Type 1 von Willebrand disease.

Since its first description in 1926, the precise nature and indeed significance of von Willebrand factor (VWD) in the area of human bleeding has been unsure and often controversial. The recognition of VWD as a distinct entity in blood and the cloning of the von Willebrand factor (VWF) gene in the 1980s encouraged both phenotypic and genotypic studies, culminating in 1994 with the recognition, by the VWF subcommittee of the Scientific and Standardization Committee (SSC) of International Society of Thrombosis and Haemostasy (ISTH), of three types of VWD, characterized by severe plasma VWF deficiency (type 3), functionally deficient plasma VWF (type 2) and reduced (below normal) levels of plasma VWF, which is functionally essentially normal (type 1; 70% of all cases). Since then, whereas gene analysis has recognized VWF gene (VWF) mutations in most individuals with type 3 and type 2 disease, the latter mutations correlating well with recognized functional domains within the VWF protein, few mutations have been reported in cases with type 1 VWD. This led to speculation that other factors, particularly ABO blood group, may be primarily responsible for the majority of such patients, perhaps combined with a generic bleeding tendency throughout the normal population. Recent large studies in Europe and Canada have considerably clarified this situation, revealing that the majority of type 1 VWD is associated with mutations within VWF. The role of these mutations in the aetiology of the disease opens up new approaches to the study of the diagnosis and treatment of the condition. Conversely, the lack of a change in the VWF gene in many recruited families will lead to enhanced efforts to identify non-VWF gene causes both at the genetic and epigenetic level.