Von Willebrand disease type 2M: Correlation between genotype and phenotype

Dominique P.M.S.M. Maas, Ferdows Atiq, Nicole M.A. Blijlevens, Paul P  T Brons, Sandy Krouwel, Britta A.P. Laros-van Gorkom, Frank W  G Leebeek, Laurens Nieuwenhuizen, Selene C.M. Schoormans, Annet Simons, Daniëlle Meijer, Waander L. van Heerde, Saskia E.M. Schols*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

5 Citations (Scopus)
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Background: An appropriate clinical diagnosis of von Willebrand disease (VWD) can be challenging because of a variable bleeding pattern and laboratory phenotype. Genotyping is a powerful diagnostic tool and may have an essential role in the diagnostic field of VWD. 

Objectives: To unravel the clinical and laboratory heterogeneity of genetically confirmed VWD type 2M patients and to investigate their relationship. 

Methods: Patients with a confirmed VWD type 2M genetic variant in the A1 or A3 domain of von Willebrand factor (VWF) and normal or only slightly aberrant VWF multimers were selected from all subjects genotyped at the Radboud university medical center because of a high suspicion of VWD. Bleeding scores and laboratory results were analyzed. 

Results: Fifty patients had a clinically relevant genetic variant in the A1 domain. Median bleeding score was 5. Compared with the nationwide Willebrand in the Netherlands study type 2 cohort, bleeding after surgery or delivery was reported more frequently and mucocutaneous bleedings less frequently. Median VWF activity/VWF antigen (VWF:Act/VWF:Ag) ratio was 0.32, whereas VWF collagen binding activity/VWF antigen (VWF:CB/VWF:Ag) ratio was 0.80. Variants in the A3 domain were only found in two patients with low to normal VWF:Act/VWF:Ag ratios (0.45, 1.03) and low VWF:CB/VWF:Ag ratios (0.45, 0.63). 

Conclusion: Genetically confirmed VWD type 2M patients have a relatively mild clinical phenotype, except for bleeding after surgery and delivery. Laboratory phenotype is variable and depends on the underlying genetic variant. Addition of genotyping to the current phenotypic characterization may improve diagnosis and classification of VWD.

Original languageEnglish
Pages (from-to)316-327
Number of pages12
JournalJournal of Thrombosis and Haemostasis
Issue number2
Early online date10 Nov 2021
Publication statusPublished - Feb 2022

Bibliographical note

Funding Information:
Dr. Atiq received the CSL Behring‐professor Heimburger Award 2018 and a travel grant from Sobi. Dr. Laros‐van Gorkom has received unrestricted educational grants from Baxter and CSL Behring. Dr. Leebeek received research support from CSL Behring and Shire/Takeda for performing the Willebrand in the Netherlands (WiN) study and Sobi and uniQure for studies not related to this manuscript, 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. Dr. van Heerde reports speaker and consultant and travel fees from Takeda, Bayer, CSL Behring, and Sobi. He is also cofounder and CSO of Enzyre. Dr. Schols has received travel grants from Bayer and Takeda, and consultancy grants from Takeda and Novo Nordisk. None of the other authors has a conflict of interest to declare.

Publisher Copyright:
© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis


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