A molecular approach to the classification of von Willebrand disease

The marked heterogeneity of von Willebrand disease was already recognized b y von Willebrand in 1926. The accumulating knowledge of the different clini cal phenotypes and the pathophysiological basis of the disease was translat ed into a classification that differentiated between quantitative and quali tative defects by means of quantitative and functional parameters and by an alysing the electrophoretic pattern of von Willebrand factor multimers. The increasing number of different von Willebrand disease phenotypes required a revision of the nomenclature at a time when only a few types of von Wille brand disease had already been analysed at the molecular level. Consequentl y, the molecular data played only a minor role in the revised classificatio n. Given the pronounced, even intra-individual, variation in the manifestat ion of von Willebrand disease and the diagnostic difficulties caused by a n on-standardized methodology, it is clear that biochemical methods alone are insufficient for a clear classification. The advent of molecular technique s provided the opportunity for genotype-phenotype studies that recently hel ped to elucidate or confirm not only the important functions of von Willebr and factor and the steps of its post-translational processing, but also man y disease-causing defects. The reproducible correlation between certain phe notypes and particular mutations can now be used for a molecular approach t owards a final classification of von Willebrand disease, equally useful for the clinician and for research requirements.