The National Hemophilia Foundation State of the Science Research Summit initiative: executive summary

1

ABSTRACT

Introduction

The National Hemophilia Foundation State of the Science Research Summit initiative sought to unify research efforts in the US inherited bleeding disorders (BDs) community around key topics of importance to people living with inherited BDs, the lived experience experts.

Areas covered

This community-led and -informed project focused on six broad areas – hemophilia A or B; von Willebrand Disease (VWD), platelet dysfunctions and other mucocutaneous inherited BDs; ultra-rare inherited BDs; the unique challenges of people with the potential to menstruate with inherited BDs; diversity, equity and inclusion, health services research, and implementation science; and facilitating research in the inherited BD community through designing an optimizied research infrastructure, enabling resources and funding, and furthering workforce capabilities required to execute the research priorities.

Expert opinion

The work summarized here, and in the accompanying supplement manuscripts , has implications not only for the US population but for people globally who have inherited BDs. The information is equally relevant to people living with hemophilia, VWD, the spectrum of inherited platelet disorders, ultra-rare factor deficiencies, and all other inherited BDs as it is to the health care providers and researchers focused on the care and treatment of inherited BDs in the US and globally.

KEYWORDS:

• Community
• health equity
• inherited bleeding disorder
• National Hemophilia Foundation
• research

1. Introduction

People with hemophilia (PWH), those living with von Willebrand disease (VWD) and ultra-rare coagulation factor deficiencies, people with rare inherited platelet disorders, as well as others with various inherited bleeding disorders (BDs) all aspire to a state of health and wellness enjoyed by their unaffected peers [1]. Health equity for people living with inherited bleeding disorders (PWIBD) can only be achieved when everyone can attain their full potential for health and wellbeing [2]. Understanding the biological determinants of health, for example, a specific diagnosis (e.g. a mutation in either the ITGA2B or ITGB3 gene resulting in Glanzmann thrombasthenia) is a priority in achieving this goal. However, the psychosocial conditions affecting people living with these disorders across the lifespan must also be addressed, as must the structural (political, legal, and economic) determinants of health, social norms, and the institutional decision-making processes impacting how, when, and where resources are distributed [3].

The National Hemophilia Foundation (NHF), a patient advocacy organization serving all inherited bleeding and blood disorders [4], sought to remedy the current situation in which PWIBD are disadvantaged in terms of health outcomes. In 2020, NHF launched a bold and potentially transformative community initiative to identify research priorities to ensure every PWIBD has access to safe, effective, convenient, and culturally appropriate therapeutics, diagnostics, and digital technologies to deliver optimal health outcomes at the lowest total cost of care – steps on the path to health equity.

2. The National Hemophilia Foundation State of the Science Research Summit

The NHF State of the Science Research Summit (SOS RS) was an effort to unify research efforts in the United States (US) inherited BD community around key topics of importance to PWIBD [5]. Further, the SOS RS sought to consider gaps in care and design research to generate the knowledge to close those gaps, enhancing the health and wellbeing of PWIBD. Ultimately, the goal of the SOS RS was to create a foundation for a National Research Blueprint with the intention of achieving health equity between those living with inherited BDs and their unaffected peers [1].

A first step was enlisting the support and partnership of the American Thrombosis and Hemostasis Network (ATHN), an independent nonprofit organization seeking to improve the lives of people affected by bleeding and clotting disorders by using technology to secure data, advance knowledge, and transform their care [6]. Together, the two organizations started by asking PWIBD what they seek for themselves through extensive community consultations, individual and group discussions, formal focus groups, and a cross-community survey. Several major categories of community-prioritized research emerged from these efforts (Table 1) [5]. To begin addressing these broad areas of need, focus areas were identified and community-prioritized research themes developed with the ultimate goal of transforming the lives of all PWIBD, including innovating solutions for the rarest disorders and underrepresented populations [5].

Table 1. Major categories of community-prioritized research revealed by consultations [5].

Continuation of the hemophilia treatment center (HTC) model of care

Health care disparities between various communities (based on race, ethnicity, gender, education, income, etc.)

Access to research and mechanisms (ways) to conduct research

Access to specialized care

Mental health (depression, anxiety, emotional impact, substance use disorders, etc.)

