Bridging the Evidence Gap in von Willebrand Disease: A Call to Action for Equitable, Evidence-Based Care

Abstract

Von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting up to 1% of the population [1]. Over the past two decades, there has been significant progress in understanding its pathophysiology, classification and clinical management. However, research in VWD continues to lag behind that of haemophilia—a rarer condition that has benefited from earlier and more sustained investment. Today, haemophilia care is supported by robust national and global registries, individualized pharmacokinetic (PK) dosing strategies and a rich therapeutic pipeline, including gene and non-factor therapies [2, 3].

VWD spans a spectrum of biologically distinct subtypes, each with unique genetic drivers, bleeding patterns and variable severity. This diversity complicates every stage of research—patient selection, endpoint harmonization and treatment stratification—prompting industry partners and investigators to call for innovative, subtype-sensitive trial designs. Scientific complexity is only part of the challenge: limited access to specialized diagnostics, sparse clinical trial infrastructure and historical underinvestment in patient-relevant outcome measures have further slowed progress. Diagnostic variability—including frequent misclassification of subtypes and uneven availability of advanced assays—adds another layer of fragmentation to both clinical care and research. Table 1 summarizes interventional trials completed or underway in the past 20 years, highlighting areas of progress while revealing persistent gaps in scope and scale. For comparison, a search for interventional studies completed or underway in haemophilia over the same 20-year period yielded 442 studies.

Although VWD research has not progressed as rapidly as haemophilia, recent efforts signal meaningful momentum. A World Federation of Hemophilia (WFH) Congress Plenary by Peter Lenting—later published in Blood [4]—highlighted the imbalance between haemophilia and VWD, helping galvanize the community around a renewed research agenda. Since then, initiatives such as the ASH/ISTH/NHF/WFH 2021 guidelines [5, 6] and the development of CoreVWD [7] have established a foundation for standardized diagnosis, management and outcome measurements. These initiatives are evidence of a maturing research foundation with potential for further growth.

Haemophilia trials routinely enrol hundreds of participants across continents [8, 9]. Most VWD studies, by comparison, remain small and geographically limited. Even the landmark prophylaxis trial by Peyvandi et al. [10] enrolled only 19 participants, with 12 participants completing the study. Recent studies, including WIL-31 [11] and VWDMin [12], signal a growing interest in VWD research, with their scale and scope offering a springboard for broader, coordinated programmes such as seen in haemophilia. Moreover, VWD trial endpoints often undercapture the lived experiences of patients with frequent mucosal or menstrual bleeding, limiting clinical relevance.

Existing studies frequently underrepresent women, girls and people who have potential to menstruate (WGPPM), as well as those with type 2 and type 3 VWD. Paediatric populations are similarly underrepresented, despite unique pharmacokinetic and developmental considerations that merit dedicated studies. This research gap may, in part, reflect broader systemic issues in medicine, including the historical underrecognition of women's health. VWD, which disproportionately affects women due to menstruation and reproductive bleeding, has arguably suffered from historical neglect, hindering investment, delaying diagnosis and limiting research [13]. As the bleeding disorders community works towards equity, research must centre the experiences of WGPPM, especially in areas such as heavy menstrual bleeding and postpartum haemorrhage. There is an urgent need for inclusive, scalable research programmes that reflect the full spectrum of patient experiences and clinical realities.

Research limitations lead to clinical uncertainties in VWD care, especially in decisions such as identifying candidates for prophylaxis, determining treatment intensity, or how to provide perioperative or peripartum care. In the absence of high-quality data, decisions are often extrapolated from haemophilia studies or based on clinician experience—leading to wide practice variability. Some patients receive empirical therapy; others may go untreated despite significant bleeding.

Traditional endpoints such as annualized bleeding rate (ABR), widely used in haemophilia, are poorly suited to VWD. ABR does not fully capture symptom variability or treatment response [14]. It also fails to reflect the clinical impact of recurrent, often unpredictable, mucosal bleeding that—though rarely life-threatening—can significantly affect iron balance, daily function and quality of life [14]. Without validated, disease-specific and patient-relevant outcomes, assessing therapeutic efficacy and advocating for expanded care becomes difficult.

The WFH's 2017 Call to Action on VWD [21] was a pivotal step towards global recognition of this underrepresented condition. The 2021 ASH/ISTH/NHF/WFH guidelines [5, 6] marked another major milestone by offering structure and evidence-based consensus in VWD diagnosis and management. Yet both documents also highlight the limitations in the quality of the current evidence base, which remains heavily reliant on expert opinion and extrapolation from haemophilia.

The bleeding disorders community is also undergoing an important reckoning with identity and inclusivity. Historically, the dominance of haemophilia in naming conventions—such as the World Federation of Hemophilia and Hemophilia Treatment Centres—has unintentionally marginalized those with other conditions like VWD. The decision by the National Hemophilia Foundation to rebrand as the National Bleeding Disorders Foundation represents a critical and welcomed step towards inclusivity. As we move forward, language matters. Adopting terminology that reflects the diversity of bleeding disorders is essential to fostering a sense of belonging and prioritizing equity in research, policy and care.

There is now widespread consensus that VWD deserves—and is beginning to receive—a research agenda that reflects its prevalence, complexity and patient burden. This call for continued investment is not a critique of past efforts, but rather an evolution of a maturing field. Encouragingly, recent collaborations, therapeutic innovations and international guideline efforts have laid a strong foundation. Continued support from funders, regulators, industry partners and the bleeding disorders community is needed to build upon this momentum and convene around a coordinated research roadmap for VWD. This includes investing in trial infrastructure, inclusive outcome development, PK tools and sustained stakeholder engagement. BDTCs must embrace their role in strengthening data collection, standardizing care and engaging patients in research. Equitable care requires equitable evidence—and equitable evidence requires collaboration. No condition is too rare or too complex to study—VWD is simply too important to overlook and must be part of a broader, coordinated, and inclusive research agenda.

K.U. drafted the initial manuscript. P.J., N.C. and R.K. reviewed and revised the manuscript and provided feedback. All authors approved the final version of the manuscript.

K.U. has received educational grants from CSL Behring, Roche and Novo Nordisk, research funding from Bayer, Novo Nordisk and Pfizer, consultancy fees from Bayer, Biocryst Pharmaceuticals, Novo Nordisk, Roche, Sanofi and Takeda, speaker fees from Bayer, CSL Behring, Pfizer, Roche, Sanofi and Takeda, and travel support from Novo Nordisk, Octapharma, Roche and Sanofi. P.J. reports consultancy for Star/Vega Therapeutics, Band/Guardian Therapeutics, Roche and BioMarin. N.C. reports serving as a consultant for Takeda and OctaPharma AG, participating in advisory boards for Bayer, CSL Behring, Genentech, Medzown, Pfizer, Sanofi Genzyme and Takeda, and receiving honoraria/travel support from OctaPharma AG and Roche. R.K. is supported by the Department of Medicine Meridith Marks Research Chair in Medical Education and declares research support from the Canadian Hemophilia Society and Association of Hemophilia Clinic Directors of Canada, as well as consultancy fees from CSL Behring, Novo Nordisk, Pfizer, Roche, Sanofi and Takeda and speaker fees from Bayer, Pfizer, Sanofi and Takeda.

This article is a commentary and does not report on or involve any original research with human participants or animals. Therefore, ethical approval and informed consent were not required.

The authors declare no conflicts of interests.