mutations in the GPIbalpha-binding vWF A1 domain disrupt intramolecular interactions within WT vWF A1 that regulate binding to GPIbalpha and flow-enhanced platelet rolling and adhesion (see the related article beginning on page 3195). Together, these studies reveal molecular mechanisms regulating GPIbalpha-vWF bond formation and platelet adhesion under shear stress.

Figure 1. vWF-dependent platelet adhesion at high shear.

GPIb–IX-V–dependent adhesion of human platelets to multimeric vWF on the vessel wall — initiating thrombus formation — involves GPIbα binding vWF A1, a conformationally activated domain of vWF. In their study in this issue of the JCI, Yago et al. (8) show how shear force disrupts vWF A1 electrostatic interactions of D1269 with R1306 and R1450, reorientating vWF A1 relative to receptor and aligning R1334 of vWF to interact with E14 on GPIbα, facilitating adhesion under flow (red and blue circles denote negatively and positively charged residues, respectively; see ref. for structures). The authors show that vWD type 2B mutations (R1306Q or R1450E) constitutively disrupt interactions with D1269, enhancing binding to GPIbα, as well as promoting ADAMTS-13–dependent cleavage within vWF A2. These findings explain how these vWD mutations lead to enhanced vWF binding to platelet GPIbα and depletion of vWF associated with type 2B vWD. In WT vWF, the shear-induced changes in the binding interaction between vWF and GPIbα show how platelet adhesion is enhanced under the influence of shear force and how thrombus formation can be initiated at the vessel wall in flowing blood.