Pain management

Treatment for all BDs (gene therapy, non-factor replacements, etc.)

Specific treatment for other RBDs (non-hemophilia, non-VWD)

Women’s health and access to care

Treatment of other chronic disorders and issues affecting PWIBD (e.g. heart disease, diabetes, etc.)

Treatment of the aging population with BDs

Joint disease management

BD: bleeding disorder, HCP: health care provider, HTC: hemophilia treatment center, RBD: rare bleeding disorder, VWD: von Willebrand diseaseReproduced with permission from Valentino et al. (2022) [5]

The prioritized areas of research focus fall into three types. Some were applicable across all inherited BDs, for example assessment of pain and pain management irrespective of the disease state causing the pain. Other priorities were specific to a particular inherited BD, for example, developing novel therapeutics for the treatment of VWD. Finally, opportunities were identified to enhance research capacity and create a sustainable, fit-for-purpose infrastructure to address the needs of the inherited BD community. Six working groups (WGs) addressed these community-prioritized research themes (Table 2); the detailed composition of these WGs is reported in the manuscripts of this supplement [7–12] and in the previously published scoping paper [5].

Table 2. Six working groups convened to distill research questions from community priorities in specific focus areas [5].

WG1	Hemophilia A and B
WG2	Von Willebrand disease (VWD), platelet dysfunction, and other mucocutaneous inherited BDs
WG3	Ultra-rare inherited BDs
WG4	Women, girls, and people with the potential to menstruate
WG5	Diversity, equity, and inclusion; health services research; and implementation science
WG6	Facilitating priority research in the inherited BD community (infrastructure, workforce, resources and funding)

BD: bleeding disorder, WG: working groupReproduced with permission from Valentino et al. (2022) [5]

Members of WG1 concentrated their efforts on research having the potential to transform hemophilia A or B to a manageable disorder compatible with a full, active life [7]. The group defined 63 priority research questions addressing the impact of arthropathy and pain, bone health, and inhibitors on health outcomes; novel diagnostics and gene therapies with the potential to transform an affected individual’s life; optimizing pediatric to adult transition of care; health disparities faced by the community; and better understanding how senior health is impacted by both hemophilia and the diseases of aging, in particular cardiovascular disease. The development of precision diagnostics and the application of bioinformatics to advance the next generation of therapeutics, as well as improving our understanding of the biology of joint disease and the immunology of inhibitors in PWH were identified by the community as priorities for multidisciplinary basic or translational research.

Members of WG2 were tasked with addressing the unique needs of people living with excessive or abnormal mucocutaneous bleeding as a result of an inherited platelet disorder, hereditary hemorrhagic telangiectasia (HHT), hypermobility spectrum disorders (HSD) and Ehlers-Danlos syndromes (EDS), and VWD [8]. The physical and psychological wellbeing of those who live with these disorders was also reviewed and research priorities identified. In total, 38 high priority research questions to elucidate the underlying biology of the in-scope disorders were articulated as well as research to better describe their natural history, with particular attention to aging with a mucocutaneous BD. The need for collaborative studies and novel therapeutic approaches were also prioritized. An ultimate goal for these disorders was to develop curative therapies.

Members of WG3 had the charge to develop research priorities for ultra-rare inherited BDs including some of the disorders addressed by WG2 [9]. This WG defined and prioritized thematic areas for future emphasis rather than research questions per se. Future priorities included the development of better diagnostics and therapeutics for these ultra-rare disorders including a curative approach with gene therapy. Gaining a better understanding of the mechanisms of disease and the biology of rare and ultra-rare factor deficiencies through systems biology and mechanistic science was a goal, as was improved data collection across the lifespan especially among those aging with these disorders. Many of these ultra-rare disorders lack a correlation between residual plasma factor activity and clinical presentation making mechanistic research important to advance the field. The imperative of having flexible and innovative research and regulatory approaches was an expressed priority to advance science for ultra-rare disorders strongly supported by WG3.

