Promise, Pitfalls, and Precision: Standardizing Clinical Framework for Hereditary Hemorrhagic Telangiectasia and a Call for Cost-Conscious Innovation

Despite its prevalence as the second most common inherited bleeding disorder affecting 1 in 5000 individuals, research and therapeutic development in Hereditary hemorrhagic telangiectasia (HHT) has historically lagged in momentum as compared with hemophilia. The recent decade has ushered in a new era of treatment, including repurposing of existing anti-VEGF agents and development of HHT-specific therapeutics [1]. The economic burden of HHT has not been well described. The pivotal study by Dr. Al-Samkari et al. [2] published in this issue of the American Journal of Hematology provides a comprehensive analysis of healthcare resource utilization and direct medical costs associated with HHT.

The cornerstone of HHT management over the past decade has evolved from procedural interventions alone to the emergence of disease-modifying medical therapies. With randomized controlled trials evaluating antifibrinolytics, antiangiogenic agents, and other novel therapeutics, there is growing urgency for harmonized outcome measures. The consensus report by Dr. Al-Samkari and colleagues offers a robust framework to support future clinical trials, cohort studies, and regulatory submissions [3].

HHT has long been underrepresented in health economics literature. The study by Dr. Al-Samkari and colleagues provides a comprehensive analysis of United States health insurance claims data (Medicare, Medicaid, and commercial insurance), representing 92% of the population [2]. The study's findings are striking, demonstrating that HHT surpasses direct medical costs associated with sickle cell disease by ~20%, with a mean per-patient-per year (PPPY) cost of $19 386 compared with $16 538. For patients who are anemic and have HHT, that PPPY cost escalates to $27 147, rivaling that of muscular dystrophy. Most notably, patients requiring hematologic support, such as intravenous iron or red blood cell transfusion, incur costs nearing $40 298 annually.

The authors discuss the growing use of systemic pharmacologic interventions, including antiangiogenic (bevacizumab and pazopanib) [4, 5] and immunomodulatory (pomalidomide) [6] agents for management of HHT-related epistaxis and gastrointestinal bleeding. This therapy, albeit costly, are promising in efficacy in reducing bleeding and anemia.

The greatest limitation of the study is that the claims data are collected for patients with confirmed HHT, excluding individuals who have not yet been diagnosed. Unfortunately, diagnostic delay is not uncommon in HHT. As this was a claims-based analysis, there is absence of detailed clinical outcome data to correlate with treatment efficacy.

The sobering reality is that bleeding and its sequelae is the primary cost driver in HHT, and it is indeed very expensive.

This study serves as a clarion call for clinicians, researchers, and policymakers. HHT is a high-cost, high-need condition that requires innovative, cost-conscious solutions. Clinical excellence must be accompanied by economic stewardship to improve patient outcomes and ensure sustainability. Investment in early diagnosis and preventive care in HHT patients may potentially mitigate downstream costs. The authors highlight the need for a global call to action to adopt standardized, evidence-based guidelines to optimize clinical trial design.

Research initiatives in HHT have been impeded by an absence of standardized severity definitions, outcomes criteria, and terminology. The manuscript by Al-Samkari et al. [3] proposes consensus-based standardized terminology and definitions for outcomes and severity classification for bleeding and anemia in HHT to improve consistency in clinical trial design, aid therapeutic treatment guideline development, and provide a framework for regulatory agencies. The panel consisted of international expert HHT clinician-investigators from the Global Research and Medical Advisory Board (GRMAB) of the Cure HHT foundation, external experts in HHT and bleeding disorders, lived experience experts, and patient advocates.

The manuscript aims to standardize the goals of treatment, bleeding severity classification, as well as specific measures and outcomes pertaining to epistaxis, hematologic measures, health-related quality of life, and bleeding severity classification.

The consensus on the primary therapeutic goal is to reduce the frequency, duration, and severity of HHT-related epistaxis and gastrointestinal bleeding. These endpoints are clinically meaningful and lend themselves to standardized measurement in clinical trials.

