2 Molecular basis of von Willebrand disease

Abstract

von Willebrand disease (vWD), the most common congenital bleeding disorder in man, is related to quantitative and/or qualitative abnormalities of von Willebrand factor (vWF), a protein necessary for platelet-vessel wall interactions and for carrying factor VIII. Distinct abnormalities of vWF are responsible for the three main types of vWD. Types 1 and 3 are defined by a quantitative defect of vWF whereas type 2, comprising subtypes 2A, 2B, 2M and 2N, refers to patients with a qualitative defect of vWF. Recent progress in the molecular biology of vWF has led to the identification of the molecular basis of vWD in a significant number of patients. Type 2A is characterized by a decreased platelet-dependent function of vWF and includes subtypes IIA and IIC. In all the cases of subtype IIA, aa substitutions have been identified in the A2 domain of vWF which contains a proteolytic site. In the rare subtype IIC, some aa substitutions or insertion have been found within the propeptide of vWF. In type 2B, defined by an increased affinity of vWF for platelet GPIb, various aa substitutions or insertions have been localized within the A1 domain containing binding sites for GPIb, collagen, heparin and sulfatides. In type 2N, characterized by a defective binding of vWF to factor VIII, several aa substitutions have been identified within the factor VIII-binding domain in the N-terminal part of vWF. The identification of gene defects is difficult in types 1 and 3 of vWD. Whereas various abnormalities (gross, partial or point deletions, point insertions, nonsense mutations) have been shown to be at the origin of the quantitative vWF defect in type 3, the molecular basis of type 1 is still unknown in most cases. A data base of gene defects in vWD has been recently established. Its updating may contribute to consider a future classification of vWD based on the nature of the gene defect. Furthermore, the characterization of mutations in vWD presents a more fundamental interest in providing further insight into the structure-function relationship and the synthesis of vWF.