von Willebrand factor: an emerging target in stroke therapy

Abstract

Thrombus formation is of paramount importance in the pathophysiology of acute ischemic stroke. Current antithrombotics used to treat or prevent cerebral ischemia are only moderately effective or bear an increased risk of severe bleeding. von Willebrand factor (VWF) has long been known to be a key player in thrombus formation at sites of vascular damage. While the association between VWF and coronary heart disease has been well studied, knowledge about the role of VWF in stroke is much more limited. However, in recent years, an increasing amount of clinical and preclinical evidence has revealed the critical involvement of VWF in stroke development. This review summarizes the latest insights into the pathophysiologic role of VWF-related processes in ischemic brain injury under experimental conditions and in humans. Potential clinical merits of novel inhibitors of VWF-mediated platelet adhesion and activation as powerful and safe tools to combat thromboembolic disorders including ischemic stroke are discussed. Preclinical and clinical evidence illustrates an important role of VWF in ischemic stroke, suggesting that VWF could become a promising target in stroke therapy.

Figure 1. Schematic representation of VWF

VWF is a multimeric protein composed of dimeric building blocks. The VWF domains, the binding sites of major binding partners and the cleavage site for ADAMTS13 are indicated. Adapted from De Meyer et al.

Figure 2. Schematic representation of VWF-mediated platelet adhesion and aggregation

VWF that is immobilized on collagen with its A3 domain or released from endothelial Weibel-Palade (WP) bodies recruits platelets by binding with its A1 domain to platelet GPIbα. Together with fibrinogen (not shown), VWF further cross-links platelets via binding of its C1 domain to platelet GPIIb/IIIa.

Figure 3. Schematic representation of mode-of-action of various VWF inhibitors

VWF-mediated platelet adhesion can be blocked by inhibiting binding of VWF to either collagen or GPIbα, or by cleaving VWF by ADAMTS13.