Genetic Background of von Willebrand Disease: History, Current State, and Future Perspectives

Abstract

Sequencing of the gene encoding for von Willebrand factor (VWF) has brought new insight into the physiology of VWF as well as its pathophysiology in the context of von Willebrand disease (VWD). Molecular testing in VWD patients has shown high variability in the overall genetic background of this condition. Almost 600 mutations and many disease-causing mechanisms have been described in the 35 years since the VWF gene was identified. Genetic testing in VWD patients is now available in many centers as a part of the VWD diagnostic algorithm. Molecular mechanisms leading to types 2 and 3 VWD are well characterized; thus, information from genetic analysis in these VWD types may be beneficial for their correct classification. However, the molecular basis of type 1 VWD is still not fully elucidated and most likely represents a multifactorial disorder reflecting a combined impact of environmental and genetic factors within and outside of VWF. Regarding sequencing methods, the previous gold-standard Sanger sequencing is gradually being replaced with next-generation sequencing methods that are more cost- and time-effective. Instead of gene-by-gene approaches, gene panels of genes for coagulation factors and related proteins have recently become a center of attention in patients with inherited bleeding disorders, especially because a high proportion of VWD patients, mainly those with low VWF plasma levels (type 1), appear to be free of mutations in VWF. Whole-exome sequencing (WES) and whole-genome sequencing (WGS) are accessible in a very limited number of laboratories. Results from these studies have presented several genes other than VWF or ABO possibly affecting VWF levels, and such findings will need further validation studies.

Navigating the Myriad of von Willebrand Factor Assays

“…An alternative commercial method is now available that can also in general distinguish 2A and 2M VWD. 24,25 Recognize, however, that VWD represents a continuous variable, with hundreds of separate VWF mutations identified, 39 and thus some patients will still remain in an equivocal zone with exhaustive testing, even including VWF multimers and genetic testing. Be also aware that the commercial VWF multimer method cannot distinguish multimer changes in a triplet structure, as sometimes used to identify rarer forms of type 2 VWD.…”

Classification of von Willebrand disease in the context of modern contemporary von Willebrand factor testing methodologies

“…Table 1 provides a summary of the classification description and what may be expected in terms of VWF test findings, including multimers, for VWD. It should be recognized that although this table will in general hold true for most cases of VWD, there are always exceptions, given the great heterogeneity in both VWD (on a case‐by‐case basis) and VWF defects (as highlighted by the large number of “mutations” evident in both the VWF database and published literature 17 ).…”

How we diagnose 2M von Willebrand disease (VWD): Use of a strategic algorithmic approach to distinguish 2M VWD from other VWD types

“…Finally, with next-generation sequencing it becomes ever easier to obtain genetic testing [38][39][40] ; however, current caveats remain (Table S1). Whilst in experienced hands, genetic testing is greatly valued, in inexperienced hands there is a potential danger to overcall genetic variants as damaging or disease causing when they are not.…”