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von Willebrand disease

Nature Reviews Disease Primers volume 10, Article number: 51 (2024) Cite this article

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Abstract

von Willebrand disease (VWD) is the most common inherited bleeding disorder. The disorder is characterized by excessive mucocutaneous bleeding. The most common bleeding manifestations of this condition include nosebleeds, bruising, bleeding from minor wounds, menorrhagia or postpartum bleeding in women as well as bleeding after surgery. Other less frequent symptoms include gastrointestinal bleeding, haematomas or haemarthroses. VWD pathophysiology is complex and results from defects in von Willebrand factor (VWF) glycoprotein. Quantitative deficiencies are responsible for type 1 VWD with a partial decrease of VWF and type 3 with the complete absence of VWF. Qualitative abnormalities cause type 2 VWD, being further divided into types 2A, 2B, 2M and 2N. Although common, VWD is at risk of misdiagnosis, overdiagnosis and underdiagnosis owing to several factors, including complex diagnosis, variability of bleeding symptoms, presence of external variables (blood groups and other physiological modifiers such as exercise, thyroid hormones, oestrogens, and ageing), and lack of disease awareness among non-specialist health-care providers. Establishing the correct VWD diagnosis requires an array of specialized phenotypic assays and/or molecular genetic testing of the VWF gene. The management of bleeding includes increasing endogenous VWF levels with desmopressin or infusion of exogenous VWF concentrates (plasma-derived or recombinant). Fibrinolytic inhibitors, topical haemostatic agents and hormonal therapies are used as effective adjunctive measures.

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Fig. 1: Structure of the VWF gene and pseudogene.
Fig. 2: VWF life-cycle.
Fig. 3: The role of VWF in haemostasis.
Fig. 4: Disease mechanisms in type 2 VWD.
Fig. 5: Clinical manifestations in patients with VWD.
Fig. 6: Diagnostic algorithm of VWD.
Fig. 7: Domain distribution of all pathogenic variants reported in VWD.

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Acknowledgements

The authors acknowledge P. M. Mannucci for his critical advice. O.S., L.B. and F.P. acknowledge support from the Italian Ministry of Health-Bando Ricerca Corrente.

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Authors and Affiliations

  1. Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy

    Omid Seidizadeh & Flora Peyvandi

  2. Department of Internal Medicine, Division of Thrombosis and Hemostasis, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands

    Jeroen C. J. Eikenboom

  3. Laboratory for Hemostasis, Inflammation & Thrombosis, Unité Mixte de Recherche 1176, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, Le Kremlin-Bicêtre, France

    Cécile V. Denis & Peter J. Lenting

  4. Department of Paediatrics, Medical College of Wisconsin, Milwaukee, WI, USA

    Veronica H. Flood

  5. Department of Medicine, Queen’s University, Kingston, Ontario, Canada

    Paula James

  6. Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy

    Luciano Baronciani & Flora Peyvandi

  7. Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland

    James S. O’Donnell

  8. Department of Pathology and Molecular Medicine, Queen’s University, Kingston, Ontario, Canada

    David Lillicrap

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Contributions

Introduction (O.S. and F.P.); Epidemiology (O.S. and F.P.); Mechanisms/pathophysiology (D.L., L.B., C.V.D., P.J.L., J.S.O. and O.S.); Diagnosis, screening and prevention (J.C.J.E., V.H.F., P.J., F.P., D.L., L.B. and O.S.); Management (V.H.F., P.J., F.P., C.V.D., P.J.L., J.S.O. and J.C.J.E.); Quality of life (J.S.O. and J.C.J.E.); Outlook (D.L. and O.S.); overview of the Primer (O.S. and F.P.).

Corresponding author

Correspondence to Flora Peyvandi.

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Competing interests

F.P. reports participation at educational meetings of Takeda and Spark, and the advisory board of CSL Behring, Biomarin, Roche, Sanofi, and Sobi. C.V.D. and P.J.L. are co-inventors on patents related to von Willebrand factor and von Willebrand disease treatment and received research grants to the institute from Roche, Sanofi, Sobi and Biomarin. D.L. received research support from Biomarin, CSL Behring and Sanofi, and serves advisory roles for Biomarin, CSL Behring, Novo Nordisk, Pfizer and Sanofi. V.H.F. served on an advisory board for Octapharma. J.S.O. served on the speaker’s bureau for Baxter, Bayer, Novo Nordisk, Sobi, Boehringer Ingelheim, Leo Pharma, Takeda and Octapharma. He has also served on the advisory boards of Baxter, Sobi, Bayer, Octapharma, CSL Behring, Daiichi Sankyo, Boehringer Ingelheim, Takeda and Pfizer. J.S.O. has also received research grant funding awards from 3M, Baxter, Bayer, Pfizer, Shire, Takeda and Novo Nordisk. P.J. received consultancy fees from Star/Vega, Band/Guardian, Biomarin and Roche. J.C.J.E. received a research grant from CSL Behring, all funds paid to the institute. O.S. and L.B. declare no competing interests.

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Nature Reviews Disease Primers thanks A. C. Weyand, P. A. Kouides, N. Connell, M. V. Ragni and F. Atiq who co-reviewed with A.-M. Hulshof and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Seidizadeh, O., Eikenboom, J.C.J., Denis, C.V. et al. von Willebrand disease. Nat Rev Dis Primers 10, 51 (2024). https://doi.org/10.1038/s41572-024-00536-8

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