On the versatility of von Willebrand factor

Abstract

Von Willebrand factor (VWF) is a large multimeric protein, the function of which has been demonstrated to be pivotal to the haemostatic system. Indeed, quantitative and/or qualitative abnormalities of VWF are associated with the bleeding disorder Von Willebrand disease (VWD). Moreover, increased plasma concentrations of VWF have been linked to an increased risk for thrombotic complications. In the previous decades, many studies have contributed to our understanding of how VWF is connected to the haemostatic system, particularly with regard to structure-function relationships. Interactive sites for important ligands of VWF (such as factor VIII, collagen, glycoprotein Ibα, integrin αIIbβ3 and protease ADAMTS13) have been identified, and mutagenesis studies have confirmed the physiological relevance of the interactions between VWF and these ligands. However, we have also become aware that VWF has a more versatile character than previously thought, given its potential role in various non-hemostatic processes, like intimal thickening, tumor cell apoptosis and inflammatory processes. In the presence review, a summary of our knowledge on VWF structure-function relationships is provided in the context of the "classical" haemostatic task of VWF and in perspective of pathological processes beyond haemostasis.

Figure 1. Domain structure of VWF

The molecular architecture of VWF is characterized by the presence of distinct domain structures. Panel A represents the arrangement of five different structures according to the original analysis of the VWF sequence (reviewed by Pannekoek & Voorberg). The numbering of the domain boundaries has been used in our laboratory in the previous years. Panel B shows the domain organization as has recently been proposed by Zhou et al. One striking difference with the original domain structure is the replacement of the B1-3 - C1 - C2 domain region by 6 homologous C-domains. In addition, their analysis revealed that the D-domains consist of various independent structures, which are highlighted in panel C. The D1, D2 and D3 domains each contain a VW-domain, a trypsin inhibitor-like (TIL)-structure, a C8 fold and an E module. The D′ region lacks the VW domain and TIL-structure. The D4 domain lacks the E module, but instead comprises a unique sequence designated D4N.

Figure 2. The functional diversity of VWF

VWF is best known for its link with the hemostatic system, where it participates in the recruitment of platelets to the injured vessel wall and acts as a carrier protein for FVIII. The physiological relevance of this function is underscored by VWF being associated with bleeding problems (VWD and acquired VW syndrome) as well as thrombotic complications (myocard infarction, stroke and venous thrombosis). More recently it has been found that VWF is involved in other patho-physiological processes as well, such as tumor metastasis (inducing tumor cell death), angiogenesis (which could provide a rationale for the relatively frequent occurrence of angiodysplasia in VWD patients), cell proliferation (associated with enhanced intima thickening after angioplasty and in CADASIL), and inflammatory processes (as observed in animal models for atherosclerosis, stroke, wound healing and experimental allergic encephalomyelitis).