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CC BY 4.0 · Thromb Haemost
DOI: 10.1055/a-2616-5161
Coagulation and Fibrinolysis

Landscape and Spectrum of VWF Variants in Type 2 Von Willebrand Disease: Insights from a German Patient Cohort

Authors

  • Hamideh Yadegari  ‡   *

    1   Institute of Experimental Haematology and Transfusion Medicine, Medical Faculty, University of Bonn, Bonn, Germany

  • Susan Halimeh‡   *

    2   Coagulation Center Rhein-Ruhr, Duisburg, Germany

  • Alexander Krahforst

    1   Institute of Experimental Haematology and Transfusion Medicine, Medical Faculty, University of Bonn, Bonn, Germany

  • Anna Pavlova

    1   Institute of Experimental Haematology and Transfusion Medicine, Medical Faculty, University of Bonn, Bonn, Germany

  • Behnaz Pezeshkpoor 

    1   Institute of Experimental Haematology and Transfusion Medicine, Medical Faculty, University of Bonn, Bonn, Germany

  • Jens Müller

    1   Institute of Experimental Haematology and Transfusion Medicine, Medical Faculty, University of Bonn, Bonn, Germany

  • Bernd Pötzsch

    1   Institute of Experimental Haematology and Transfusion Medicine, Medical Faculty, University of Bonn, Bonn, Germany

  • Arijit Biswas

    1   Institute of Experimental Haematology and Transfusion Medicine, Medical Faculty, University of Bonn, Bonn, Germany

  • Natascha Marquardt

    1   Institute of Experimental Haematology and Transfusion Medicine, Medical Faculty, University of Bonn, Bonn, Germany

  • Ute Scholz

    3   Center of Hemostasis, MVZ Labor Leipzig, Leipzig, Germany

  • Heinrich Richter

    4   Münster Hemostasis Center, Münster, Germany

  • Heiner Trobisch

    5   Laboratory and Ambulance for Coagulation Disorders, Duisburg, Germany

  • Karin Liebscher

    6   Institute of Transfusion Medicine and Clinical Hemostaseology, Klinikum St. Georg GmbH, Leipzig, Germany

  • Martin Olivieri

    7   Pediatric Thrombosis and Hemostasis Unit, Dr. Von Hauner Children's Hospital, LMU Clinic, Munich, Germany

  • Karolin Trautmann-Grill

    8   University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

  • Oliver Tiebel

    9   Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

  • Ralf Knöfler

    10   Pediatric Hemostaseology Unit, Department of Pediatrics, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

  • Johannes Oldenburg

    1   Institute of Experimental Haematology and Transfusion Medicine, Medical Faculty, University of Bonn, Bonn, Germany
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Abstract

Introduction

von Willebrand disease (VWD) type 2 arises from variants in von Willebrand factor (VWF) that disrupt its essential hemostatic functions. As per ISTH guidelines, it is classified as type 2A, 2B, 2M, and 2N based on the affected VWF roles.

Objectives

This population-based study aims to uncover the genotype and laboratory phenotypes in type 2 VWD, providing insights into underlying genetics and genotype–phenotype associations.

Patients/Methods

Our cohort included 247 patients from 196 families. Patients were characterized through multiple VWF phenotypic assays and genetic analyses, including DNA sequencing, copy number variation evaluations, and bioinformatic assessments.

Results

A total of 86 index patients (IPs, 44%) were diagnosed with type 2A, the most prevalent subtype. Additionally, 27 IPs (14%) were diagnosed with type 2N, 24 IPs (12%) with type 2B, 17 IPs (9%) with type 2M, and 42 IPs categorized as type U VWD carried VWD-associated variants but could not be assigned to a specific subtype. VWF variants were detected in 187 out of 196 (95%) individuals. A total of 222 VWF variants were identified: 187 missense (84%), 22 null alleles (10%), 5 regulatory (2%), 6 gene conversions (3%), and 2 silent variants (1%). Many variants were recurrent in our cohort, resulting in 114 distinct variants. Of these, 45 (39%) were novel.

Conclusion

Our data expands the spectrum of disease-associated variants in VWF, including many newly identified variants. This provides valuable insights for accurate diagnosis and personalized treatment. Additionally, the significant genetic heterogeneity among type 2 patients highlights the challenges in sub-classification.

Keywords

von Willebrand disease - von Willebrand factor - type 2 von Willebrand disease - genetic variation

Authors' Contribution

H.Y. designed the study, interpreted the data, supervised the research, and wrote the paper. S.H. contributed to genetic analysis, phenotypic laboratory analysis, and data acquisition. A.K. analyzed the data and did the bioinformatic analysis. A.P. and B.P. performed genetic analysis, including DNA sequencing and copy number variation analysis, and aided in data interpretation. J.M. and B.P. contributed to phenotypic laboratory analysis. A.B. contributed to the in silico structural analysis. N.M., U.S., H.R., H.T., K.L., M.O., K.T.-G., O.T. and R.K. contributed to data acquisition, phenotypic laboratory analysis, and provided final approval. J.O. assisted in data interpretation and manuscript review.


* These authors contributed equally as co-first authors.




Publikationsverlauf

Eingereicht: 09. Januar 2025

Angenommen: 09. April 2025

Accepted Manuscript online:
20. Mai 2025

Artikel online veröffentlicht:
05. Juni 2025

© 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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