Genetics of type 2B von Willebrand Disease: “True 2B,” “tricky 2B,” or “Not 2B.” What Are the Modifiers of the Phenotype?

Abstract

Type 2B von Willebrand disease (VWD) is a qualitative type of VWD with a unique feature among VWD types, resulting from an increased binding of von Willebrand factor (VWF) to its platelet receptor glycoprotein 1b-alpha (GP1BA). This heightened responsiveness takes place in vivo without endothelial injury or shear stress induction, typically resulting in loss of the hemostatically most active high-molecular-weight VWF multimers and leading to a bleeding diathesis. This process also typically leads to clearance of platelets and thus usually mild thrombocytopenia. At least this describes the classic representation of type 2B VWD (i.e., the typical picture we have come to know since the description/classification of this disorder in the early 1990s). Over more recent years, several reports have described individual cases, groups of patients, and families diagnosed with type 2B VWD where this picture was not typical in one or more aspects. This review discusses type 2B-like disorders and sheds light on potential phenotypic modifiers that might be responsible for the variation encountered with the classic picture of type 2B VWD as well as the impact on the diagnostic certainty of type 2B VWD.

Reduced survival of type 2B von Willebrand factor, irrespective of large multimer representation or thrombocytopenia

“…Most of them are associated with a shortage of large VWF multimers (type 2B VWD) but some have a full complement of large VWF multimers. 22,23,32 For the purpose of the study, and to emphasize the difference from and similarity to classic type 2B, these latter patients are identified as cases of atypical type 2B VWD.…”

Genetic testing for von Willebrand disease: the case against

“…PT-VWD clinically and phenotypically mimics type 2B VWD. Although PT-VWD and 2B VWD can be distinguished by special phenotypic evaluation [13] or by a genetic approach (analysis of the GPIBA and/or VWF genes [14]), the fact remains that the GPIBA receptor is able to moderate the phenotypic expression of VWF and this can lead to a condition that is difficult for many to distinguish from VWD caused by a mutation in the VWF gene.…”

“…Such diagnostic ÔclarityÕ is likely to be more elusive than currently appreciated. A recent evaluation of the VWD database [22] and literature has highlighted several genetic classification discrepancies (Table 1 and [14,23]). Thus, several mutations have been ascribed to different VWD types by different researchers, different amino acid substitutions within the same location can also lead to discrepancies in VWD typing, and adjacent or close-proximity mutations will also be ascribed to different VWD types.…”

Inherited platelet disorders: a clinical approach to diagnosis and management

“…Inherited platelet disorders: a clinical approach to diagnosis & management menorrhagia and excessive bleeding after tooth extraction, tonsillectomy and other surgical procedures; however, severe bleeding symptoms have also been reported [25,27]. Although the platelet count may be normal, thrombocytopenia can be observed, which may become more severe under conditions of stress, pregnancy and infection due to the increased release of endogenous VWF under these conditions.…”