Abstract
Introduction: People with mild to moderate hemophilia are frequently underrepresented in clinical trials and registries, leading to gaps in evidence-based guidance. While early prophylaxis is standard in severe hemophilia, treatment approaches for non-severe disease remain inconsistent. This is often driven by the misconception that prophylaxis is appropriate only for individuals with residual factor ≤2%, despite increasing evidence of recurrent bleeds in non-severe cases. Heterogeneous bleeding phenotypes, evolving patient preferences, and provider uncertainty further contribute to this variation. Real-world data describing the use, selection, and safety of prophylaxis are essential to improving care for this population.
Methods: ATHN Transcends (NCT04398628) is a prospective, longitudinal, cohort study conducted at over 60 ATHN-affiliated sites across the United States. The Hemophilia Natural History Arm captures safety and effectiveness of hemophilia therapies including clinical and participant-reported outcomes. This analysis includes demographic and baseline clinical data for participants with mild (residual levels 6-<40%) or moderate (residual levels 1-5%) Hemophilia A (HA) or Hemophilia B (HB) enrolled participants from March 2021 to April 2025.
Results: A total of 158 participants were included: 110 with HA and 48 with HB. Participants with HA, 50 had moderate disease (mean FVIII 3.1% (1.4), median 3.0%) and 60 had mild disease (mean FVIII 18.1% (11.5), median 14.0%). Participants with HB, 26 had moderate disease (mean FIX 2.4% (1.0), median 2.0%) and 22 had mild disease (mean FIX 7.6% (10.4), median 15.5%). The mean age at enrollment was 16.4 years (min=0, max=78) for moderate HA and 29.4 years (2, 86) for mild HA. For HB, the mean age was 28.6 years (0, 71) for moderate and 18.7 years (2, 55) for mild disease. Females accounted for 13 (21.7%) of mild HA and 6 (27.3%) of mild HB participants; no females with moderate disease were enrolled. A target joint was reported in 6 (12%) of moderate HA, 4 (15.4%) of moderate HB, and 5 (8.3%) of mild HA participants. The mean age at first bleed was earlier in moderate compared to mild participants: 2.1 years (3.9) vs. 6.4 years (9.4) in HA, and 3.3 years (5.0) vs. 7.4 years (8.5) in HB. For HA participants, the head was the most reported site of first bleeding in both moderate and mild cases. In contrast, the most frequent site of first bleed for HB participants was the mouth. At enrollment, 58% of moderate HA and 37% of moderate HB participants reported use of continuous prophylaxis. In mild participants, 21.8% of HA and 15.8% of HB were also receiving prophylaxis. Short-term/intermittent prophylaxis was reported in 2% and 4.2% of moderate HA and HB, and in 7.3% and 10.5% of mild HA and HB, respectively. Females with mild HA, 2 (15%) reported continuous prophylaxis use. Among HA participants, emicizumab was the most used prophylactic agent (82.8% in moderate, 50.0% in mild), followed by standard half-life (SHL) recombinant FVIII concentrates in moderate HA (6.9%) and ultra-extended half-life (UEHL) FVIII concentrates for mild HA (21.4%). Most emicizumab users reported SHL concentrates as their as-needed therapy (41.9% in moderate, 58.3% in mild HA). The 2 females with mild HA on prophylaxis, one reported use of SHL and the other UEHL recombinant FVIII concentrates. In HB, extended half-life (EHL) recombinant factor IX concentrates were the most used prophylactic agents (77.8% in moderate, 60.0% in mild).
Conclusions: In this analysis, we demonstrate that over one third of ATHN Transcends participants with non-severe hemophilia were already receiving continuous prophylaxis, including a significant subset with mild disease. Prior publications reported prophylaxis use in fewer than one-third of moderate and under 30% of mild cases*. This shift reflects growing recognition that bleeding risk may not correlate with factor levels and supports a phenotype-driven approach to care. Our findings also highlight the role of emicizumab in HA, while HB patients still rely on FIX concentrates for prophylaxis. Ongoing follow-up will determine whether treatment patterns and adoption of newer hemostatic agents continue to evolve. These findings underscore the need to revisit prophylaxis guidelines and reinforce the importance of real-world data in shaping evidence-based, personalized care in non-severe hemophilia.
*Iorio A, et al. Haemophilia. 2023 Jan;29(1):33-44.