Von Willebrand disease is a congenital or acquired disorder of the coagulation system caused by quantitative or qualitative alterations of the von Willebrand factor (vWF). Including all mild forms, it is the most common bleeding disorder with a prevalence of approximately 1%. However, clinically symptomatic patients with von Willebrand disease type 1, 2, or 3 occur with a prevalence of only 1:10,000. The major functions of vWF include promotion of platelet adhesion via glycoprotein Ib, which is localized to platelet surfaces, and binding of factor VIII, protecting it from rapid degradation. Platelet adhesion is dependent on the large multimers of vWF.
All functions of vWF are affected by variants in the VWF gene, which generally have a quantitative effect on vWF expression. Variants that affect the formation of large multimers only affect vWF function in primary hemostasis. In contrast, when the factor VIII-binding region is defective, function in secondary hemostasis is affected. Quantitative effects are divided into relative reduction (type I) and total absence (type III). Qualitative defects (type II) are very heterogeneous. Identification of specific variants associated with reduced expression of vWF, disruption of post-translational modification, impairment of intracellular transport, or functional defects can reconcile the highly heterogeneous clinical phenotype with genotype. Molecular genetics can be help with a correct diagnosis and classification and facilitate the choice of appropriate therapy.
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