Early factor VIII exposure and subsequent inhibitor development in children with severe haemophilia A

Abstract

Summary. 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 ¼ 0.018), no significant difference was observed in children treated at different time points during the first year of life (P ¼ 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 ¼ 0.006) and in those with a major molecular defect (P ¼ 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.

F8 gene mutation type and inhibitor development in patients with severe hemophilia A: systematic review and meta-analysis

“…12 One study was excluded because it did not meet the criterion of a mutation detection rate of at least 80%. 13 …”

Back to the future: a recent history of haemophilia treatment

“…Nevertheless, the manufacturers chose to implement further technological improvements leading to a substantial reduction in the content of proteins other than FVIII or FIX [18][19][20]. In the last few years, experimental data [21] and two retrospective cohort studies [22,23], carried out in previously untreated boys with severe haemophilia A, have raised the suspicion that the cumulative incidence of inhibitors is higher with recombinant FVIII than with plasma-derived products containing, besides other proteins, large amounts of von Willebrand factor, the carrier and stabilizer of FVIII. There is also a published cohort study that demonstrates comparable immunogenicity of the two forms of treatment [24]; accordingly, this issue is likely to remain unsettled until randomized clinical trials are performed [25].…”

Current Controversies in the Formation and Treatment of Alloantibodies to Factor VIII in Congenital Hemophilia A

“…In that study, however, exposure to FVIII during the neonatal period was not associated with a higher incidence of inhibitors than treatment later during the first year of life. 7 An Italian case-control study of children treated exclusively with recombinant FVIII compared 60 children with inhibitors to 48 inhibitor-free controls. Although there seemed to be an increased trend for inhibitor formation if patients were treated at an early age, this did not hold true after adjustment for genetic factors.…”