Type 2A and 2M von Willebrand disease (VWD) broadly show similar phenotypic parameters, but involve different pathophysiological mechanisms. This report presents the clinical and laboratory profiles of type 2A and type 2M patients genotypically diagnosed at one large center. Higher bleeding score values and a higher incidence of major bleeding episodes were observed in type 2A compared with type 2M, potentially reflective of the absence of large and intermediate von Willebrand factor (VWF) multimers in 2A. In type 2A, most of disease-causing variants (DCVs) appeared to be responsible for increased VWF clearance and DCV clustered in the VWF-A1 domain resulted in more severe clinical profiles. In type 2M, DCV in the VWF-A1 domain showed different laboratory patterns, related to either reduced synthesis or shortened VWF survival, and DCV in the VWF-A2 domain showed patterns related mainly to shortened survival. VWF-type 1 collagen binding/Ag (C1B/Ag) showed different patterns according to DCV location: in type 2A VWD, C1B/Ag was much lower when DCVs were located in the VWF-A2 domain. In type 2M with DCV in the VWF-A1domain, C1B/Ag was normal, but with DCV in the VWF-A2 domain, C1B/Ag was low. The higher frequency of major bleeding in VWD 2M patients with DCV in the VWF-A2 domain than that with DCV in the VWF-A1 domain could be a summative effect of abnormal C1B/Ag, on top of the reduced VWF-GPIb binding. In silico modeling suggests that DCV impairing the VWF-A2 domain somehow modulates collagen binding to the VWF-A3 domain. Concomitant normal FVIII:C/Ag and VWFpp/Ag, mainly in type 2M VWD, suggest that other nonidentified pathophysiological mechanisms, neither related to synthesis/retention nor survival of VWF, would be responsible for the presenting phenotype.

2A 型和 2M 型血管性血友病 (VWD) 广泛显示相似的表型参数，但涉及不同的病理生理机制。本报告介绍了在一个大型中心进行基因分型诊断的 2A 型和 2M 型患者的临床和实验室概况。与 2M 型相比，在 2A 型中观察到更高的出血评分值和更高的大出血事件发生率，这可能反映了 2A 中缺乏大的和中间的血管性血友病因子 (VWF) 多聚体。在 2A 型中，大多数致病变异 (DCV) 似乎是导致 VWF 清除率增加的原因，并且聚集在 VWF-A1 域中的 DCV 导致更严重的临床特征。在 2M 型中，VWF-A1 域中的 DCV 显示出不同的实验室模式，与合成减少或 VWF 存活期缩短有关，VWF-A2 域中的 DCV 和 DCV 显示出主要与缩短生存期相关的模式。VWF 1 型胶原结合/Ag (C1B/Ag) 根据 DCV 位置显示出不同的模式：在 2A 型 VWD 中，当 DCV 位于 VWF-A2 域时，C1B/Ag 低得多。在 VWF-A1 域 DCV 的 2M 型中，C1B/Ag 正常，但在 VWF-A2 域 DCV 时，C1B/Ag 低。VWF-A2 域 DCV 的 VWD 2M 患者的大出血频率高于 VWF-A1 域 DCV 患者的大出血频率，这可能是除 VWF-GPIb 结合减少之外异常 C1B/Ag 的总和效应。计算机模拟表明，损害 VWF-A2 结构域的 DCV 以某种方式调节胶原蛋白与 VWF-A3 结构域的结合。伴随的正常 FVIII:C/Ag 和 VWFpp/Ag，主要在 2M 型 VWD 中，表明其他未确定的病理生理机制，