von Willebrand disease: clinical and laboratory lessons learned from the large von Willebrand disease studies

Abstract

During the past 25 years, our knowledge concerning the pathogenesis, diagnostic strategies, and treatment of von Willebrand disease (VWD) has increased significantly. Following the immunological differentiation of factor VIII (FVIII) and von Willebrand factor (VWF) in the 1970s and the cloning of the FVIII and VWF genes in the mid-1980s, substantial progress has been made in our understanding of this, the most common inherited bleeding disorder. We now recognize that VWD represents a range of genetic diseases all with the clinical endpoint of increased mucocutaneous bleeding. The molecular pathology of Type 2 and 3 VWD is now comprehensively documented and involves rare sequence variants at the VWF locus. In contrast, the genetic causation of Type 1 disease remains incompletely defined and in many cases appears to involve genetic determinants in addition to or instead of VWF. The diagnostic triad of a personal history of excessive mucocutaneous bleeding, laboratory tests for VWF that are consistent with VWD, and a family history of the condition remain the keystone to VWD identification. In the laboratory, measurement of VWF antigen and function continue to be the most important diagnostic studies, and while our understanding of the molecular genetic pathology of VWD has advanced considerably in the past decade, genetic testing as a component of diagnosis is limited to certain distinct subtypes of the disorder. Treatment of VWD has been relatively unchanged for the past decade and continues to involve either stimulation of the release of intrinsic VWF with desmopressin or the infusion of VWF concentrates.

Figure 1

Location of the missense mutations resulting in type 2 VWD.

Figure 2

Pathogenetic mechanisms resulting in Type 2A VWD.

Figure 3

The genetic characteristics of von Willebrand disease subtypes.

Figure 4

Summary of key findings in the four recent Type 1 VWD genetic studies.

Figure 5

The life-cycle of von Willebrand factor from gene expression to receptor-mediated clearance. Pathogenic mechanisms localized to any of these processes can result in a reduction in plasma VWF levels.

Figure 6

Novel non-VWF genetic loci characterized in the recent CHARGE genome-wide association study meta-analysis as being associated with plasma levels of VWF.

Figure 7

A model for the influence of rare and frequent genetic variants on the levels of VWF.