Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Bonn, Germany.
Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Bonn, Germany.
J Thromb Haemost. 2024 Nov;22(11):3010-3034. doi: 10.1016/j.jtha.2024.06.026. Epub 2024 Jul 11.
Von Willebrand disease (VWD), the most prevalent hereditary bleeding disorder, results from deficiency of von Willebrand factor (VWF).
This large cohort study aims to offer a comprehensive exploration of mutation spectra and laboratory features in quantitative VWF deficiencies, shedding light on genetic underpinnings and genotype-phenotype associations.
Our cohort consisted of 221 Caucasian index patients with quantitative VWD, along with 47 individuals whose plasma VWF levels fell within the lower normal boundaries (50-70 IU/dL). We conducted comprehensive VWF assays and genetic analyses, encompassing VWF gene sequencing, copy number variation investigations, and bioinformatic assessments.
Following International Society on Thrombosis and Haemostasis-Scientific and Standardization Committee VWF guidelines, 77 index patients were characterized as having type 1 VWD (VWF antigen [VWF:Ag] < 30 IU/dL), 111 as having type 1 VWD (VWF:Ag, 30-50 IU/dL), and 33 as having type 3 VWD. Mutation detection rates were 88%, 65%, and 92%, respectively. Notably, blood group O overrepresentation was evident in type 1 with VWF:Ag of 30 to 50 IU/dL, particularly among mutation-negative patients, suggesting a potential causal role of blood group O. A total of 223 VWF variants, comprising 147 distinct variations, were identified in quantitative VWD patients, of which 57 were novel variants (39%). Additionally, approximately 70% of individuals with VWF levels within the lower normal boundaries (50-70 IU/dL) displayed VWF variants.
Our data advance our understanding of the molecular mechanisms underlying quantitative VWD, offering valuable insights for future research and clinical management. Distinct mutation patterns were observed among subgroups, particularly the contrast between type 1 VWD (VWF:Ag < 30 IU/dL) and type 1 VWD (VWF:Ag, 30-50 IU/dL), an area with limited prior investigation.
血管性血友病（VWD）是最常见的遗传性出血性疾病，其病因是血管性血友病因子（VWF）缺乏。
本大型队列研究旨在全面探讨定量 VWF 缺乏症的突变谱和实验室特征，揭示遗传基础和基因型-表型相关性。
我们的队列包括 221 名白人定量 VWD 指数患者，以及 47 名血浆 VWF 水平处于较低正常范围（50-70IU/dL）的个体。我们进行了全面的 VWF 检测和基因分析，包括 VWF 基因测序、拷贝数变异研究和生物信息学评估。
根据国际血栓与止血学会-科学与标准化委员会 VWF 指南，77 名指数患者被确定为 1 型 VWD（VWF 抗原[VWF:Ag] < 30IU/dL），111 名患者为 1 型 VWD（VWF:Ag，30-50IU/dL），33 名患者为 3 型 VWD。突变检出率分别为 88%、65%和 92%。值得注意的是，1 型 VWF:Ag 为 30 至 50IU/dL 的患者中存在 O 型血过度表达，尤其是在突变阴性患者中，这表明 O 型血可能具有因果关系。在定量 VWD 患者中发现了 223 种 VWF 变异，包括 147 种不同的变异，其中 57 种为新变异（39%）。此外，大约 70%的 VWF 水平处于较低正常范围（50-70IU/dL）的个体存在 VWF 变异。
我们的数据增进了对定量 VWD 分子机制的理解，为未来的研究和临床管理提供了有价值的信息。在亚组中观察到不同的突变模式，特别是在 1 型 VWD（VWF:Ag < 30IU/dL）和 1 型 VWD（VWF:Ag，30-50IU/dL）之间存在差异，这是一个以前研究较少的领域。
