V. PATHOPHYSIOLOGY

The characteristics of the three main types of von Willebrand disease are summarized in the chart below.

von Willebrand's disease: Classification
Type 1	Autosomal dominant Quantitative deficiency of von Willebrand factor Failure of export from storage organelles
Type 2	Usually occurs as an autosomal dominant disorder with abnormalities in von Willebrand factor function. Gene with point mutations, insertions, and missense mutations.
Type 2A	Characterized by absence of the higher molecular weight multimers of von Willebrand factor. Impaired multimerization. Increased proteolysis
Type 2B	Characterized by absence of the higher molecular weight multimers of von Willebrand factor. Associated with thrombocytopenia due to a gain of function mutation resulting in a von Willebrand factor molecule with higher affinity for the GPIb-IX-V receptor, thus enhancing platelet agglutination.
Type 2-M	Decreased binding to subendothelial connective tissue. Reduced binding of von Willebrand factor to GPIb-IX-V.
Type 2-N	Rare autosomal recessive disorder arising from a mutation in the factor VIII binding site on the von Willebrand factor molecule. Without the protection provided by von Willebrand factor binding, factor VIII levels fall because of a markedly decreased half life. von Willebrand multimers and antigen and activity levels may be normal. Levels of factor VIII are low enough to make it possible to confuse this with classic hemophilia. Specific diagnosis either requires demonstrating the lack of binding of von Willebrand factor to factor VIII or genetic analysis.
Type 3	Autosomal recessive. Patients have a near absence of von Willebrand factor. Due to mutations that result in either a complete absence of the protein or a markedly truncated molecule. The most severe form (very impaired hemostasis). Usually recognized in early childhood.

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