Fu Anne, Kazmirchuk Thomas D D, Bradbury-Jost Calvin, Golshani Ashkan, Othman Maha
Department of Biomedical and Molecular Sciences, School of Medicine, Queen's University, Kingston, Ontario, Canada.
Department of Biology, and the Ottawa Institute of Systems Biology (OISB), Carleton University, Ottawa, Ontario, Canada.
Semin Thromb Hemost. 2025 Mar;51(2):219-226. doi: 10.1055/s-0044-1789183. Epub 2024 Aug 27.
von Willebrand disease (VWD) is the most common well-studied genetic bleeding disorder worldwide. Much less is known about platelet-type VWD (PT-VWD), a rare platelet function defect, and a "nonidentical" twin bleeding phenotype to type 2B VWD (2B-VWD). Rather than a defect in the von Willebrand factor () gene, PT-VWD is caused by a platelet mutation leading to a hyperaffinity of the glycoprotein Ibα (GPIbα) platelet surface receptor for VWF, and thus increased platelet clearing and high-molecular-weight VWF multimer elimination. Nine mutations are known. It is historically believed that this enhanced binding was enabled by the β-switch region of GPIbα adopting an extended β-hairpin form. Recent evidence suggests the pathological conformation that destabilizes the compact triangular form of the R-loop-the GPIbα protein's region for VWF binding. PT-VWD is often misdiagnosed as 2B-VWD, even the though distinction between the two is crucial for proper treatment, as the former requires platelet transfusions, while the latter requires VWF/FVIII concentrate administration. Nevertheless, these PT-VWD treatments remain unsatisfactory, owing to their high cost, low availability, risk of alloimmunity, and the need to carefully balance platelet administration. Antibodies such as 6B4 remain undependable as an alternative therapy due to their questionable efficacy and high costs for this purpose. On the other hand, synthetic peptide therapeutics developed with to disrupt the association between GPIbα and VWF show preliminary promise as a therapy based on in vitro experiments. Such peptides could serve as an effective diagnostic technology for discriminating between 2B-VWD and PT-VWD, or potentially all forms of VWD, based on their high specificity. This field is rapidly growing and the current review sheds light on the complex pathology and some novel potential therapeutic and diagnostic strategies.
血管性血友病（VWD）是全球研究最多的常见遗传性出血性疾病。对于血小板型VWD（PT-VWD），一种罕见的血小板功能缺陷，以及与2B型VWD（2B-VWD）“不同”的双出血表型，人们了解得要少得多。PT-VWD不是由血管性血友病因子（VWF）基因缺陷引起的，而是由血小板突变导致糖蛋白Ibα（GPIbα）血小板表面受体对VWF的亲和力过高，从而增加血小板清除和高分子量VWF多聚体清除。已知有九种血小板突变。历史上认为，这种增强的结合是通过GPIbα的β-转换区采用延伸的β-发夹形式实现的。最近的证据表明，病理构象使R环（GPIbα蛋白与VWF结合的区域）的紧密三角形形式不稳定。PT-VWD常被误诊为2B-VWD，尽管两者的区分对于正确治疗至关重要，因为前者需要输注血小板，而后者需要给予VWF/FVIII浓缩物。然而，这些PT-VWD治疗方法仍然不尽人意，因为它们成本高、可用性低、存在同种免疫风险，并且需要仔细平衡血小板输注。诸如6B4之类的抗体作为替代疗法仍然不可靠，因为其疗效存疑且为此目的成本高昂。另一方面，基于体外实验，开发用于破坏GPIbα与VWF之间关联的合成肽疗法显示出初步的治疗前景。基于其高特异性，此类肽可作为区分2B-VWD和PT-VWD或潜在所有形式VWD的有效诊断技术。该领域正在迅速发展，当前的综述揭示了复杂的病理学以及一些新的潜在治疗和诊断策略。
