Untreated Bleeding in Hemophilia A – An Underestimated Problem? To What Extent?

Introduction

Prophylaxis in individuals with hemophilia A aims to prevent bleeding; however, experience shows that even patients receiving it may experience breakthrough bleeds. An interesting fact is that most studies focused on bleeding control in hemophilia record only treated bleeds. Thus, this data might not completely capture the total bleeding rate in these individuals and might be underestimated. The analysis cited below therefore focused, among other things, on the total rate of bleeding events, the nature of untreated bleeds, and their location.

Analyzed Data

Data were obtained from patients with hemophilia A with or without FVIII inhibitor. The Bleed and Medication Questionnaire was used, and data were prospectively gathered from three cohorts of patients: Cohort A included adults or adolescents over 12 years with FVIII inhibitor, Cohort B included children under 12 years with FVIII inhibitor, and Cohort C included adults or adolescents without FVIII inhibitor. Untreated bleeding episodes were assessed by location, frequency, and reason for bleeding. Data were compared with those from the same patients during emicizumab prophylaxis after transitioning to the phase III HAVEN study.

The definition of bleeding in Cohort A and in HAVEN 1 study was based on ISTH SSC, where bleeding was defined by the sensation of aura combined with other joint bleeding symptoms. In Cohort C and HAVEN 3 study, aura was not included. In Cohort B and HAVEN 2 study, joint bleeding was defined based on the location of the described bleeding as joint-related.

Non-Interventional Study (NIS)

NIS was a global prospective observational study that collected data on individuals with hemophilia A with and without FVIII inhibitor, who were receiving standard therapy at that time. Data from NIS were used to estimate the number of treated and untreated bleeds and to provide insight into differences between populations with and without FVIII inhibitor.

A total of 221 participants were included in the NIS study, divided into Cohort A (n=103), Cohort B (n=24), and Cohort C (n=94). A total of 659 untreated bleeds were recorded in Cohort A, 156 in Cohort B, and 433 in Cohort C. The incidence of untreated bleeds was 40% of all bleeds in patients with inhibitor and 26.2% in adults and adolescents without the inhibitor. Approximately 70% of all treated bleeds and 54% of all untreated bleeds in adults and adolescents were joint bleeds. Untreated bleeds were less frequent (7.1%) in children; these were mostly knee and oral cavity bleeds.

HAVEN Studies

Among participants receiving prophylaxis in NIS, 24 transitioned to HAVEN 1, 14 children to HAVEN 2, and 48 adults and adolescents to HAVEN 3. All received emicizumab at a dose of 1.5 mg/kg weekly. Intra-individual comparison showed a reduction in both treated and untreated bleeds after switching to emicizumab prophylaxis. The proportion of untreated bleeds was higher in each of the HAVEN studies compared to the previous NIS cohort.

Conclusion

The authors conclude that a significant proportion of bleeding episodes (26-40%) in individuals with hemophilia A remain untreated. Additionally, some joint bleeds are difficult to recognize or distinguish from issues due to existing arthropathy. There is a definite need to focus further on why some bleeds remain untreated and to find a way to accurately identify them in all clinical studies.

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Source: Callaghan M. U., Asikaniu E., Lehle M. et al. Untreated bleeds in people with hemophilia A in a noninterventional study and intrapatient comparison after initiating emicizumab in HAVEN 1–3. Res Pract Thromb Haemost 2022; 6: e12782, doi: 10.1002/rth2.12782.