Genetic variants, thrombocytopenia, and clinical phenotype of type 2B von Willebrand disease: a median 16-year follow-up study.

IF 5.5 2区医学 Q1 HEMATOLOGY

Journal of Thrombosis and Haemostasis Pub Date : 2024-09-28 DOI:10.1016/j.jtha.2024.08.028

Calvin B van Kwawegen, Ferdows Atiq, Dara Endenburg, Karin Fijnvandraat, Karin P M van Galen, Marjon H Cnossen, Saskia E M Schols, Marieke J H A Kruip, Waander L van Heerde, Joke de Meris, Johanna G van der Bom, Jeroen Eikenboom, Karina Meijer, Frank W G Leebeek

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引用次数: 0

Abstract

Background: 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.

Objectives: We investigated associations between genotype and phenotype over a median of 16 years follow-up in a large cohort of well-characterized patients.

Methods: 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.

Results: 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 × 10⁹/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.

Conclusion: This study reveals a strong association between VWF variant p.Arg1306Trp and thrombocytopenia in type 2B VWD patients.

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2B 型 von Willebrand 病的基因变异、血小板减少和临床表型：一项中位 16 年随访研究。

背景/目的：2B 型冯-威廉氏病（VWD）是由 VWF 基因的功能增益变异引起的出血性疾病。2B 型的实验室和临床表型各不相同。我们对一大批特征明确的患者进行了中位 16 年的随访，研究了基因型与表型之间的关联：我们纳入了 64 名经基因证实的 2B 型 VWD 患者，这些患者来自全国多中心 "荷兰的威廉"（WiN）研究，并从电子病历中回顾性地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症、出血表型以及导致内皮激活和 VWF 分泌的事件（包括手术、去氨加压素用药、妊娠和分娩）之间的关系：67.2%的患者表现为血小板减少，不同基因变异的发生率不同（p.Arg1306Trp：75.0%；p.Arg1308Cys：58.3%）。决定血小板减少的最重要因素是 p.Arg1306Trp VWF 变异（OR 25.1）。血小板计数随时间变化很大，p.Arg1306Trp 患者中有 37.5%的血小板计数持续为 9，而 p.Arg1308Cys 患者中只有 8.3%的血小板计数持续为 9。在我们的分析中，内皮活化不是血小板减少症发生的独立决定因素（OR 1.3）。血小板减少与累积出血评分或年出血率之间没有关联。在所有足月妊娠（n=8）中，有四名妇女的血小板计数在妊娠三个月内下降，并在分娩前一周急剧下降。尽管使用 VWF 浓缩物进行了预防性治疗，但仍有 5/8 例分娩发生了产后出血（定义为分娩时估计失血量大于 500 毫升）：本研究揭示了 VWF 变体 p.Arg1306Trp 与 2B 型患者血小板减少症之间的密切联系。

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来源期刊

Journal of Thrombosis and Haemostasis 医学-外周血管病

CiteScore

24.30

自引率

3.80%

发文量

321

审稿时长

1 months

期刊介绍： The Journal of Thrombosis and Haemostasis (JTH) serves as the official journal of the International Society on Thrombosis and Haemostasis. It is dedicated to advancing science related to thrombosis, bleeding disorders, and vascular biology through the dissemination and exchange of information and ideas within the global research community. Types of Publications: The journal publishes a variety of content, including: Original research reports State-of-the-art reviews Brief reports Case reports Invited commentaries on publications in the Journal Forum articles Correspondence Announcements Scope of Contributions: Editors invite contributions from both fundamental and clinical domains. These include: Basic manuscripts on blood coagulation and fibrinolysis Studies on proteins and reactions related to thrombosis and haemostasis Research on blood platelets and their interactions with other biological systems, such as the vessel wall, blood cells, and invading organisms Clinical manuscripts covering various topics including venous thrombosis, arterial disease, hemophilia, bleeding disorders, and platelet diseases Clinical manuscripts may encompass etiology, diagnostics, prognosis, prevention, and treatment strategies.