An Increase in Factor VIII Levels with Increasing Age in a Subgroup of Individuals with Mild Hemophilia A

Hemophilia A is an X-linked hereditary disorder resulting in absent or reduced levels of functional factor VIII (FVIII:C). The baseline FVIII:C levels are important in the determination of treatment and management options in individuals with mild hemophilia who by definition exhibit FVIII:C levels between 6–40 U/dL. In individuals without hemophilia, FVIII:C increases with physiological age and this trend has not been well characterized in mild hemophilia. This is important to consider in mild hemophilia because treatment with factor concentrate or DDAVP may paradoxically increase the risk of venous or arterial thrombosis in older patients. Objectives: To describe the changes in baseline FVIII:C levels with time in a cohort of pediatric and adult subjects with mild hemophilia registered in the British Columbia Provincial and Southern Alberta Bleeding Disorder programs. Methods: All medical records for subjects with FVIII:C levels 6–40 U/dL registered with the BC Provincial and Southern Alberta Bleeding Disorder programs were reviewed for eligibility. Male subjects with a minimum of 2 FVIII:C level measurements at least 5 years apart were included in the analysis. Retrospective data was extracted from database/medical records, including age, gender, blood group, FVIII mutation, historical FVIII:C levels, historical DDAVP response (>3 fold and/or >50 U/dL), and co-infection (Hepatitis C, B and HIV) status. Linear mixed effects regression models were used to examine time trend of FVIII:C levels and subjects were stratified into 3 groups based on baseline FVIII:C (FVIII:C<15 U/dL, 15–24 U/dL, and ≥25 U/dL). Results: 198 records were reviewed and 116 subjects excluded from the analysis (chart unavailable, n=28; inadequate FVIII:C data, n=79; female, n=9) leaving 82 subjects who met eligibility criteria. The mean age at first FVIII:C measurement was 24.0 years (SD 19.6; Range 0.0–77.8). The mean follow-up time was 16.5 years (SD 19.6; Range 4.8–44.8). There was no observable trend of FVIII:C with time in the primary analysis of the whole cohort (p=0.667). However, for subjects with baseline FVIII:C<15 U/dL, who were ≥25 years of age (n=31), an increase in baseline FVIII:C levels of 0.11 percent per year (p<0.05) was observed. Subjects with baseline FVIII:C<15 U/dL (n=40) also showed less FVIII:C variability between measurements than subjects with FVIII:C≥15 U/dL (n=42). Subjects with baseline FVIII:C≥25 U/dL (n=18) demonstrated a decreasing trend of −0.15 percent per year (p<0.05), however also demonstrated the greatest variability between FVIII:C measurements. Co-infections were present in 24% (n=20) of subjects and included Hepatitis C (n=18), Hepatitis B (n=1), HIV (n=1). 73 subjects had known DDAVP response; >3-fold but ≤50 U/dL (n=11), ≤3-fold but >50 U/dL (n=15), >3-fold & >50 U/dL (n=23), ≤3-fold & ≤50 U/dL (n=24). Conclusion: This study suggests that there is an increase in FVIII:C with time in the subgroup of individuals with mild hemophilia ≥25 years of age and baseline FVIII:C levels <15 U/dL. Further long-term data particularly in the older cohort of subjects is needed to confirm this preliminary finding and further characterize this trend in subgroups with different baseline FVIII:C.

No relevant conflicts of interest to declare.