In 1926, Erik von Willebrand, a Finnish internist, reported his studies of a family living on the Aland Islands, in the Gulf of Bothnia between Finland and Sweden. The proband was a 5-year-old girl with severe spontaneous bleeding. Three of her sisters had died before age 4 of severe bleeding. Both parents and many relatives had mild bleeding histories, and the disease clearly differed from both haemophilia and Glanzmann thrombasthenia. Severe disease was transmitted through males and females, among whom some were mildly symptomatic and others were asymptomatic. During the ensuing 70 years, our understanding of von Willebrand disease (VWD) has advanced to the point that we can discuss its pathogenesis in molecular detail. Nevertheless, VWD remains a clinical diagnostic problem for many of the reasons that were evident from the earliest reports. Chief among these are that no bleeding symptoms are specific for VWD, and heterozygous transmitters of VWD may be phenotypically normal. This presentation will consider the classification of VWD and some practical problems associated with its diagnosis.

Von Willebrand factor (VWF) is a large, multimeric protein that circulates in the blood plasma. VWF also is stored in granular of endothelial cells and platelets, and can be secreted from these sites in response to appropriate stimuli. VWF performs two major roles in hemostasis; it mediates the adhesion of platelets to sites of vascular injury, and it is a carrier protein for factor VIII. Defects in VWF, therefore, may cause bleeding by impairing either platelet adhesion or blood clotting. A database of VWD mutations and VWF polymorphisms, maintained by Dr. David Ginsburg and colleagues, is on the Internet at http://mmg2.im.med.umich.edu.

This increasingly complex basic information has led to a simplified classification for VWD (Table 1). This includes three major categories: partial quantitative deficiency (type 1), qualitative deficiency (type 2), and total deficiency (type 3). Qualitative type 2 VWD is divided further into four variants - 2A, 2B, 2M, and 2N - based upon the nature of the phenotype. These six categories correspond to distinct pathophysiologic mechanisms with distinct clinical features and therapeutic requirements.