Secondary treatment goals include reducing other HHT-related bleeding sources (e.g., visceral and mucocutaneous), correcting iron deficiency and anemia, minimizing red cell transfusion and iron infusion requirements, and improving health-related quality of life. Importantly, these outcomes must be achieved with minimal treatment-related toxicity, particularly in patients with less severe bleeding phenotypes.

The panel also identified emerging areas for investigation. The impact and confounding effect of heavy menstrual bleeding, reported by the majority of women with HHT, warrants systematic evaluation in future trials. Additionally, therapies that promote vascular remodeling may offer disease-modifying potential by targeting telangiectasia and visceral AVMs. While these endpoints remain exploratory, their inclusion in clinical studies could provide valuable insights into long-term therapeutic impact.

Hereditary Hemorrhagic Telangiectasia (HHT) is characterized by chronic bleeding, often punctuated by acute, potentially life-threatening episodes. Bleeding in HHT is typically progressive, with individuals potentially transitioning from mild to severe bleeding phenotype over time. As such, bleeding severity in HHT must account for both chronic and emergent manifestations. The expert panel emphasizes the use of “bleeding severity” rather than “disease severity” to reflect the variability in bleeding and non-bleeding complications.

Major acute bleeding is defined by criteria adapted from the International Society on Thrombosis and Haemostasis (hemoglobin drops ≥ 2 g/dL or hemodynamic instability) to include HHT-specific complications, such as acute onset of severe epistaxis or gastrointestinal bleeding requiring intervention and solid organ bleeding due to ruptured arteriovenous malformation.

For clinical studies, the first two domains are recommended for baseline severity classification. The panel also emphasized the importance of protocolized thresholds for intravenous iron and red cell transfusion administration to reduce variability and bias in clinical trials. Oral iron is difficult to standardize due to variability in absorption. When used, consistent dosage and frequency should be used.

Composite measures such as the Hematologic Support Score (HSS) and Hematologic Impact Score (HIS) are recommended to capture the full picture of hematologic burden.

The expert panel recommends epistaxis-based endpoints as primary measures in trials involving participants with moderate to severe bleeding, given the near-universal presence of epistaxis in HHT. These endpoints can be assessed using validated instruments such as the Epistaxis Severity Score (ESS) or the Nasal Outcome Score for Epistaxis in HHT (NOSE HHT), or through prospective epistaxis diaries. While ESS has been widely used, its susceptibility to recall bias and placebo effects has raised concerns. Electronic diaries with time-locked entries may offer improved accuracy and reduced bias. Hematologic endpoints may be more appropriate in trials targeting individuals with severe bleeding symptoms, particularly when evaluating therapies with higher risk of toxicity.

HRQoL is a central concern for people with HHT. While generic tools have shown limited sensitivity, HHT-specific instruments, such as the Quality of Life Questionnaire in HHT and the HHT-Specific Quality of Life Scale, should be included in prospective trials as secondary or exploratory endpoints. HRQoL measures should be included in prospective studies to capture patient-centered outcomes. Ultimately, the choice of primary endpoint should align with the severity of the study population and the therapeutic profile, with secondary endpoints complementing the primary measure to ensure comprehensive evaluation.

This consensus report is a blueprint for the future of HHT research and care. It provides the clarity needed to design rigorous clinical trials and improved consistency for regulatory approval. As the field moves toward its first drug approvals and beyond, the adoption of these standards by investigators, regulators, and industry partners is imperative.

A major strength of the consensus report is the multi-specialty and international expert panel, which is in large part necessitated by the complexity of HHT and the frequent need for involvement of multiple specialists. Perhaps the greatest strength of this consensus report is its pragmatism, focusing efforts on standardization and adapting pre-existing tools to HHT-specific needs. The outcome exemplifies the power of patient-centered expert collaboration in overcoming entrenched barriers to conduct clinical trials in HHT.

GRMAB and the Cure HHT Foundation should be commended for their leadership and vision. The standardization of terminology and outcomes in HHT marks a turning point in the field—one that promises to accelerate innovation, improve care, and bring us closer to a cure.

The author has nothing to report.

The author has nothing to report.

The author declares no conflicts of interest.