ON WILLEBRAND disease (vWD) was first described V by Erik von Willebrand in 1926l in several members of a family from the hand archipelago in Finland. The proband, a 7-year-old girl, and 9 of her 11 siblings all had significant bleeding symptoms, four dying of hemorrhage between the ages of 2 and 4 and the proband herself dying of hemorrhage at the age of 13 at the time of her fourth menstrual period. von Willebrand coined the term “hereditary pseudohaemophilia” for the disease that subsequently bore his name. In retrospect, the first case of vWD may actually have been described by Minot and Lee in 1920, 2 and a similar clinical disorder was reported independently by four American groups in 1928.3, 4 In 1953, an association between decreased factor VI11 (FVIII) procoagulant activity and vWD was first described, leading to some confusion concerning the protein defects responsible for hemophilia A and vWD.~,~ An explosion in the understanding of von Willebrand factor (vWF) and FVIlI began with the immunologic characterization of the proteins in the early 1970s, culminating in the cDNA cloning of FVIII in 19845, 6 and vWF in 1985.7-10 Molecular defects responsible for hemophilia and vWD were first detected by Southern blot analysis in 198S1 and 1987, 12, 13 respectively. The subsequent identification of point mutations in DNAs from large numbers of hemophilic and vWD patients was made possible by the discovery of the polymerase chain reaction in 1985 and the application of Tuq polymerase in 1987.14 J5 This review will focus on the molecular genetics of vWD. The biosynthesis, structure, and function of the vWF protein will only be briefly introduced. For a more detailed discussion of these latter topics, the interested reader is referred to several excellent recent reviews. 16-20 vWF BIOSYNTHESIS

The vWF monomeric subunit of approximately 250 Kd in molecular weight is assembled into multimers containing up to 100 subunits with molecular weights in excess of 20 x loh daltons. vWF is synthesized exclusively in endothelial cells and megakaryocytes and has become a standard marker of endothelial cell origin for histochemical studies. vWF is first synthesized as a large prescursor form that initially dimerizes and subsequently multimerizes with coincident processing to the mature vWF subunit. Within the endothelial cell, vWF is secreted via both constitutive and regulated pathways. Dimerization of vWF and early carbohydrate processing begin in the endoplasmic reticulum with final carbohydrate processing and multimerization restricted to golgi and post-golgi compartments. A specific storage compartment for vWF has been identified within the endothelial cell termed the Weibel-Palade body. This structure contains densely packed vWF with a characteristic appearance under the electron microscope. The only other protein known to be contained within the Weibel-Palade body is the recently described selectin, GMP140