People who have or had the potential to menstruate (PPM) with inherited BDs face challenges in receiving appropriate diagnoses and care and in participating in research. Members of WG4 were asked to develop research priorities to enhance the understanding of sex and gender biology on the manifestation of the range of BDs addressed by WGs 1–3, with the explicit goal of improving the health of women, girls, and PPM [10]. Collaboration and communication among the WGs were critical to the success of WG4, avoiding duplication of efforts and maximizing the impact of the deliberations of each WG. WG4 defined 44 top priority research questions based on the community-identified priorities with focus on sex and gender biology across the lifespan; health care delivery for this population which historically has been marginalized resulting in challenges in access to care and clinical research; a more thorough understanding of uterine biology and physiology, especially in the context of an inherited BD and excessive uterine bleeding; the unique interplay of sex hormones on bone and joint health; and the development of innovative clinical research methodology and new validated tools to more adequately measure patient-important (reported) outcomes, quality-of-life, and mental health in this population.

Members of WG5 focused on diversity, equity, and inclusion; health services research; and implementation science with the goal of imparting the greatest impact on equitable access to care across the continuum of PWIBD [11]. To better understand the complexities in this area, the following information is provided. The Centers for Disease Control and Prevention (CDC) and Health Resources and Services Administration (HRSA) support and fund a national network of over 140 hemophilia treatment centers (HTCs) across the US serving people with coagulation disorders in all states and US territories [13]. In the calendar year 2021, contact was reported with 117,118 unique individuals with more than 33 different coagulation disorders [13]. Delivering highly specialized health care, education, and facilitating participation in research to this large number of people with diverse coagulation disorders living in urban, rural, and remote parts of the US, with diverse backgrounds is challenging and requires an investment in outreach, education, training, and workforce development. That 78% of the population served by HTCs report their race to be White (non-Hispanic) [13] is concerning considering 59.3% of the US population in 2021 was White (non-Hispanic) [14]. Based on these data, it is currently unclear if there are underlying genetic and/or racial differences in the prevalence of BDs and their phenotypic expression among people of different genetic and racial backgrounds, although the epidemiology of inhibitor development in severe hemophilia A suggests there could be [15]. However, it is clear there are differences in clinical outcomes due to limitations in access to care, education, and other services among marginalized and minoritized populations (such as those of a given social standing, race, ethnicity, sex, gender identity, sexuality, age, income, disability status, language, culture, faith, geographic location, or country of birth) [3,16–19]. Health care providers (HCPs) of the future must be proficient in person-centered care principles including mutual respect for the dignity and responsibility of each individual to engage in their health care through shared decision-making, and addressing and overcoming their own biases with regards to the populations they serve and the treatments they embrace in order to optimize the physical, mental, sociocultural, and spiritual wellbeing of the individual while striving to reduce disease burden.

To tackle their considerable charge, WG5 divided the perceived challenges into those addressable through health services research and implementation trials, and work related directly to addressing and researching diversity, equity, and inclusion [11]. There were five priority research questions to be addressed by new investments in the field of health services research to study access to care, treatment adherence, as well as patient outcomes and satisfaction. To address diversity, equity, and inclusion, six top priority research questions emphasizing the importance of how racism, sexism, and other explicit and implicit phobias and biases operate within the practices of data collection, clinical care, and engagement with the community were put forward. Bridging research to clinical practice is a critical step in adopting, integrating, and sustaining evidence-based interventions to improve health outcomes, affect patient and provider satisfaction, and improve the health of a population. To address this crucial need, five top priority research questions were proposed by WG5 in implementation science.

Members of WG6 were charged with facilitating research in the inherited BD community. This involved three areas of focus: developing and facilitating an optimized research infrastructure; enabling resources and funding to execute the research priorities identified by the other WGs; and strategies for recruitment, retention, mentorship, and networking of a future workforce to ensure the human capital for expert health care delivery, conducting key research, and implementing evidence-based practices through education of the next generation of HCPs [12]. The HTC integrated model of care has emerged as a center of excellence and medical home since Congress first authorized and funded hemophilia programs at the CDC and HRSA in 1974, providing funding for surveillance, prevention, and services for PWIBD [20,21]. This integrated model of care has become the ‘gold standard,’ emulated by other rare disease communities [22,23]. Changes in the therapeutic landscape of hemophilia care and challenges to the reimbursement structure operative in HTCs has brought their future sustainability into question. WG6 highlighted this activity as a critical need. The clinical and translational research network in which HTCs operate must be sustained, but critical enhancements in infrastructure are required for the comprehensive care system to serve as a platform for collaborative research while improving efficiencies and burden of research participation for both subjects and providers.

