Influence of Factor V G1691A or Prothrombin G20210A Mutation On Inhibitor Development in Patients with Severe Hemophilia A - an Israeli-German Database Study.

Abstract 2234

It has been reported that the clinical phenotype of severe hemophilia A (HA) is influenced by co-inheritance with the factor V (FV) G1691A mutation and that the first symptomatic bleeding onset in children with severe HA carrying prothrombotic risk factors, namely the FV or the factor II (FII) G20210A variant, is significantly later in life than in non-carriers. Until today many factors, such as a positive family history, the use of recombinant FVIII [rFVIII] concentrates, or high dose FVIII administration, are included as potential risk factors for inhibitor development. The present non-concurrent Israeli-German database study was performed to investigate the impact of FV and FII mutations on clinical meaningful inhibitor development (outcome variable) in patients with severe HA. 272 patients with HA < 1% consecutively ascertained from Israel (n=88) and four different German catchment areas (n=184) born between 1980 and 2011 were followed after initial HA diagnosis over the first 200 exposure days. To avoid family cluster effects [inhibitor; IT] in both countries only the first HA patient who presented for diagnosis at the treatment center was included in the present study. From the entire cohort 80% were tested for thrombophilia [IT]. 32 of 216 children (14.8%) carried either the FV or the FII variant. During the follow-up period of 200 exposure days 54 of 216 (26%) developed a clinical meaningful inhibitor: 14 out of 32 carriers of IT (44%) compared with 40 of 184 (22%) without IT [Hazard ratio [HR]/95% confidence intervals [CIs] 2.1/1.16–3.9]. In addition, univariate Cox regression analysis for patients treated with rFVIII products compared with plasma-derived [pdFVIII] showed a significant increased risk for inhibitor development [HR/CI: 2.1/1.3–3.6]. Multivariate analysis adjusted for patient's individual median single FVIII dose, administered during the first three months, first-line use of pdFVIII (n=82) versus rFVIII concentrations (n=134) and treatment periods [1980–2011] revealed that the presence of IT independently increases the risk of inhibitor development to a hazard of 2.5 [CI: 1.1–5.8]. In addition, the increase of FVIII per one IU/kgbw was significantly associated with the risk to develop a high responding inhibitor [HR/CI: 1.2/1.04–1.1]. In multivariate analysis neither rFVIII products, nor treatment periods showed a statistically significant influence on clinical important inhibitor development. Data presented here suggest that clinical meaningful inhibitor development is of multifactorial origin and that apart from a positive family history also FV and FII mutations should be included in the aetiology research.