Von Willebrand factor in diagnostics and treatment of cardiovascular disease: Recent advances and prospects

Abstract

Von Willebrand factor (VWF) is a large multimeric glycoprotein involved in hemostasis. It is essential for platelet adhesion to the subendothelium of the damaged endothelial layer at high shear rates. Such shear rates occur in small-diameter arteries, especially at stenotic sites. Moreover, VWF carries coagulation factor VIII and protects it from proteolysis in the bloodstream. Deficiency or dysfunction of VWF predisposes to bleeding. In contrast, an increase in the concentration of high molecular weight multimers (HMWM) of VWF is closely associated with arterial thrombotic events. Severe aortic stenosis (AS) or hypertrophic obstructive cardiomyopathy (HOCM) can deplete HMWM of VWF and lead to cryptogenic, gastrointestinal, subcutaneous, and mucosal bleeding. Considering that VWF facilitates primary hemostasis and a local inflammatory response at high shear rates, its dysfunction may contribute to the development of coronary artery disease (CAD) and its complications. However, current diagnostic methods do not allow for an in-depth analysis of this contribution. The development of novel diagnostic techniques, primarily microfluidic, is underway. Such methods can provide physiologically relevant assessments of VWF function at high shear rates; however, they have not been introduced into clinical practice. The development and use of agents targeting VWF interaction with the vessel wall and/or platelets may be reasonable in prevention of CAD and its complications, given the prominent role of VWF in arterial thrombosis.

Keywords: ADAMTS-13; Heyde syndrome; cardiovascular disease; coronary artery disease; von Willebrand factor.

FIGURE 1

A schematic representation of the domains and binding sites of the Von Willebrand factor (VWF) monomer. The A1 domain contains a binding site for the glycoprotein complex Ib/IX/V (GP Ib) of platelets; collagen types I, IV, VI; and heparin. The A2 domain contains binding sites for the ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif 13) metalloprotease and VWF molecules. The A3 domain contains binding sites for collagen types I and III. The C4 domain contains a binding site for the platelet integrin αIIbβ3 (GPIIb/IIIa). C domains facilitate VWF flexibility. The D’D3 domain contains a binding site for coagulation factor VIII. The C-terminal cysteine knot (CTCK) is involved in the dimerization of VWF. All D domains are involved in the formation of disulfide bonds between VWF dimers.

FIGURE 2

A schematic representation of the multimeric structure of Von Willebrand factor (VWF). In the bloodstream, VWF is present in a range of multimers, from dimers (around 500 kDa) to high-molecular weight multimers (10,000 kDa and more). The larger the VWF multimer is, the more hemostatically active it is. VWF monomers are dimerized in the C-terminal cysteine knot (CTCK) through disulfide bonds. Other disulfide bonds bind VWF dimers in D domains to form multimers.

FIGURE 3

Shear-rate dependent activation of Von Willebrand factor (VWF) at the site of atherosclerotic stenosis. High shear rates occurring in the bloodstream at sites of significant atherosclerotic narrowing of the arterial lumen trigger unfolding of VWF multimers. Unfolded VWF presents a range of binding sites for proteins of subendothelial matrix, platelets and leukocytes. It is also subjected to proteolysis by ADAMTS-13 that cleaves unfolded VWF multimers at the A2 domains and reduces their hemostatic activity.