Members of WG6 identified eight key priorities related to building the integrated research infrastructure of tomorrow. Progress in conducting multidisciplinary clinical trials and observational research was deemed to be dependent on the development of a research culture across the inherited BD community (a goal shared by all WGs); on the greater inclusion of women and girls with inherited BDs (emphasized by WG4) [10]; on the inclusion of the principles of diversity, equity, and inclusion and the incorporation of health services research and implementation science (work of WG5) [11]; as well as on the development of a facilitative clinical research infrastructure and expert workforce (mandate of WG6) [12]. This WG emphasized the requirement for a diverse, well-trained, high-quality workforce capable of participating in research, delivering education and counseling, and providing high-quality health care to a wide variety of individuals living with coagulation disorders served by HTCs. All of this requires identifying, procuring, and managing not just the funding to conduct these activities but also a myriad of other resources essential to facilitating prioritized research in the inherited BD community in an equitable and just way, following the principles of diversity, equity, inclusion, and justice highlighted by WG5 [11].

3. Prioritized research questions and initiatives: the foundation for a National Research Blueprint

The WGs proposed research questions informed by community input and refined following expert consultation; lived experience experts (LEEs) were key participants in each group [24]. Ultimately, WGs scored their research questions/initiatives against predetermined criteria for feasibility, impact, and risk grounding their prioritization in pragmatic considerations, with summing of the three scores facilitating the comparison of very different questions and initiatives, with diverse strengths and potentials [5,25].

Using this schema, WG1 which focused on research priorities in hemophilia A and B, developed 63 priority research questions in six areas: arthropathy, pain, and bone health (9); inhibitors (5); diagnostics (13); gene therapy (16); pediatric to adult transition of care (9); disparities (5); and cardiovascular disease (6) [7].

WG2, focused on VWD, inherited qualitative platelet dysfunction, and other mucocutaneous inherited BDs; identified 38 priority research questions in six areas including studying: the biology of mucocutaneous BDs (10); VWD (5); inherited qualitative platelet function defects (4); disorders of collagen and bleeding (8); novel therapeutics to treat mucocutaneous BDs (5); and aging in this population (6) [8].

WG3 examined research to impact ultra-rare inherited BDs. This group identified priority research questions in the areas of: diagnostics, systems biology and mechanistic science (13); clinical, data collection, and research infrastructure (2); and the regulatory process (5) [9].

WG4, focused on research to advance the health of women, girls, and PPM included six focus areas with questions on: lifespan sex biology (8), pregnancy and the postpartum period (10), uterine physiology and bleeding (13), bone and joint health (4), health care delivery (5), and patient-reported outcomes and quality-of-life research questions (7) [10].

Focusing on health services research WG5 included questions related to: telehealth (6); behavioral health services (4); the cost of care, insurance, and outcomes (4); the HTC model of care (8); marginalized and minoritized populations (14); quality of care metrics (2); patient-reported outcomes (3); and advocacy (1). In the area of diversity, equity, and inclusion, they prioritized questions related to: facilitators and barriers to care (4), engagement policies (7), and data availability (2). In the area of implementation science questions focused on: national level changes (5); diversity, equity, and inclusion (6); and patient level changes to be implemented (16) [11].

WG6, focusing on resources and funding, identified 22 priority research questions falling into 5 categories dealing with: structure (3), trials (5), partnerships (5), resources and approach (7), and funding (2) [12]. Focusing on infrastructure they identified a further 8 questions and in the area of workforce development: 5 near-term priorities, 3 mid-term priorities, and 5 long-term priorities [12].

