Bleeding phenotype according to factor level in 825 children with non-severe hemophilia; data from the PedNet cohort

Abstract

BackgroundInformation on bleeding phenotype in non-severe hemophilia may be used to determine target factor levels for prophylaxis or gene therapy in severe hemophilia. ObjectivesTo assess the association between endogenous factor level and bleeding phenotype in children with non-severe (FVIII/FIX-activity 1%-25%) hemophilia A (HA) and B (HB) without prophylaxis. Patients and methodsData on annualized (joint)bleeding rate (A(J)BR) and onset of bleeding were extracted from the international PedNet cohort including children born since 2000. Mean A(J)BR was modeled and compared according to FVIII/FIX endogenous activity (1-2%; 3-5%; 6-10%; 11-15%; 16-20%; 21-25%) using negative binomial regression. Onset of bleeding was analyzed using Kaplan-Meier Survival. Findings825 children (40% moderate hemophilia; 87% HA) with median follow-up of 7.4 years/child were included. The median age at onset of bleeding and median bleeding rates changed with increasing endogenous activity. From endogenous FVIII 1-2% to 21-25%, the age at onset of bleeding changed from median 1.4 to 14.2 years, ABR from 1.6 to 0.1/yr, and AJBR from 0.5 to 0.0/yr. From endogenous FIX 1-2% to 16-25%, the onset of bleeding changed from median 1.7 to 6.1 years, ABR from 0.5 to 0.1/yr and AJBR from 0.1 to 0.0/yr. The negative correlation between AJBR and factor level was most strongly pronounced up to a factor level of 6% in HA and HB. InterpretationEndogenous factor activity of >5% was identified as a threshold to significantly lower joint bleeding rate, while FVIII >15% and FIX >10% levels were sufficient to achieve the goal of zero bleeds in this pediatric cohort.