title: Early factor VIII exposure and subsequent inhibitor development in children with severe haemophilia A.
abstract: Recent reports have suggested that the incidence of inhibitors in haemophilia is the highest in those first exposed to factor VIII under 6 months of age. In this study, we investigated inhibitor development in children first exposed to FVIII as neonates and also examined the effect of other genetic and environmental variables. Three hundred and forty-eight children with severe haemophilia A were investigated. Inhibitors developed in 68 of 348 (20%), with 34 of 348 (10%) high titre inhibitors. The incidence in relation to initial FVIII exposure was: <1 month nine of 35 (26%), 1-6 months 13 of 51 (25%), 6-12 months 27 of 130 (21%), 12-18 months 13 of 66 (20%) and >18 months six of 66 (9%). While we observed a significant difference in inhibitor development and age at first exposure across all age groups (P = 0.018), no significant difference was observed in children treated at different time points during the first year of life (P = 0.44). Similar results were obtained for high titre inhibitors. There was also no difference in the incidence of inhibitors in relation to initial FVIII exposure in a subgroup of 144 children with the intron 22 mutation. Inhibitors developed more frequently in those initially treated with recombinant when compared with plasma-derived FVIII (P = 0.006) and in those with a major molecular defect (P = 0.009). In this study, exposure to FVIII during the neonatal period was not associated with a higher incidence of inhibitors than those treated later during the first year of life. Initial treatment with recombinant FVIII and the presence of a major molecular defect were the most important variables affecting inhibitor development.
authors.affiliation: Royal Hospital for Sick Children, Glasgow, UK. elizabeth.chalmers@yorkhill.scot.nhs.uk
authors.forename: E A
authors.initials: EA
authors.lastname: Chalmers
authors.forename: S A
authors.initials: SA
authors.lastname: Brown
authors.forename: D
authors.initials: D
authors.lastname: Keeling
authors.forename: R
authors.initials: R
authors.lastname: Liesner
authors.forename: M
authors.initials: M
authors.lastname: Richards
authors.forename: D
authors.initials: D
authors.lastname: Stirling
authors.forename: A
authors.initials: A
authors.lastname: Thomas
authors.forename: V
authors.initials: V
authors.lastname: Vidler
authors.forename: M D
authors.initials: MD
authors.lastname: Williams
authors.forename: D
authors.initials: D
authors.lastname: Young
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D019774:Blood Coagulation Factor Inhibitors / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D005169:Factor VIII / Q000276:immunology* / Q000627:therapeutic use; D006467:Hemophilia A / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D010375:Pedigree; D012307:Risk Factors
chemical_list: D019774:Blood Coagulation Factor Inhibitors; D005169:Factor VIII