von Willebrand factor (VWF) is a complex multimeric glycoprotein that is found in plasma, in platelet α granules, and in subendothelial connective tissue. VWF performs two biologic functions that are required for normal hemostasis: it binds to specific receptors on the platelet surface and in subendothelial connective tissue to form a bridge between the platelet and areas of vascular damage, and it binds to and stabilizes blood coagulation factor VIII. This interaction between VWF and factor VIII is necessary for normal factor VIII survival in the circulation. Deficiency of VWF results in defective platelet adhesion and also causes a secondary deficiency of factor VIII. Consequently, deficiency of VWF may cause bleeding that mimics either platelet dysfunction or hemophilia.
Inherited deficiency of VWF causes von Willebrand disease (VWD). Clinically significant VWD affects approximately 125 people per million population, a prevalence approximately twice that of hemophilia A. The prevalence of severely affected homozygous or compound heterozygous patients suggests that between 1500 and 3500 people per million population are heterozygous for a defective VWF allele; therefore, a relatively small fraction of persons harboring VWF mutations are symptomatic.
VWD is a heterogeneous disorder that has been classified into several major subtypes (dominant, MIM 193400; recessive, MIM 277480). The most common form (type 1) is transmitted as an autosomal dominant trait and appears to be due to simple quantitative deficiency of all VWF multimers. Recessive inheritance and virtual absence of VWF characterize a clinically severe variant (type 3). Variants that are characterized by a dysfunctional protein are classified as type 2. Type 2 VWD is further subdivided into four variants (2A, 2B, 2M, and 2N) based on the functional characteristics of the mutant protein.
Bleeding in severe VWD is treated with blood products containing factor VIII-VWF complex; these include certain factor VIII concentrates and plasma cryoprecipitate. Clinically milder variants can often be treated without exposure to blood products through pharmacologic manipulation of plasma VWF levels. For many patients with VWD the intravenous or intranasal administration of the vasopressin analogue DDAVP causes a rise in plasma VWF that is sufficient either to treat spontaneous and traumatic bleeding or to sustain normal hemostasis during surgery.
Molecular defects have been characterized in many types of VWD. Nonsense mutations and gene deletions are causes of severe VWD (type 3). Gene deletions predispose to the development of alloantibody inhibitors to transfused VWF, a rare complication of therapy. Missense mutations have been characterized that cause specific gain-of-function and loss-of-function variants of type 2 VWD. Many polymorphisms have been described for the VWF gene that can augment the use of biochemical testing for genetic counseling.