Presence of Factor V Leiden or Prothrombin Mutation Influence Inhibitor Development in Children with Severe Hemophilia A: Data of a Multicenter Cohort Study

It has been recently suggested that the clinical phenotype of severe hemophilia A (HA) is influenced by co-inheritance with the factor V (FV) G1691A mutation. In addition, we have recently demonstrated that the first symptomatic bleeding onset in children with severe HA carrying prothrombotic risk factors, namely the FV Leiden or the factor II (FII) G20210A variant, is significantly later in life than in non-carriers. The course of bleeding episodes, however, is also controversially discussed with respect to individual therapeutic regimens performed, and recently a protective effect of early use of prophylaxis on inhibitor development in hemophilic children compared with on-demand therapy has been reported. Thus, the present non-concurrent cohort study was performed to investigate the impact of FV and FII (prothrombin) mutations on clinical meaningful inhibitor development (outcome variable) in white children with severe HA. 122 patients with HA consecutively ascertained from four German catchment areas were followed over a median (min-max) period of 15 years (1–24) from HA onset. 19 of 122 children (15.6%) additionally carried either the FV or the FII variant. During the follow-up period 28 of 122 children (22.9%) developed a clinical meaningful inhibitor: 9 out of 19 in carriers of thrombophilia (47.4%) compared with 19 of 103 (18.44%) in the non-thrombophilia affected cohort [p=0.01]. Multivariate analysis (Cox regression), adjusted for age at first bleeding onset, substitution regimen (start of prophylaxis latest at second joint bleed versus more than two joint bleeds), FVIII dosage (≤ 30 IU/kgbw versus > 30 IU/kgbw), and first-line use of plasma-derived versus recombinant FVIII concentrations revealed that the presence of thrombophilia independently increases the risk of clinical meaningful inhibitor development to a hazard of 2.4 [95%CI: 1.1–5.5]. The cumulative high-responder-free survival with respect to FVIII exposure days was significantly reduced in carriers of the factor V or II mutation (logrank p=0.009). None of the confounders adjusted for, showed a statistically significant influence on clinical important inhibitor development. Data presented here support the hypothesis that clinical meaningful inhibitor development is of multifactorial origin and that FV and FII mutations should be included in the aetiology research in future studies.