Von Willebrand Factor and Cardiovascular Disease: From a Biochemical Marker to an Attractive Therapeutic Target

Abstract

Background: Despite recent advances, there is still an unmet need in antithrombotic therapy. New drugs have to overcome old targets, looking for new complementary strategies to counteract thrombus formation and propagation. Since its initial recognition in the 50's, von Willebrand Factor (VWF) has proved to be a contributor in clot formation. The contribution of VWF to platelet adhesion and aggregation is pivotal at high shear rates (i.e. microcirculation and critical artery stenosis), where globular-inactive-VWF elongates in a long chain-active conformation. Particularly, at sites of plaque erosion/disruption the activation of VWF may contribute critically to post-stenotic thrombus formation. In this context, VWF is a potential target of antithrombotic therapies. The plasma concentration of VWF increases in high risk population and predicts cardiovascular (CV) outcome. VWF demonstrates an emerging role in different clinical settings; for example, in valvular heart disease where it has been recently proposed as a new fluido-dynamic marker of disease severity and a predictor of successful correction. Drugs used in daily clinical practice (LMWHs, statins, N-acetylcysteine, glycoprotein IIb/IIIa inhibitors) may have an unselective antagonism on the VWF-pathway. Recently, several "tailor-made" inhibitors of VWF have been investigated. In animal models and clinical studies monoclonal antibodies, aptamers and nanobodies have been demonstrated to directly interfere with the VWF pathway. These studies proved the powerful antithrombotic property and the acceptable level of safety of this strategy.

Conclusion: We provide an overview of the drugs that a have a role in VWF-antagonism, illustrating how they might become a potential option to overcome current limitations of antithrombotic therapy.

Keywords: Von Willebrand factor; acute coronary syndromes; antithrombotic therapy; atherothrombosis; microvascular disease; platelets; valvular heart disease.