Laboratory for Hemostasis, Inflammation & Thrombosis, Unité Mixed de Recherche S1176, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, Le Kremlin-Bicêtre, France.
Institut National de la Santé et de la Recherche Médicale Unité 1011, Institut Pasteur de Lille, Centre Hospitalier Universitaire de Lille, Université de Lille, Lille, France; and.
Blood. 2021 Apr 29;137(17):2299-2306. doi: 10.1182/blood.2020008501.
von Willebrand disease (VWD) is characterized by its heterogeneous clinical manifestation, which complicates its diagnosis and management. The clinical management of VWD has remained essentially unchanged over the last 30 years or so, using von Willebrand factor (VWF) concentrates, desmopressin, and anti-fibrinolytic agents as main tools to control bleeding. This is in contrast to hemophilia A, for which a continuous innovative path has led to novel treatment modalities. Despite current VWD management being considered effective, quality-of-life studies consistently reveal a higher than anticipated burden of VWD on patients, which is particularly true for women. Apparently, despite our perceived notion of current therapeutic efficiency, there is space for innovation with the goal of reaching superior efficacy. Developing innovative treatments for VWD is complex, especially given the heterogeneity of the disease and the multifunctional nature of VWF. In this perspective article, we describe several potential strategies that could provide the basis for future VWD treatments. These include genetic approaches, such as gene therapy using dual-vector adenoassociated virus and transcriptional silencing of mutant alleles. Furthermore, protein-based approaches to increase factor FVIII levels in VWD-type 3 or 2N patients are discussed. Finally, antibody-based options to interfere with VWF degradation (for congenital VWD-type 2A or acquired von Willebrand syndrome-type 2A) or increase endogenous VWF levels (for VWD-type 1) are presented. By highlighting these potential strategies, we hope to initiate an innovative path, which ultimately would allow us to better serve VWD patients and their specific needs.
血管性血友病（von Willebrand disease，VWD）的临床表现存在异质性，这使得其诊断和管理变得复杂。在过去的 30 年左右，VWD 的临床管理基本上没有改变，主要使用血管性血友病因子（von Willebrand factor，VWF）浓缩物、去氨加压素和抗纤维蛋白溶解剂来控制出血。相比之下，血友病 A 则不断创新，出现了新的治疗方法。尽管目前的 VWD 管理被认为是有效的，但生活质量研究始终表明，VWD 给患者带来的负担高于预期，尤其是女性。显然，尽管我们认为目前的治疗效果有效，但仍有创新的空间，以达到更高的疗效。开发 VWD 的创新疗法很复杂，特别是考虑到该病的异质性和 VWF 的多功能性。在这篇观点文章中，我们描述了几种可能的策略，这些策略可能为未来的 VWD 治疗提供基础。其中包括基因治疗方法，例如使用双载体腺相关病毒的基因治疗和突变等位基因的转录沉默；增加 VWD 型 3 或 2N 患者因子 FVIII 水平的蛋白治疗方法；以及干扰 VWF 降解（用于先天性 VWD 型 2A 或获得性血管性血友病综合征型 2A）或增加内源性 VWF 水平（用于 VWD 型 1）的抗体治疗方法。通过强调这些潜在策略，我们希望能够开启一个创新的路径，最终能够更好地满足 VWD 患者及其特定需求。
