von Willebrand disease: advances in pathogenetic understanding, diagnosis, and therapy

Abstract

von Willebrand disease (VWD) is the most common autosomally inherited bleeding disorder. The disease represents a range of quantitative and qualitative pathologies of the adhesive glycoprotein von Willebrand factor (VWF). The pathogenic mechanisms responsible for the type 2 qualitative variants of VWF are now well characterized, with most mutations representing missense substitutions influencing VWF multimer structure and interactions with platelet GPIbα and collagen and with factor VIII. The molecular pathology of type 3 VWD has been similarly well characterized, with an array of different mutation types producing either a null phenotype or the production of VWF that is not secreted. In contrast, the pathogenetic mechanisms responsible for type 1 VWD remain only partially resolved. In the hemostasis laboratory, the measurement of VWF:Ag and VWF:RCo are key components in the diagnostic algorithm for VWD, although the introduction of direct GPIbα-binding assays may become the functional assay of choice. Molecular genetic testing can provide additional benefit, but its utility is currently limited to type 2 and 3 VWD. The treatment of bleeding in VWD involves the use of desmopressin and plasma-derived VWF concentrates and a variety of adjunctive agents. Finally, a new recombinant VWF concentrate has just completed clinical trial evaluation and has demonstrated excellent hemostatic efficacy and safety.

Figure 1

Diagram representing the revised annotation of the VWF mature subunit structure. This annotation, derived from electron microscopy analysis, demonstrates that the VWF D assemblies are composed of 4 smaller modules: VWF, 8-cysteine (C8), trypsin-like inhibitor (TIL), and E or fibronectin type 1-like modules (E). The previous B and C domains are now re-annotated as 6 tandem VWF C domains. The electron micrograph image of the D1 assembly shown here is from Zhou et al. As indicated, there is growing evidence that VWF interacts with a large number of ligands with a range of biological functions. VWFpp indicates VWF propeptide; OPG, osteoprotegerin; PSGL-1, P-selectin glycoprotein ligand-1; β2GPI, beta2 glycoprotein 1; and TSP1, thrombospondin 1.

Figure 2

Figure illustrating the location of mutations resulting in the various VWD subtypes. Types 1 and 3 VWD are caused by different types of mutation throughout the VWF sequence. In contrast, the type 2 VWD mutations are localized to distinct functional domains of VWF, affecting multimer structure (2A), binding to FVIII (2N), platelets (2B and 2M), and collagen (2M).