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

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. Progress is underway. Collaborative groups, national research networks and global stakeholders have laid a strong foundation. Figure 1 outlines a coordinated agenda to accelerate momentum, address evidence gaps and guide clinical and policy decisions. To reflect the diverse bleeding phenotypes in VWD, future studies should more precisely characterize mucosal bleeding—including epistaxis, menstrual bleeding and gastrointestinal bleeding—and incorporate endpoints that align with patient priorities. Beyond bleed frequency, trials should assess severity, duration and quality-of-life impact. Adaptive designs and subgroup analyses are crucial for understanding differences across VWD types and addressing the needs of underrepresented groups, including WGPPM and those with type 2 and 3 VWD. Dedicated efforts are also needed to capture paediatric bleeding phenotypes and age-specific outcomes. In some cases, pragmatic grouping based on laboratory investigations such as VWF or FVIII levels—rather than strict subtype—may enhance trial feasibility. However, care must be taken not to obscure clinically meaningful differences. The inclusion of patient-reported outcomes and qualitative data can further enhance the relevance and patient-centredness of clinical research. Regulatory bodies are increasingly recognizing the value of patient-reported outcomes and real-world evidence in evaluating therapeutic benefit. Incorporating these elements—alongside unbiased assessments of care pathway improvements—will be essential for regulatory alignment and accelerating uptake to ensure that advances are applied equitably across diverse patient populations. Initiatives such as coreVWD [7] and the work of Connell and James et al. [15] have established core outcome sets (COSs) and research definitions tailored to VWD, encompassing domains like bleeding severity, reproductive health and functional impact. Broad adoption of COS can harmonize research design, facilitate data pooling and enhance the clinical applicability of findings. These efforts will also help bridge the gap between clinical trials and real-world care. In haemophilia, PK-guided dosing has revolutionized prophylaxis by enabling individualized treatment based on factor kinetics, supported by platforms such as WAPPS-Hemo [16]. In VWD, PK studies have similarly demonstrated interindividual and product-specific variability in VWF and FVIII clearance [17-19]. However, PK protocols have not been adopted in routine VWD management. This may reflect the absence of standardized, user-friendly tools akin to those available in haemophilia, as well as challenges such as limited clinician familiarity, product-specific complexity and variability in institutional practice. Developing validated and accessible PK platforms for VWD—alongside broader provider education—could improve dosing precision, reduce bleeding and thrombotic risk, and support more cost-effective, individualized care. Expanding research networks is critical for conducting multicentre trials and generating pragmatic evidence. National registries, such as the Canadian Bleeding Disorders Registry, offer a platform for both trial recruitment and real-world data collection. Internationally, the WFH's World Bleeding Disorders Registry (WBDR) has recently been expanded to include patients with VWD, providing an important global infrastructure for longitudinal data collection and benchmarking. According to the WFH's 2023 Annual Global Survey, over 100,000 individuals with VWD have been reported by national member organizations—underscoring both the significant global burden of disease and the opportunity for coordinated data collection [20]. Linking clinical, administrative and patient-reported data will enhance understanding of long-term outcomes and help identify gaps in access and care delivery. Facilitating the use of large-scale health and environmental data requires coordinated advocacy to balance data protection with research advancement. These efforts are often hampered by country-specific legislation and infrastructure limitations, particularly in building international databases that rely on individual-level data. Implementation science offers additional tools to study and accelerate the integration of research findings—such as COSs and care pathways—into both clinical trials and routine practice, enabling their evaluation and refinement in real-world settings. Sustained progress will depend on meaningful engagement of patients, caregivers and frontline providers throughout the research process. Co-designing studies with these stakeholders helps ensure that research questions reflect real-world priorities, enhances recruitment and promotes successful implementation. To support this shift, funders and trial sponsors should embed such partnerships into study trial design, governance structures and dissemination plans. Advocacy initiatives—such as WFH's 2017 Call to Action on VWD [21] campaign aimed at improving diagnosis and global access—play a vital role in catalysing these partnerships and ensuring that research and care efforts reach marginalized communities as well. Although national and global coordination is vital, individual Bleeding Disorder Treatment Centres (BDTCs) also have a critical role in advancing VWD care and research. BDTCs can standardize bleeding assessments using validated tools such as the International Society of Thrombosis and Haemostasis Bleeding Assessment Tool [22], apply COSs in routine clinical care and contribute to national or international registries. Where feasible, BDTCs should prioritize the inclusion of patients with VWD in observational studies or pragmatic clinical trials. BDTCs can also build interdisciplinary collaboration across specialties—including gynaecology, gastroenterology, otolaryngology and primary care—to improve recognition and referral pathways for individuals with unexplained bleeding symptoms. BDTCs should also ensure equitable access to care and research participation across geographic regions, racial and ethnic backgrounds, socioeconomic groups, and other marginalized or underserved populations, by addressing systemic and structural barriers that contribute to exclusion from care and research. Patient education and engagement initiatives that centre the experiences of WGPPM and underrepresented VWD subtypes are equally essential. By embedding these actions into daily clinical practice, BDTCs can help close the evidence gap from the ground up. 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. No new data were generated or analysed in this study. All data referenced in the article are publicly available and cited appropriately in the reference list.