von Willebrand disease is due to an abnormality, either quantitative or qualitative, of the von Willebrand factor, which is a large multimeric glycoprotein that functions as the carrier protein for factor VIII (FVIII). von Willebrand factor is also required for normal platelet adhesion. von Willebrand factor is composed of dimeric subunits that are linked by disulfide bonds to form complex multimers of low, intermediate, and high molecular weights. High&8211;molecular weight multimers have higher numbers of platelet-binding sites and greater adhesive properties.

Each multimeric subunit has binding sites for the receptor glycoprotein Ib on nonactivated platelets and the receptor glycoprotein IIb/IIIa on activated platelets. This facilitates both platelet adhesion and platelet aggregation, making high molecular weight multimers most important for normal platelet function Structure and domains of von Willebrand factor. von Willebrand disease can be classified into 3 main types

Type 1 von Willebrand disease, which accounts for 70-80% of cases, is characterized by a partial quantitative decrease of qualitatively normal von Willebrand factor and FVIII. An individual with type 1 von Willebrand disease generally has mild clinical symptoms, and this type is usually inherited as an autosomal dominant trait; however, penetrance may widely vary in a single family. In addition, clinical and laboratory findings may vary in the same patient on different occasions.

Typically, a proportional reduction in von Willebrand factor activity, von Willebrand factor antigen, and FVIII is observed in type 1 von Willebrand disease. Type 2 disease accounts for 15-20% of von Willebrand disease cases. Type 2 von Willebrand disease is a variant of the disease with primarily qualitative defects of von Willebrand factor. Type 2 von Willebrand disease can be either autosomal dominant or autosomal recessive.

Of the 4 described type 2 von Willebrand disease subtypes (ie, 2A, 2B, 2M, 2N), type 2A von Willebrand disease is by far the most common Type 2A von Willebrand disease is inherited as an autosomal dominant trait and is characterized by normal-to-reduced plasma levels of factor VIIIc (FVIIIc) and von Willebrand factor. Analysis of von Willebrand factor multimers reveals a relative reduction in intermediate and high molecular weight multimer complexes.

The multimeric abnormalities are commonly the result of in vivo proteolytic degradation of the von Willebrand factor. The ristocetin cofactor activity is greatly reduced, and the platelet von Willebrand factor reveals multimeric abnormalities similar to those found in plasma. Type 2B von Willebrand disease is also an autosomal dominant trait.

Medical Editor.

von Willebrand Disease (Hematology).

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