Characteristics and Bleeding Behavior of Females with Mild Hemophilia A: Longitudinal Study from Picnichealth Hemophilia A Database

Background: Hemophilia A (HA) is an X-linked condition characterized by factor VIII (FVIII) levels below the normal range, leading to excessive bleeding. Disease severity can be categorized as mild (FVIII: >5-40%), moderate (FVIII: 1-5%) or severe (FVIII: <1%) (Blanchette et al. J Thromb Haemost 2014). Females represent a minority of patients with HA and their bleeding phenotypes are poorly characterized in scientific literature. In this retrospective cohort study, the real-world, patient-centric PicnicHealth database, which integrates clinical data with patient-reported outcomes, is used to examine the epidemiology and bleeding phenotype in females with mild HA (FwHA) compared with a cohort of males with mild HA (MwHA).

Methods: FwHA and MwHA have been recruited since June 2020 in the United States. Severity of HA was based on physician-reported provider notes, or baseline FVIII levels if provider notes were inconclusive (for this analysis, mild HA was defined as FVIII >5-50%). Demographics, disease characteristics, and patient-reported outcomes were collected. Bleeding phenotype was assessed up to a year prior to enrollment and described according to bleed etiology (i.e., traumatic, spontaneous, procedure-related, unknown), bleed frequency, and bleed management (use of FVIII concentrates). A two-tailed test was used to analyze differences between the cohorts, with p<0.05 considered significant.

Results: At data cut-off on May 31, 2022, 68 patients with mild HA had been recruited: 23 FwHA and 45 MwHA (Table 1A). There were no differences in racial demographics, with approximately 70% identifying as 'White' in both groups. The median FVIII level was significantly higher in the female cohort at 26% (Q1, Q3: 17, 36%), compared with the male cohort at 10% (Q1, Q3: 6, 13%; p=<0.001). Median (Q1, Q3) age at first diagnosis was also significantly higher in the female cohort, at 24.3 (8.71, 36.0) years, compared with the male cohort, at 10.5 (1.02, 21.4) years (p=0.048). However, after adjusting for median FVIII levels, the difference in age at first diagnosis was not statistically significant (p=0.56) between males and females. Median (Q1, Q3) follow-up periods available from medical records were similar for FwHA and MwHA (8.92 [5.60, 12.9] years and 9.22 [4.27, 12.4] years, respectively). FVIII inhibitors were not identified in any FwHA but were present in 13.3% of MwHA. The majority of patients’ records had no evidence of HIV, hepatitis B, or hepatitis C status; however, 5.9% of MwHA were reported to be positive for hepatitis B and C, compared with no FwHA. Prevalence of iron deficiency anemia was higher in FwHA compared with MwHA, at 27.7% vs. 6.7% (significance not assessed due to low numbers). Access to hemophilia treatment centers was numerically higher for FwHA compared with MwHA (82.6% vs. 73.3%), but this difference was not significant.

Evaluation of bleeding phenotype in the female and male cohorts is described in Table 1B. The small number of recorded events does not allow for meaningful conclusions about the differences in bleeding phenotypes between females and males with mild disease. The proportion of FwHA treated with FVIII prophylaxis (30.4%) was numerically lower than the MwHA (40.0%), but not statistically significant (p=0.611). For patients on prophylaxis in the year before enrollment, the median (Q1, Q3) number of days on prophylaxis was 209 (149, 268) days for FwHA and 365 (168, 365) days for MwHA (significance not assessed due to low numbers). On-demand FVIII concentrate usage was similar in both groups with 47.8% of FwHA and 51.1% of MwHA receiving FVIII.

Conclusions: This real-world cohort study observed differences in disease characteristics between FwHA and MwHA, but statistical analysis was limited by low participant numbers. FwHA had higher baseline FVIII levels compared with MwHA. On-demand use of FVIII concentrates was comparable between the cohorts. Recorded bleeding events were too low in number to draw conclusions regarding bleeding phenotype. As this database relies on patient participation, there was a potential selection bias towards those with more symptomatic disease, and some data were incomplete. Future studies will analyze ongoing prospective data, collect more granular data on bleeding phenotype, and conduct comparative analyses of cohorts stratified by baseline FVIII levels.

Weyand:Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Research Funding; Genentech, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Spark: Consultancy. Hiew:Roche Products Ltd: Current Employment; University Hospital Dorset: Ended employment in the past 24 months. Jiang:Roche Products Ltd: Current Employment; Whittington Health NHS Trust: Ended employment in the past 24 months. Siadimas:F. Hoffmann-La Roche AG: Current Employment, Current equity holder in private company, Research Funding. Nissen:F. Hoffmann-La Roche Ltd: Current Employment, Current holder of stock options in a privately-held company. Hanson:PicnicHealth: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Cibelli:PicnicHealth: Current Employment, Current holder of stock options in a privately-held company. Moreno:F. Hoffmann La Roche Ltd.: Current Employment, Current equity holder in publicly-traded company, Honoraria. Zhang:F. Hoffmann-La Roche Ltd: Current Employment. Sharathkumar:University of Iowa: Current Employment; Amgen, CDC/ATHN/HRSA: Research Funding; Genentech, Takeda, CSL: Honoraria; University of Iowa Clinical Committee: Membership on an entity's Board of Directors or advisory committees.