Chapter 126: Von Willebrand Disease

SUMMARY

von Willebrand factor (VWF) is a central component of hemostasis, serving both as an adhesive link between platelets and the injured blood vessel wall and as a carrier for clotting factor VIII (FVIII). Abnormalities in VWF function result in von Willebrand disease (VWD), the most common inherited bleeding disorder in humans. The overall prevalence of VWD has been estimated to be as high as 1 percent of the general population, although the prevalence of clinically significant disease is probably closer to 1:1000. VWD is associated with either quantitative deficiency (type 1 and type 3) or qualitative abnormalities of VWF (type 2). The uncommon type 3 variant is the most severe form of VWD and is characterized by very low or undetectable levels of VWF, a severe bleeding diathesis, and a generally autosomal recessive pattern of inheritance. Type 1 VWD, the most common variant, is characterized by VWF that is normal in structure and function but decreased in quantity (in the range of 20 to 50 percent of normal). In type 2 VWD, the VWF is abnormal in structure and/or function. Type 2A VWD is associated with selective loss of the largest and most functionally active VWF multimers. Type 2A is further subdivided into group 1, as a result of mutations that interfere with biosynthesis and secretion, and group 2, in which the mutant VWF exhibits an increased sensitivity to proteolysis in plasma. Type 2B VWD is caused by mutations clustered within the VWF A1 domain, in a segment critical for binding to the platelet glycoprotein Ib receptor. These mutations produce a “gain of function” resulting in spontaneous VWF binding to platelets and clearance of the resulting platelet complexes, leading to thrombocytopenia and loss of the most active (large) VWF multimers. Type 2N VWD is characterized by mutations within the FVIII binding domain of VWF, leading to disproportionately decreased factor VIII and a disorder resembling mild to moderate hemophilia A, but with autosomal rather than X-linked inheritance. Type 1 VWD can often be effectively managed by treatment with DDAVP (1-deamino-8-D-arginine vasopressin, desmopressin), which produces a two- to threefold increase in plasma VWF level due to release from endothelial storage sites in the vessel wall. Response to DDAVP is generally poor in type 3 and some type 2 VWD variants. These disorders often require treatment with factor replacement in the form of VWF/FVIII concentrates containing large quantities of intact VWF multimers.

Acronyms and Abbreviations

ADAMTS13, a disintegrin and metalloprotease with thrombospondin type 1 motifs; aPTT, activated partial thromboplastin time; DDAVP, 1-desamino-8-D-arginine vasopressin or desmopressin; ER, endoplasmic reticulum; GP, glycoprotein; HHT, hereditary hemorrhagic telangiectasia; PCR, polymerase chain reaction; RIPA, ristocetin-induced platelet aggregation; VWD, von Willebrand disease; VWF, von Willebrand factor.