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Inherited bleeding disorders, such as hemophilia, have long been recognized, tracked, and researched in males. However, the Centers for Disease Control and Prevention (CDC) currently estimates that inherited bleeding disorders affect up to 1% of all women and girls in the United States.1 Through direct engagement with the bleeding disorders (BD) community, the Hemophilia Federation of America (HFA) has likewise identified a need for more support for females and individuals assigned female at birth, as well as intersex and non-binary individuals, with bleeding disorder diagnoses or symptoms. In response to this, the work of HFA’s Engagement and Community Health Outcomes (ECHO) team (formerly Research) in recent years has placed a focus on females in the bleeding disorders community; this work has included assessing the needs of females as well as providing education around bleeding disorders in females. Through this work, HFA has identified a gap in bleeding disorders research specific to females. Because the presentation of bleeding disorders in females is often different than that of men, this lack of research represents a gender-based health disparity. In addition, HFA determined that females are often willing and interested in participating in research but have not been provided opportunities to do so thus far. Access to novel therapies for females has historically been limited, since trials have largely only been conducted on males; this further illustrates the need for the inclusion of females in bleeding disorders research overall. Additionally, trials that do not exclude females can further prioritize females in study participant recruitment. This can improve representation of females in existing studies, as well as highlight a desire from the community for researchers
to approach study participants that they have not previously routinely considered.
With this in mind, HFA has engaged females in the bleeding disorders community through funding from the Eugene Washington PCORI Engagement Awards (Engagement Awards) program, an initiative of the Patient-Centered Outcomes Research Institute (PCORI); this engagement has been built upon a foundational belief that a focus on the perspective of stakeholders, including patients, throughout all stages of research will enhance research overall by improving its relevance to those upon whom it is focused.2 For example, including the patient voice in planning phases will focus research questions around what patients feel is most important to their own quality of life and will inform patient engagement protocols by enumerating barriers study participants may experience and how they can be accommodated and fairly compensated, thus improving research recruitment and retention; meanwhile, patient input on dissemination of research findings can enhance accessibility of findings to those who are most directly affected. This engagement, completed by HFA between 2019 and 2021, aimed to educate females within the bleeding disorders community about patient-centered and comparative effectiveness research with the goal of further increasing their interest and capacity in participating in future research initiatives. After the completion of this engagement, a new module was launched on HFA’s online learning management system (LMS), Learning Central, providing continued access to this educational content for patient audiences. Because of this work, HFA feels that the female bleeding disorders community is primed to participate in, and contribute to, research focused on their needs.
To encourage research around females with bleedings disorders, a Community-Based Research Network (CBRN) was established in 2021 as part of HFA’s Females in Research Sharing and Translation (FIRST) project, consisting of researchers, patients, and representatives of patient advocacy programs. The goal of the CBRN was to create a roadmap that outlines and addresses the unmet needs of females in the bleeding disorders community from both the patient and provider perspectives. To work toward that goal, the CBRN engaged in discussions to develop a shared research agenda that would guide current and future projects involving females with bleeding disorders. The research agenda, outlined below, is designed as a reference for research organizations to inform projects, with the aim of ensuring projects are directly useful to community members, supply research that informs policy and practice, and increase the capacity of stakeholders to conduct and use research. To that end, the CBRN identified research topics for females, listed in Appendix A, as areas of focus for work for the next three to five years. In addition, the CBRN outlined a few example research questions within these areas, listed below.
The research topics and questions created by the CBRN were then further refined, added to, and vetted in 2022 by a Steering Committee (SC) comprised of additional researchers, females with bleeding disorders, and other bleeding disorder stakeholders. The research agenda document was then shared more broadly among the colleagues/contacts of the SC to garner further input, refinement, and approval.
Research topics and questions were built out within the following focus areas:
Topics outlined in this area are not specific to any particular age or stage in life but could affect females throughout their lifespan. This area also encompasses research topics related to underserved communities or groups and associated social health disparities and negative health outcomes. Example research questions generated include:
- What are the patient-centric clinical endpoints that should be utilized in every clinical trial?
- What is the burden of disease, especially in the context of clinical bleeding, quality of life, pain, and medication use?
