Department of Hematology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
Amsterdam UMC, University of Amsterdam, Emma Children's Hospital, Pediatric Hematology, Amsterdam, The Netherlands; Department of Plasma Proteins, Sanquin Research, Amsterdam, The Netherlands.
J Thromb Haemost. 2024 Dec;22(12):3460-3472. doi: 10.1016/j.jtha.2024.08.028. Epub 2024 Sep 28.
Type 2B von Willebrand disease (VWD) is a bleeding disorder caused by gain-of-function variants in the VWF gene. The laboratory and clinical phenotype of type 2B VWD is heterogeneous.
We investigated associations between genotype and phenotype over a median of 16 years follow-up in a large cohort of well-characterized patients.
We included 64 genetically confirmed type 2B VWD patients from the national multicenter "Willebrand in the Netherlands" study and retrospectively collected clinical and laboratory data from electronic patient records. We analyzed associations between genotype and thrombocytopenia, bleeding phenotype, and events leading to endothelial activation and von Willebrand factor (VWF) secretion, including surgery, desmopressin administration, pregnancy, and delivery.
Thrombocytopenia manifested in 67.2% of patients, with varying occurrences between genetic variants (p.Arg1306Trp: 75.0%, p.Arg1308Cys: 58.3%). The most important determinant of thrombocytopenia was the p.Arg1306Trp VWF variant (odds ratio, 25.1). Platelet counts strongly varied over time and were continuously <150 × 10/L in 37.5% of patients with p.Arg1306Trp vs 8.3% in p.Arg1308Cys. In our analysis, endothelial activation was not an independent determinant (odds ratio, 1.3) for thrombocytopenia occurrence. No association was found between thrombocytopenia and cumulative bleeding scores or annual bleeding rates. Four women showed declining platelet counts in all full-term pregnancies (n = 8) during the third trimester with a sharp decrease in the week before delivery. Postpartum hemorrhage, defined as >500 mL estimated blood loss at delivery, occurred in 5 of 8 deliveries, despite prophylactic treatment with VWF concentrates.
This study reveals a strong association between VWF variant p.Arg1306Trp and thrombocytopenia in type 2B VWD patients.
2B 型血管性血友病（VWD）是一种由 VWF 基因突变引起的出血性疾病。2B 型 VWD 的实验室和临床表型存在异质性。
我们在一项大型、特征明确的患者队列中，通过中位数为 16 年的随访，研究了基因型与表型之间的相关性。
我们纳入了来自全国多中心“荷兰血管性血友病”研究的 64 例基因确诊的 2B 型 VWD 患者，并从电子病历中回顾性收集了临床和实验室数据。我们分析了基因型与血小板减少、出血表型以及导致内皮激活和血管性血友病因子（VWF）分泌的事件之间的相关性，包括手术、去氨加压素治疗、妊娠和分娩。
67.2%的患者出现血小板减少，不同遗传变异之间的发生率存在差异（p.Arg1306Trp：75.0%，p.Arg1308Cys：58.3%）。血小板减少的最重要决定因素是 p.Arg1306Trp VWF 变异（比值比，25.1）。血小板计数随时间变化很大，在携带 p.Arg1306Trp 的患者中，有 37.5%的患者血小板计数持续<150×10/L，而在携带 p.Arg1308Cys 的患者中，这一比例为 8.3%。在我们的分析中，内皮激活不是血小板减少发生的独立决定因素（比值比，1.3）。血小板减少与累积出血评分或年出血率之间无相关性。4 名女性在所有 8 次足月妊娠的第三个孕期中均出现血小板计数下降（n=8），在分娩前一周急剧下降。尽管预防性使用 VWF 浓缩物，但仍有 5 例 8 例分娩发生产后出血（定义为分娩时估计失血量>500mL）。
本研究揭示了 2B 型 VWD 患者 VWF 变异 p.Arg1306Trp 与血小板减少之间的强烈相关性。
