von Willebrand's disease in the year 2003: towards the complete identification of gene defects for correct diagnosis and treatment

Von Willebrand's disease (VWD) is an autosomally inherited bleeding disorder caused by a deficiency or abnormality of von Willebrand factor (VWF). VWF is a multimeric adhesive protein which plays an important role in primary hemostasis by promoting platelet adhesion to the subendothelium at sites of vascular injury and platelet-platelet interactions in high shear-rate conditions. It is also the carrier of factor VIII (FVIII), thus indirectly contributing to the coagulation process. VWD has a prevalence of about 1% in the general population, but the figure for clinically relevant cases is lower (about 100/million inhabitants). Bleeding manifestations are heterogeneous: mucosal bleeding is typical of all VWD cases but hemarthrosis and hematomas may also be present when FVIII levels are low. Most cases appear to have a partial quantitative deficiency of VWF (type 1 VWD) with variable bleeding tendency, whereas qualitative variants (type 2 VWD), due to a dysfunctional VWF, are clinically more homogeneous. Type 3 VWD is rare and the patients have a moderate to severe bleeding diathesis because of the virtual absence of VWF, and a recessive pattern of inheritance. The diagnosis of VWD, especially type I, may be difficult, because the laboratory phenotype is highly heterogeneous and is confounded by the fact that factors outside the VWF gene (e.g., blood group) influence VWF levels. An array of tests is usually required to characterize the VWD types of the disorder and establish the best treatment modality. The aim of treatment is to correct the dual defect of hemostasis, i.e. abnormal coagulation expressed by low levels of FVIII and abnormal platelet adhesion expressed by the prolonged bleeding time (BT). Desmopressin (DDAVP) is the treatment of choice for type 1 VWD because it corrects the FVIII/VWF levels and the prolonged BT in the majority of cases. In type 3 and in severe forms of type 1 and 2 VWD, DDAVP is not effective and for these patients plasma virally-inactivated concentrates containing FVIII and VWF are the mainstay of treatment. These concentrates are clinically effective and safe, although they do not always correct the BT.