Type 2 von Willebrand disease causing defective von Willebrand factor-dependent platelet function

Type 2 von Willebrand disease causing defective von Willebrand factor-depen dent platelet function comprises mainly subtypes 2A, 2B and 2M. The diagnos is of type 2 von Willebrand disease may be guided by the observation of a d isproportionately low level of ristocetin cofactor activity or collagen-bin ding activity relative to the von Willebrand factor antigen level. The decr eased platelet-dependent function is often associated with an absence of hi gh molecular weight multimers (types 2A and 2B), but the high molecular wei ght multimers may also be present (type 2M and some type 2B), and supranorm al multimers may exist (as in the Vicenza variant). Today, the identificati on of mutations in particular domains of the pre-proven Willebrand factor i s helpful to classify these variants and to provide further insight into th e structure-function relationship and the biosynthesis of von Willebrand fa ctor. Thus, mutations in the D2 domain, involved in the multimerization pro cess, are found in patients with type 2A, formerly named IIC von Willebrand disease. Mutations in the D3 domain characterize the Vicenza variant, or t ype IIE patients. Mutations in the Al domain may modify the binding of von Willebrand factor multimers to platelets, either increasing (type 2B) or de creasing (types 2M and 2A/2M) the affinity of von Willebrand factor for pla telets. In type 2A disease, molecular abnormalities identified in the A2 do main, which contains a specific proteolytic site, are associated with alter ations in folding that impair the secretion of von Willebrand factor or inc rease its susceptibility to proteolysis. Finally, a mutation localized in t he C terminus cysteineknot domain, which is crucial for the dimerization of von Willebrand factor subunit, has been identified in a rare subtype 2A, f ormerly named IID.