4. Conclusion

In conclusion, this project and its priority research questions/initiatives represent a call to action for the entire inherited BD community to engage with each other to ensure the execution of the National Research Blueprint. Each stakeholder has a key role to play. PWIBD and their close family members, the true lived experience experts (LEEs) [24], must continue to provide input and insights, to engage with and participate in research, and to hold all stakeholders accountable to translate research into an optimized and personalized standard of care. This will require research as detailed in the articles of this supplement [7–12]. Investigators and researchers in academia, advocacy, and industry should look to these articles for direction and inspiration as they design their research programs and create innovative technologies to close the gaps in care for PWIBD. The priorities outlined in the supplement articles represent the areas of greatest need for those living with an inherited BD and their families. As such, funding agencies should foster and accelerate research programs in these areas through targeted mechanisms designed to close the gaps in care. A more efficient and affordable infrastructure is needed to execute on priority research and a sustainable pipeline of clinicians, clinician scientists, and basic science researchers are needed to deliver safe, effective, and convenient diagnostics, therapeutics, and digital technologies into the future potentially enhancing the health and wellbeing of PWIBD. Finally, we all must see these gaps and challenges through the lens of health equity and address the social drivers of health including those not directly related to the delivery of health care but impacting a person’s ability to access and fully engage in their health care.

5. Expert opinion

The work summarized in this manuscript and the accompanying manuscripts in this supplement has implications not only for the population of people living in the US but globally with inherited BDs. The information is equally relevant to those with hemophilia, VWD, ultra-rare inherited platelet disorders and factor deficiencies, and other inherited BDs. The World Federation of Hemophilia estimates, based on prevalence at birth and the current live birth population globally, approximately 20,000 people are born with hemophilia worldwide each year, including about 7,000 who have a severe form of the disease [26]. Moreover, the predicted number of PWH worldwide is 818,928, of which about 278,200 have severe disease. Most of these people, and in particular, those living in the developing world, remain undiagnosed and untreated leading to substantial morbidity and increased mortality compared to their unaffected peers. A striking example of this is found in the data reported from Africa in which 7,385 PWH have been identified representing only 8% of the estimated 97,946 in these countries [26]. These inequities in diagnosis and hence treatment lead to premature death among PWIBD in the developing world. For example, among the 21,350 PWH reported from India, only 11% were 45 years of age or older compared to 36% in the United Kingdom [26]. These inequities in diagnosis and treatment are also found in more common BDs such as VWD and in ultra-rare inherited BDs alike. Addressing these inequities will require the intentional establishment of a research culture embracing innovation and collaboration to transform the lives of PWIBD [12].

Additional focus on health services research with an emphasis on diversity, equity, inclusion, and antiracism and utilization of implementation science, as described in Byams, et.al [11], provide opportunities to advance equitable and just approaches not only to the delivery of new therapies in clinical practice, but also to how health care is delivered in the future. Despite the clear opportunity to advance equitable outcomes for PWIBD, health services research and implementation science have historically received minimal attention in the BD community and have not been funded at a federal, local, or organizational level.

To achieve the goal of equitable and just outcomes for PWIBD, the HTC integrated model of care, which has emerged as a center of excellence and medical home for PWIBD in the US since Congress first authorized and funded hemophilia programs in the 1970s [20,21], must be sustained into the future. Sustaining this model of care requires continued investment in future generations of a well-trained workforce, not only consisting of physicians but also other members of the multidisciplinary team including nurses, physiotherapists, social workers, mental health experts, surgeons, and research coordinators along with the infrastructure to support clinical, translational and basic science research with the ultimate goal of achieving health equity for all PWIBD, including those yet to be diagnosed.

Over the next decade, the development of a sustainable workforce and a research infrastructure supporting the generation of real-world data to inform evidence-based diagnostic and treatment guidelines for PWIBD is needed. Facilitating innovative research as outlined in the papers of this supplement has the ability to create paradigm shifts on the path to health equity. The intentional establishment of an international research culture embracing innovation and collaboration to transform the lives of PWIBD must be the ultimate goal [12]. We have laid the foundation for a National Research Blueprint specifically developed to address the gaps identified by those living with inherited BDs in the US but this work transcends national borders and is highly relevant to the international inherited BD community and the global health care ecosystem [27].

Article highlights

• Despite significant advances in the care and treatment of hemophilia in developed countries, approximately 75% of people globally with hemophilia remain undiagnosed and/or lack access to treatment.

• Additional gaps in care remain beyond the hemophilia population, especially for those with ultra-rare bleeding disorders (BDs), people with rare inherited platelet disorders, and those with von Willebrand disease.

