Importance of Genotyping in von Willebrand Disease to Elucidate Pathogenic Mechanisms and Variability in Phenotype

Ferdows Atiq, Johan Boender, Waander L. Van Heerde, Juan M. Tellez Garcia, Selene C. Schoormans, Sandy Krouwel, Marjon H. Cnossen, Britta A.P. Laros-Van Gorkom, Joke De Meris, Karin Fijnvandraat, Johanna G. Van Der Bom, Karina Meijer, Karin P.M. Van Galen, Jeroen Eikenboom, Frank W.G. Leebeek*

*Corresponding author for this work

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Abstract

Genotyping is not routinely performed at diagnosis of von Willebrand disease (VWD). Therefore, the association between genetic variants and pathogenic mechanism or the clinical and laboratory phenotype is unknown in most patients, especially in type 1 VWD. To investigate whether genotyping adds to a better understanding of the pathogenic mechanisms and variability in phenotype, we analyzed the VWF gene in 390 well-defined VWD patients, included in the WiN study. A VWF gene variant was found in 155 patients (61.5%) with type 1, 122 patients (98.4%) with type 2, and 14 patients (100%) with type 3 VWD. Forty-eight variants were novel. For each VWF gene variant, the pathogenic mechanisms associated with reduced VWF levels was investigated using the FVIII:C/VWF:Ag and VWFpp/VWF:Ag ratios. In type 1 VWD, reduced synthesis or secretion of VWF was most frequently found in patients with nonsense variants, frameshift variants, and deletions, whereas rapid clearance of VWF was mainly found in patients with missense variants. Furthermore, type 1 VWD patients with and without a VWF gene variant were clearly distinct in their clinical features such as age of diagnosis, laboratory phenotype, and bleeding phenotype. In type 2 VWD, 81% of variants were associated with an increased clearance of VWF. To conclude, we identified the pathogenic mechanisms associated with various VWF gene variants in type 1, 2, and 3 VWD patients. Additionally, major differences in the phenotype of type 1 VWD patients with and without a variant were observed, which may be of importance for clinical management.

Original languageEnglish
Article numberE718
JournalHemaSphere
Volume6
Issue number6
DOIs
Publication statusPublished - Jun 2022

Bibliographical note

Funding Information:
FA received the CSL Behring-professor Heimburger Award 2018 and a travel grant from Sobi. JB started working at Sobi after finishing this research project. WLvH reports speaker and consultant and travel fees from Takeda, Bayer, CSL Behring, and Sobi. He is also cofounder and CSO of Enzyre. MHC has received investigator-initiated research grants over the years from the Netherlands Organisation for Scientific Research (NWO), the Netherlands Organization for Health Research and Development (ZonMw), the Dutch “Innovatiefonds Zorgverzekeraars,” Baxter/Baxalta/Shire, Pfizer, Bayer Schering Pharma, CSL Behring, Sobi Biogen, Novo Nordisk, Novartis, and Nordic Pharma, and has served as a steering board member for Roche and Bayer. All grants, awards, and fees go to the Erasmus MC as institution. The institution of KF has received unrestricted research grants from CSL Behring, Sobi, and NovoNordisk, and her institution received consultancy fees from Grifols, Takeda, Novo Nordisk, and Roche. KM received research support from Bayer, Sanquin, and Pfizer; speaker fees from Bayer, Sanquin, Boehringer Ingelheim, BMS, and Aspen; consulting fees from uniQure, of which all fees go to the institution. BAPL-vG has received unrestricted educational grants from Baxter and CSL Behring. JE received research support from CSL Behring, and he has been a teacher on educational activities of Roche. KPMvG received unrestricted research support from CSL Behring and Bayer and speakers fee from Takeda. JGvdB has been a teacher on educational activities of Bayer and received consultancy fees from Novo Nordisk, paid to the Leiden University Medical Center. FWGL received research support from CSL Behring and Shire/Takeda for performing the Willebrand in the Netherlands (WiN) study and uniQure for a study not related to this article, and is consultant for uniQure, Sobi, Biomarin, and Shire/Takeda, of which the fees go to the institution, and has received a travel grant from Sobi. He is also a DSMB member for a study by Roche. All the other authors have no conflicts of interest to disclose.

Funding Information:
The WiN study was supported (in part) by research funding from the Dutch Hemophilia Foundation (Stichting Haemophilia), Shire (Takeda) and CSL Behring (unrestricted grant).

Publisher Copyright:
© 2022 Wolters Kluwer Health. All rights reserved.

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