2B or not 2B? Differential identification of Type 2B, versus pseudo‐,von Willebrand disease

Abstract

We read with interest the recent debate surrounding the diagnosis of type 2B von Willebrand disease (VWD) versus pseudo-VWD (Enayat et al, 2006; Favaloro, 2006), where the distinction between the two disorders is based on cryoprecipitate or radioimmunoprecipitation assay (RIPA)-based plasma/platelet mixing studies and genetic testing. In response to Dr Favaloro's invitation to hear of the experience of other workers, we would like to present our data at the Ipswich Hospital, UK, which serves a population of nearly half a million. From our records, we had one kindred comprising eight family members spanning over three generations who were historically diagnosed as type 2B VWD based on phenotypic data. However, we recently re-investigated this family with targeted mutation analysis of von Willebrand factor exon 28 and found this to be normal. Hence the diagnosis of type 2B VWD was questioned and so we proceeded to direct gene sequencing of the glycoprotein 1b alpha gene. We identified Gly249Val mutation, which is one of the three mutations previously described in pseudo-VWD (Miller et al, 1991) thus establishing the correct diagnosis of pseudo-VWD. For completion, we then performed RIPA-based plasma/platelet mixing studies which confirmed the diagnosis of pseudo-VWD in this family. Dr Favaloro suggests that genetic screening for pseudo-VWD is a secondary, confirmatory test that is rarely available, so the gold standard should rely on mixing studies, and he proposes that the RIPA-based mixing studies are superior to the cryoprecipitate challenge. However, as we are dealing with a rare orphan status disease, every laboratory should have the opportunity to refer samples for genetic testing at a tertiary centre (in our case Addenbrookes Hospital, Cambridge, UK). Equally it is debatable that the mixing studies are a ‘simple laboratory test’ that can be performed with local expertise, as in most cases these would also require referral elsewhere. Bearing in mind that both RIPA and cryoprecipitate-based mixing studies are cumbersome, technically complex and can yield false positive results, genetic testing remains a powerful diagnostic tool which, in the 21st century, is of prime importance in the differential identification of type 2B VWD versus pseudo-VWD.