• The National Hemophilia Foundation (NHF) State of the Science Research Summit initiative was an attempt to assess the current state of affairs for the US inherited BD community.

• People living with these disorders, lived experience experts (LEEs), were key informants and participants in the NHF State of the Science Research Summit.

• This community-led initiative represents a call to action for the entire inherited BD community to engage collaboratively in the execution of the National Research Blueprint.

The National Research Blueprint could be a steppingstone to international research and global progress toward health equity.

Table of Abbreviations

Table

ATHN	American Thrombosis and Hemostasis Network
BD	Bleeding disorder
CDC	Centers for Disease Control and Prevention
HCP	Health care provider
HRSA	Health Resources and Services Administration
HTC	Hemophilia treatment center
LEE	Lived experience expert
NHF	National Hemophilia Foundation
PPM	Person who has or had the potential to menstruate
PWH	Person with hemophilia
PWIBD	Person with an inherited bleeding disorder
RBD	Rare bleeding disorder
SOS RS	NHF State of the Science Research Summit
US	United States
VWD	Von Willebrand disease
WG	Working group

Declaration of interest

D DiMichele discloses consulting fees: paid consultant to the NHF on their State of the Science (SOS) and National Research Blueprint (NRB) projects; and support for attending meetings and/or travel: travel to meetings relevant to the SOS and NRB projects paid by NHF. M Recht discloses grants or contracts from any entity: Bayer, BioMarin, CSL Behring, Genentech, Grifols, Hema Biologics, LFB, Novo Nordisk, Octapharma, Pfizer, Sanofi, Spark, Takeda, and uniQure; consulting fees: Catalyst Biosciences, CSL Behring, Genentech, Hema Biologics, Kedrion, NovoNordisk, Pfizer, Sanofi, Takeda, and uniQure; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: Foundation for Women and Girls with Blood Disorders; Partners in Bleeding Disorders, Thrombosis and Hemostasis Societies of North America. LA Valentino and ME Santaella are employees of NHF. MW Witkop was an employee of NHF at the time of the study, and is now a paid consultant to NHF. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have received an honorarium from Expert Review of Hematology for their review work but have no other relevant financial relationships to disclose.

Author contributions

LA Valentino conceived of the manuscript. All authors contributed to drafting the manuscript, offered input and contributed to revisions of the manuscript, approved the final version to be published, and agree to be accountable for all aspects of the work.

Article highlights

• Despite significant advances in the care and treatment of hemophilia in developed countries, approximately 75% of people globally with hemophilia remain undiagnosed and/or lack access to treatment.

• Additional gaps in care remain beyond the hemophilia population, especially for those with ultra-rare bleeding disorders (BDs), people with rare inherited platelet disorders, and those with von Willebrand Disease.

• The National Hemophilia Foundation (NHF) State of the Science Research Summit initiative was an attempt to assess the current state of affairs for the US inherited BD community.nosis of CVD.

• People living with these disorders, lived experience experts (LEEs), were key informants and participants in the NHF State of the Science Research Summit.

• This community-led initiative represents a call to action for the entire inherited BD community to engage collaboratively in the execution of the National Research Blueprint.

• The National Research Blueprint could be a steppingstone to international research and global progress toward health equity.

Acknowledgments

The Executive Committee of the National Hemophilia Foundation National Research Blueprint initiative were actively engaged in the conception, design, preparation, and oversight of each of the State of the Science manuscripts in this supplement. Maria E. Santaella actively engaged with the lived experience expert (LEE) WG members throughout the process, empowering their inclusion and participation. The Executive Committee consisted of: Kevin Mills, Michael Recht, Michelle L. Witkop, Maria E. Santaella, Donna DiMichele, Keri L. Norris, Esmeralda Vázquez and Brett Spitale.

The authors acknowledge Fiona Robinson, PhD, for providing professional medical writing support during manuscript development, paid for by NHF.

Additional information

Funding

The entire State of the Science Research Summit and National Research Blueprint (to date) initiatives and this manuscript were funded by National Hemophilia Foundation. The research of State of the Science Research Summit Working Groups 1, 3, and 4 was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number NIH_NOA_1R13HL158209-01. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.