Ultra-Rare Inherited Bleeding Disorders: A Research Agenda for the Future


Investigators address 2 questions: How can we better understand the biology of these rare disorders? How can we stimulate research and optimize the regulatory process to improve diagnosis and targeted treatment?

Ultra-Rare Inherited Bleeding Disorders: A Research Agenda for the Future

Diane Nugent, MD

Credit: Researchgate

The National Hemophilia Foundation (NHF) and the American Thrombosis and Hemostasis Network have identified priorities for healthcare professionals and patients with ultra-rare inherited bleeding disorders through extensive community consultations to inform future research.1

“The establishment of a research agenda for the coming decades presents a unique opportunity to direct efforts towards initiatives that have the potential to significantly transform the experiences of people with ultra-rare inherited (bleeding disorders)," investigators stated.

To accomplish this, diverse stakeholders, including investigators, clinicians, and lived experience experts of multidisciplinary expert working groups, collaborated to identify key opportunities in diagnostics, systems biology, and mechanistic science.

According to Diane Nugent, MD, Center for Inherited Blood Disorders, Orange, California, Pediatric Hematology Division, Department of Pediatrics, University of California at Irvine, Children's Hospital of Orange County, and investigators, the objective was to streamline clinical diagnosis, data collection, and research infrastructure to fast-track the regulatory process for novel therapeutics in this area.

Building the Foundation for Ultra-Rare Bleeding Disorders

Findings from the review revealed that creating a network of specialized centers to facilitate diagnosis and expedite national research collaborations was key.

This included linking centers with advanced technology and expert research teams, training the workforce of the hemophilia treatment center and referral center in optimal sample collection and handling, and creating a national protocol for genetic analysis of ultra-rare inherited bleeding disorders

The study stated these initiatives are critical to have a significant impact on the diagnosis and treatment of ultra-rare inherited disorders.

While research regarding hemophilia A and B has yielded clinical practice guidelines and safe and effective treatment options, ultra-rare bleeding disorders are a heterogeneous group of clotting factor deficiencies and platelet disorders, making up only 3-5% of inherited these conditions.

Setting up the Study

Rare disorders are defined as those with a prevalence of ≤4-5 per 10,000 individuals, while orphan diseases refer to those occurring in <200,000 individuals in the total US population. The research explained the estimated number of rare disorders is around 7,000 to 8,000, affecting approximately 400 million people globally and 30 million in the US, with licensed therapeutics only available to treat <5% of them.

When focusing on ultra-rare disorders, the prevalence drops to <1 per 50,000, with some genetic mutations defining an N-of-1 population, or affecting <30 people worldwide. Hemophilia A and B along with other inherited bleeding disorders are among the best-known and researched ultra-rare disorders, with a combined prevalence of approximately 1.5 per 10,000.

The significant unmet need for effective treatments for rare and ultra-rare disorders was exhibited in these data, particularly those affecting small populations.

The challenge of generating a strong evidence foundation for optimal diagnosis and management is crucial, as individuals with untreated bleeding disorders, like hemophilia A, face life-threatening bleeding, delayed diagnosis, and suboptimal management of invasive procedures, in addition to other risks

The 3 Study Domains:

  • Diagnostics: systems biology, mechanistic science
  • Clinical: data collection, research infrastructure
  • Regulatory Process: novel therapeutics, required data collection

Actionable initiatives were identified and scored for feasibility, impact, and risk, and were then determined by prioritization.

A multidisciplinary expert working group distilled highly feasible opportunities for transformative ultra-rare inherited bleeding disorder research from the community-identified priorities. Of these priorities, 13 related to systems biology and mechanistic science, 2 to clinical research, data collection, and research infrastructure, and 5 to the regulatory process for novel therapeutics and required data collection.

Investigators found that centralization and expansion of expertise and resources, flexible innovative research and regulatory approaches, and inclusion of all individuals with ultra-rare inherited bleeding disorders and their healthcare professionals are essential to capitalize on the opportunities.

Investigators stated the 2 key questions at the foundation of this effort:

  1. How can we better understand the biology of these rare disorders?
  2. How can we stimulate research and optimize the regulatory process to vastly improve diagnosis and targeted treatment?

"While exciting advances in the understanding and treatment options of more common inherited bleeding disorders may make the headlines, the priorities outlined herein present important, highly impactful opportunities to transform the experiences of people with ultra-rare inherited bleeding disorders," they wrote.


  1. Nugent D, Acharya SS, Baumann KJ, et al. Building the foundation for a community-generated national research blueprint for inherited bleeding disorders: research priorities for ultra-rare inherited bleeding disorders. Expert Rev Hematol. 2023;16(sup1):55-70. doi:10.1080/17474086.2023.2175661
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