The pathophysiology of von Willebrand disease: therapeutic implications.

von Willebrand disease (VWD) is a bleeding disorder characterized by quantitative or qualitative defects in von Willebrand factor (VWF), a multimeric glycoprotein that is essential for platelet-dependent primary hemostasis. High molecular-weight multimers of VWF circulate and bind to collagen and platelets to induce primary hemostasis. The activity of VWF and its eventual proteolytic degradation are dependent on shear stress, ensuring that, under normal conditions, VWF is active in a high shear stress environment only. Deficiency in VWF results in mucocutaneous bleeding, including epistaxis, menorrhagia, and excessive bleeding after trauma or surgery. Classification of VWD is based on the combined results of multiple laboratory tests related to VWF amount and activity as well as the relative amounts of large VWF multimers as determined by gel electrophoresis. Recently, specific mutations in the gene encoding VWF have been linked to characteristic multimer profiles and may aid in subtyping patients with VWD and predicting response to therapy. These genotype-phenotype correlations are improving our understanding of the pathophysiology of VWD and helping to provide a more accurate diagnosis and classification with important treatment-related implications.