- What gaps in care exist for females in various populations due to social-economic health disparities or geographic considerations?
- Does prophylaxis in non-severe hemophilia or von Willebrand Disease (VWD) reduce bleeding events?
This stage of life, from menarche (around 11-12 years of age) through adulthood (around 18-19 years of age) is unique due to the effect of bleeding on school-related issues such as attendance, special considerations/accommodations needed during bleeding, and emotional effects on grades and social life. In addition, the existence of menarche within this age group differentiates it from other age groups, lending to potential to improving the processes for screening and diagnosis of bleeding disorders, as menstrual bleeding during adolescence is often a first indication of bleeding disorders in females. Example research questions for this age range are:
- Can the institution of a universal screening tool for Heavy Menstrual Bleeding (HMB) improve health care professional awareness of signs/symptoms of bleeding disorders in females, increase the number of females diagnosed with bleeding disorders, increase the number of hematology referrals, and improve quality of life and school attendance in adolescent females experiencing HMB?
- Do adolescents and young adults with heavy menstrual bleeding and a high fatigue score have an increased risk for an underlying bleeding disorder compared to the general population risk?
This age range (from approximately 20-50 years old) is often defined by family planning, pregnancy/childbirth, and caregiving, as well as the progression of complications from joint bleeds over time. An example research question written for this age range is:
- Would prophylactic factor or non-factor treatment slow the progression of joint damage/arthritis for females who are diagnosed later in life, especially if microbleeds are suspected?
This age group consists of females who are going through or have completed menopause (approximately 51 years of age and older). Special consideration is needed for this group who, due to the cessation of the menstrual cycle, can often be dismissed from treatment and care for their bleeding disorders. Example research questions for this life stage include:
- Do bleeding symptoms change as females age and go through menopause?
- Does menopause and its inherent hormonal changes alter hemostasis and factor levels?
Appendix A lists topics of interest identified by the CBRN and refined by the SC within each focus area. These topics, not listed in any particular order, are provided with the hope that stakeholders will be able to further refine and focus their research on topics that are of interest to them, yet essential and relevant for the care of females with bleeding disorders. Appendix B lists suggested methods and strategies for carrying out research studies based on the example questions listed above.
A Note on the Importance of Dissemination
Too often, it takes years for useful new findings from clinical research to be taken up in practice and to influence health care. In addition, research results are typically not presented in formats or language that patients and their caregivers can easily understand.3 Poised to change this landscape, HFA’s work includes the patient in every step of the research process, including plans for dissemination of any findings.
Dissemination methods of any findings of research activities resulting from this agenda could include:
- White papers
- Research Journal publication
- Patient accessible Journal articles, HFA’s Dateline
- Professional and patient conference sessions
- Webpages on affiliated sites, promoted via social media
In addition, dissemination of any new tools and/or guidelines resulting from this research would be essential. For example, in the case of the creation of a Heavy Menstrual Bleeding universal screening tool, it would be suggested that researchers:
- Provide patients with access to the tool and encourage them to take it to their Primary Care Provider (PCP) if their PCP isn’t using one
- Consider web-based platform for increased accessibility
- Share with patient organizations such as National Hemophilia Federation (NHF) and HFA
- Create a publicity campaign (posters, social media awareness, etc.)
- Share generally with organizations like the American Academy of Pediatrics, ACOG, MASAC to make policy change & recommendations
- Publish in journals wider than in the hematology space (to include OB/Gyns, family practice physicians, etc.)
- Disseminate at conferences
- Share results with medical schools and other health professional schools, encouraging them to include questions on medical school & board exams
Overall, the importance of research on females with bleeding disorders cannot be understated. The landscape of research on females with bleeding disorders has thus far remained largely unmapped, making it difficult to determine where to start. Our hope in creating this research agenda is to create a launchpad for this type of research while keeping patient needs and input at the center of the focus of research. Topics within the focus areas listed reflect the suggestions and needs of both patients in this community and physicians who provide care to it. Through this work, we hope to improve care for females with bleeding disorders across their lifespans and into future generations.
This document was funded through a Patient-Centered Outcomes Research Institute (PCORI) Eugene Washington PCORI Engagement Award EASCS-23237.