Figure 1.

Illustration of VWF mechanoactivation (inset) and the step-by-step process of GPIb-mediated platelet mechanosensing. VWF is activated by shear flow in two steps: it is first globally elongated from a globular to an extended conformation, followed by the relief of its A1 domain autoinhibition that enables binding to platelet GPIbα. Once VWF is bound to a platelet, force from the shear flow transmits from VWF to GPIbα and triggers a series of GPIbα conformational changes and allosteric effects. These events would result in the reinforcement of VWF–GPIb interaction as well as the initiation of a mechanosignaling pathway that eventually leads to intracellular calcium release and GPIIb/IIIa activation. Note: platelet GPVI and its interaction with collagen are also depicted in this graph. Agents and drugs that have the potential to inhibit arterial thrombosis by targeting GPIb-mediated or GPVI-mediated platelet binding and mechanosensing, and their respective targets, are indicated, corresponding to table 1.