title: Risk factors for high-titer inhibitor development in children with hemophilia A: results of a cohort study.
abstract: Among the discussed risk factors for high-titre inhibitor (HRI) development in patients with hemophilia A (HA) are high dose FVIII replacement therapy and use of recombinant FVIII concentrates (rFVIII). The aim of this study was to evaluate the aforementioned risk factors for HRI development in children with hemophilia A ≤2%. About 288 ascertained PUPs (Israel and Germany) were followed after initial HA diagnosis over 200 exposure days. Inhibitor-free survival, hazard ratios (HR), and 95% confidence intervals (CIs) were calculated. Adjustment was performed for factor VIII concentrates, median single dose over the first three months of treatment, first FVIII administration before the age of three months, presence of risk HA gene mutations, "intensive treatment moments" and "year of birth" (proxy for different treatment periods). HRI occurred in 71/288 children (24.7%). In multivariate analysis adjusted for "year of birth", underlying risk gene mutations (HR/CI: 2.37/1.40-3.99), FVIII dose, measured per one IU increase per kgbw (HR/CI: 1.05/1.04-1.07), and first FVIII administration before the age of three months showed a significant impact on HR development. The risk of HRI development was similar for recombinant or plasmatic FVIII products. Children at risk should be treated with carefully calculated lower dose regimens, adapted to individual bleeding situations.
authors.affiliation: Gerinnungszentrum Rhein-Ruhr (GZRR), 47051 Duisburg, Germany.
authors.forename: Susan
authors.initials: S
authors.lastname: Halimeh
authors.forename: Christoph
authors.initials: C
authors.lastname: Bidlingmaier
authors.forename: Christine
authors.initials: C
authors.lastname: Heller
authors.forename: Sven
authors.initials: S
authors.lastname: Gutsche
authors.forename: Susanne
authors.initials: S
authors.lastname: Holzhauer
authors.forename: Gili
authors.initials: G
authors.lastname: Kenet
authors.forename: Karin
authors.initials: K
authors.lastname: Kurnik
authors.forename: Daniela
authors.initials: D
authors.lastname: Manner
authors.forename: Alfonso
authors.initials: A
authors.lastname: Iorio
authors.forename: Ulrike
authors.initials: U
authors.lastname: Nowak-Göttl
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005169:Factor VIII / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000276:immunology*; D005260:Female; D006467:Hemophilia A / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D015999:Multivariate Analysis; D009154:Mutation; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: D005169:Factor VIII