https://orcid.org/0000-0003-4649-9014
The American Society of Hematology (ASH), International Society on Thrombosis and Haemostasis (ISTH), National Hemophilia Foundation (NHF; now National Bleeding Disorders Foundation), and World Federation of Hemophilia (WFH) 2021 guidelines on the diagnosis and management of von Willebrand disease (VWD) included 11 recommendations on the diagnosis of VWD and 12 recommendations on the management of VWD, the most common inherited bleeding disorder. We describe the results of a review of the 2021 guidelines by the clinical co-chairs of the guideline panels requested by ASH to inform decision-making about the need for and timing of a guideline revision. An updated MEDLINE and Embase search applied the same terms as the ASH ISTH NHF WFH 2021 guidelines limited to studies from 2020 to 30 July 2024 (diagnosis) or 24 July 2024 (management). For the diagnosis of VWD, 432 studies were identified and underwent title and abstract review, with 17 undergoing full text review, and for the management of VWD, 288 studies were identified and underwent title and abstract review, with 37 undergoing full text review, to determine whether the data would change the strength or directionality of the existing recommendation or merit development of a new recommendation. Based on this review, the clinical co-chairs noted that none of the reviewed studies would change the direction or strength of the existing guideline recommendations. There will be continued monitoring of the ASH ISTH NHF WFH 2021 guidelines on the diagnosis and management of VWD to evaluate whether there is sufficient new evidence to warrant additional revisions.
Introduction
The American Society of Hematology (ASH), International Society on Thrombosis and Haemostasis (ISTH), National Hemophilia Foundation (NHF; now the National Bleeding Disorders Foundation), and World Federation of Hemophilia (WFH) 2021 guidelines on the diagnosis and management of von Willebrand disease (VWD) were created to establish evidence-based guidelines to improve the diagnosis and management of VWD, the most common inherited bleeding disorder.1,2 The diagnosis guidelines issued 11 recommendations outlining the role of bleeding assessment tools in the assessment of people suspected of having VWD (recommendations 1-3), diagnostic assays and laboratory cutoffs for type 1 and type 2 VWD (recommendations 4, 6-8, 9), how to approach a patient with type 1 VWD with normalized levels over time (recommendation 5), and the role of genetic testing vs phenotypic assays for types 2B and 2N VWD (recommendations 10-11). The management guidelines issued 12 recommendations outlining prophylaxis for frequent recurrent bleeding (recommendation 1), desmopressin trials to determine therapy (recommendations 2A and 2B), use of antiplatelet agents and anticoagulant therapy (recommendation 3), target von Willebrand factor (VWF) and factor VIII activity levels for major surgery (recommendations 4A and 4B), strategies to reduce bleeding during minor surgery or invasive procedures (recommendations 5A and 5B), management options for heavy menstrual bleeding (recommendations 6A and 6B), management of VWD in the context of neuraxial anesthesia during labor and delivery (recommendation 7), and management in the postpartum setting (recommendation 8). This review of the 2021 guidelines by the clinical co-chairs of the guidelines was requested by ASH to inform decision-making about the need for and timing of a guideline revision.
Literature review methods
ASH contracted with Katherine Akers to refresh the literature searches originally conducted by the University of Kansas Medical Center for the 2021 guidelines. The updated MEDLINE and Embase search applied the same search terms as in the ASH ISTH NHF WFH 2021 guidelines.1-8 For the diagnosis of VWD, the search was limited to studies published from 2020 to 30 July 2024, and for the management of VWD, the search was limited to studies published from 2020 to 24 July 2024. Non-English studies and duplicates were removed. Identified diagnosis studies (n = 432) and management studies (n = 288) underwent title and abstract screening by 2 reviewers (P.D.J. and N.T.C. for diagnosis; V.H.F. and N.T.C. for management) for relevance to the scope of the guidelines. Ultimately, 17 VWD diagnosis studies and 37 VWD management studies underwent a full-text review and were assessed based on relevance to the previous recommendation with regard to the population, prioritized outcomes, and study design. Studies were then reviewed by the clinical co-chairs to assess whether the data would change the strength or the directionality of the existing recommendation or merit the development of a new recommendation.
Relevant findings
None of the identified studies that underwent full-text review were judged by the clinical co-chairs to provide data that would lead to a change in either the direction or strength of the published recommendations.
The co-chairs did find several studies that provided further support for the recommendation to use VWF-containing concentrates for prophylaxis in those with severe and frequent bleeding events (2021 Management Guideline Recommendation 1). In 2022, a phase 3, prospective, open-label, nonrandomized multicenter study (n = 23; ClinicalTrials.gov identifier: NCT02973087) evaluated the efficacy and safety of recombinant VWF prophylaxis in adults with severe VWD and showed that routine prophylaxis reduced bleeding events compared with on-demand therapy.9 The VWDMin study (n = 36; ClinicalTrials.gov identifier: NCT02606045) was a multicenter phase 3, open-label, randomized crossover trial evaluating reduction in heavy menstrual bleeding in those receiving recombinant VWF prophylaxis or tranexamic acid.10 The trial was stopped early owing to slow recruitment, but failed to show improvement of VWF prophylaxis over tranexamic acid for prophylaxis in heavy menstrual bleeding. In 2024, the WIL-31 study (n = 33; ClinicalTrials.gov identifier: NCT04052698) was a prospective, noncontrolled, international phase 3 study evaluating the efficacy and safety of Wilate prophylaxis in people with severe VWD and also showed that routine prophylaxis reduced bleeding events compared with on-demand therapy.11 Although 2 of these 3 studies published results that further supported the 2021 recommendation to use VWF concentrates for long-term prophylaxis in people with VWD who experience severe and frequent bleeding, the sample size and study design were felt to limit the likelihood that inclusion of these studies would have been sufficient to upgrade the strength of the prophylaxis recommendation from conditional to strong.
Conclusions
The ASH ISTH NHF WFH 2021 guidelines on the diagnosis and management of VWD continue to be relevant based on an updated systematic review of the medical literature. Future research based on priorities outlined by the 2021 guideline panel using published definitions for clinical research in VWD will be critical to generating new data to strengthen the recommendations outlined in the current guidelines.12 To facilitate clinical trials of therapeutics for VWD, the coreVWD project has published a core outcome set for prophylaxis and perioperative treatment of VWD, including a special subset for women, girls, and people with the potential to menstruate.13 Periodic reassessment of the published literature will be necessary to trigger an update of the guidelines when sufficient evidence becomes available.
Authorship
Contribution: P.D.J., V.H.F., and N.T.C. reviewed the search results and independently assessed the data; N.T.C. wrote the manuscript; and all authors critically reviewed, revised, and approved the final version of the manuscript for publication.
Conflict-of-interest disclosure: P.D.J. reports receiving research funding from Bayer and consultancy fees from Vega Therapeutics, Band/Guardian Therapeutics, Roche, and BioMarin. V.H.F. reports serving as a consultant and participating in advisory boards for Octapharma AG. N.T.C. reports serving as a consultant for Takeda; participating in advisory boards for Takeda, Genentech, Sanofi Genzyme, and Medzown; and receiving honoraria/travel support from Octapharma AG.
Correspondence: Nathan T. Connell, Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, 75 Francis St, SR3, Boston, MA 02115; email: NTConnell@bwh.harvard.edu.
