Meyer D, Fressinaud E, Hilbert L, Ribba A S, Lavergne J M, Mazurier C
INSERM U. 143, 84 rue du Général Leclerc, 94276 Le Kremlin-Bicêtre, France.
Best Pract Res Clin Haematol. 2001 Jun;14(2):349-64. doi: 10.1053/beha.2001.0137.
Type 2 von Willebrand disease causing defective von Willebrand factor-dependent platelet function comprises mainly subtypes 2A, 2B and 2M. The diagnosis of type 2 von Willebrand disease may be guided by the observation of a disproportionately low level of ristocetin cofactor activity or collagen-binding activity relative to the von Willebrand factor antigen level. The decreased platelet-dependent function is often associated with an absence of high molecular weight multimers (types 2A and 2B), but the high molecular weight multimers may also be present (type 2M and some type 2B), and supranormal multimers may exist (as in the Vicenza variant). Today, the identification of mutations in particular domains of the pre-provon Willebrand factor is helpful to classify these variants and to provide further insight into the structure-function relationship and the biosynthesis of von Willebrand factor. Thus, mutations in the D2 domain, involved in the multimerization process, are found in patients with type 2A, formerly named IIC von Willebrand disease. Mutations in the D3 domain characterize the Vicenza variant, or type IIE patients. Mutations in the A1 domain may modify the binding of von Willebrand factor multimers to platelets, either increasing (type 2B) or decreasing (types 2M and 2A/2M) the affinity of von Willebrand factor for platelets. In type 2A disease, molecular abnormalities identified in the A2 domain, which contains a specific proteolytic site, are associated with alterations in folding that impair the secretion of von Willebrand factor or increase its susceptibility to proteolysis. Finally, a mutation localized in the C terminus cysteine knot domain, which is crucial for the dimerization of von Willebrand factor subunit, has been identified in a rare subtype 2A, formerly named IID.
导致血管性血友病因子（vWF）依赖性血小板功能缺陷的2型血管性血友病主要包括2A、2B和2M亚型。2型血管性血友病的诊断可通过观察瑞斯托霉素辅因子活性或胶原结合活性水平相对于vWF抗原水平异常降低来指导。血小板依赖性功能降低通常与高分子量多聚体缺失（2A和2B型）相关，但高分子量多聚体也可能存在（2M型和某些2B型），并且可能存在超常多聚体（如维琴察变异型）。如今，在前体vWF特定结构域中鉴定突变有助于对这些变异型进行分类，并进一步深入了解vWF的结构-功能关系和生物合成。因此，参与多聚化过程的D2结构域中的突变见于2A型患者，2A型以前称为IIC型血管性血友病。D3结构域中的突变是维琴察变异型或IIE型患者的特征。A1结构域中的突变可能改变vWF多聚体与血小板的结合，要么增加（2B型）要么降低（2M型和2A/2M型）vWF对血小板的亲和力。在2A型疾病中，在含有特定蛋白水解位点的A2结构域中鉴定出的分子异常与折叠改变有关，这会损害vWF的分泌或增加其对蛋白水解的敏感性。最后，在一种罕见的2A型（以前称为IID型）中鉴定出位于C末端半胱氨酸结结构域的突变，该结构域对vWF亚基的二聚化至关重要。
