Role of multimeric analysis of von Willebrand factor (VWF) in von Willebrand disease (VWD) diagnosis: Lessons from the PCM-EVW-ES Spanish project

The multimeric analysis (MA) of plasma von Willebrand factor (VWF) evaluates structural integrity and helps in the diagnosis of von Willebrand disease (VWD). This assay is a matter of controversy, being considered by some investigators cumbersome and only slightly informative. The centralised study ‘Molecular and Clinical Profile of von Willebrand Disease in Spain (PCM-EVW-ES)’ has been carried out by including the phenotypic assessment and the genetic analysis by next generation sequencing (NGS) of the VWF gene (VWF). The aim of the present study was to evaluate the role of MA to the diagnosis of these patients and their potential discrepancies. Two hundred and seventy out of 480 patients centrally diagnosed with VWD had normal multimers, 168 had abnormal multimers and 42 a total absence of multimers. VWF MA was of great significance in the diagnosis of 83 patients (17.3%), it was also of help in the diagnosis achieved in 365 additional patients (76%) and was not informative in 32 cases (6.7%). With regard to discrepancies, 110 out of 480 (23%) patients centrally diagnosed with VWD presented some kind of discordance between VWF:RCo/VWF:Ag and/or VWF:CB/VWF:Ag ratios, multimeric study and/or genetic results. The VWF MA was key in the presence of novel mutations as well as in cases with phenotypic discrepancies. A comparison between the contribution of MA and VWF:CB showed a clearly higher contribution of the former in the diagnostic process. These data seem to reinforce the relevance of the VWF MA in VWD diagnosis, despite all its limitations.

血浆血管性血友病因子（von Willebrand factor, VWF）的多聚体分析（multimeric analysis, MA）可评估其结构完整性，辅助血管性血友病（von Willebrand disease, VWD）的诊断。该检测方法尚存争议，部分研究者认为其操作繁琐且诊断价值有限。由西班牙开展的集中化研究《西班牙血管性血友病分子与临床特征研究（PCM-EVW-ES）》纳入了表型评估及血管性血友病因子基因（VWF）的下一代测序（next generation sequencing, NGS）遗传分析。本研究旨在评估多聚体分析在此类患者诊断中的价值，以及其与其他检测结果间可能存在的差异。

在480例经集中确诊的血管性血友病患者中，270例的VWF多聚体结果正常，168例存在多聚体异常，另有42例完全无多聚体检出。VWF多聚体分析对83例患者（17.3%）的诊断具有关键价值，另外365例患者（76%）的诊断也得益于该检测，另有32例（6.7%）的检测结果无参考意义。

就检测结果不一致的情况而言，480例经集中确诊的血管性血友病患者中，110例（23%）存在VWF瑞斯托霉素辅因子活性/抗原比值（VWF:RCo/VWF:Ag）和/或VWF胶原结合活性/抗原比值（VWF:CB/VWF:Ag）、多聚体分析结果与遗传检测结果之间的不符。VWF多聚体分析对于检出新发突变及存在表型差异的病例具有关键作用。对比多聚体分析与VWF胶原结合活性检测的诊断贡献，前者在诊断流程中的贡献显著更高。尽管存在诸多局限性，但本研究数据进一步证实了VWF多聚体分析在血管性血友病诊断中的重要价值。