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

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 × 10 ⁹ /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.
Competing Interests: Declaration of competing interests F. Atiq is supported by a Rubicon grant (452022310) from the Netherlands Organization for Health Research and Development (ZonMw). F. Atiq received research support from CSL Behring, Takeda, Octapharma and Sobi. M.H. Cnossen has received grants from governmental research institutes, such as the Dutch Research institute (NWO), ZonMW, Innovation fund, NWO-Dutch Research Agenda, and unrestricted investigator-initiated research grants as well as educational and travel funding from various companies over the years (Pfizer, Baxter/Baxalta/Shire, Bayer Schering Pharma, CSL Behring, Sobi, Novo Nordisk, Novartis, and Nordic Pharma); she served as a member on steering boards of Roche and Bayer. All grants, awards, and fees go to the Erasmus MC. K. Meijer reports speaker fees from Alexion, Bayer, and CSL Behring; participation in trial steering committees for Bayer and Astra Zeneca; consulting fees from Uniqure and Therini; and participation in data monitoring and endpoint adjudication committee for Octapharma. M.J.H.A. Kruip received grants from governmental research institutes, such as the Dutch Research institute (ZonMW/NWO), Dutch Thrombosis Foundation, Innovation fund, unrestricted grants from Bayer, Pfizer, Daiichi Sankyo, Sobi, and Boehringer Ingelheim; and speakers fee from Bayer. W.L. van Heerde received financial support from Takeda and Novo Nordisk for activities within Enzyre BV. J. Eikenboom received research support from CSL Behring. K.P.M. van Galen received unrestricted research support from Octapharma. F.W.G. Leebeek received research support from CSL Behring and Takeda for performing the Willebrand in the Netherlands (WiN) study and uniQure and SOBI for studies not related to this article, and he is a consultant for uniQure, CSL Behring, BioMarin, and Takeda, of which the fees go to the institution. C.B. van Kwawegen, D. Endenburg, K. Fijnvandraat, S.E.M. Schols, J. de Meris and J.G. van der Bom declare no conflicts of interest.
(Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)