Genotype/phenotype association in von Willebrand disease: is the glass half full or empty?

Abstract

Since the original description of this disease in 1926, major advances have been made in our understanding of the pathogenetic mechanisms responsible for von Willebrand disease (VWD). We now recognize that this disease comprises a collection of diverse quantitative and qualitative abnormalities of the adhesive protein von Willebrand factor (VWF), the key protein involved in platelet adhesion, and the carrier protein for factor VIII (FVIII) in plasma. Since the mid-1970s there has been a growing appreciation of 'variant' forms of the disease and in the 20 years since the cloning of the VWF gene, much progress has been made in characterizing the molecular genetic pathology of type 3 VWD and the various type 2 variants, types 2A, 2B, 2M and 2N VWD. In all of these cases, mechanistic insights into VWF structure/function have been forthcoming. Most recently, preliminary results relating to the mutational landscape of type 1 disease have been published that highlight the complex pathogenic background of this mild/moderate quantitative trait.