The pharmacokinetic program PK solutions 2.0 (Summitt Research Services, Montrose, CO, USA) was used to calculate FVIII half-life. As all patients were children younger than 6 years, a normal FVIII half life was defined as 6 h or more [15].

buy PF-6463922 Partial success was defined as a reduction in inhibitor titre to <5 BU mL−1, but with FVIII recovery of <66% or FVIII half life of less than 6 h, associated with clinical response to FVIII therapy [15]. Complete success was defined as a negative inhibitor titre (≤0.3 BU mL−1) within 33 months of ITI, a FVIII recovery of at least 66% of expected, and a FVIII half life of 6 h or more after a 72-h washout period. Failure of tolerance induction was defined as absence of any evidence of a significant decline of the inhibitor titre during ITI, given for a minimum of 26 weeks [15]. Patients in whom the clinical decision was made to switch to a high dose regimen at any time point were also considered as failures. During 26 years of low dose ITI, various products were used. Plasma derived FVIII products, with different purification and virus inactivation methods, as well as recombinant

products were administered to achieve tolerance induction. Since 1995, only recombinant factor VIII products were used in all learn more young newly diagnosed haemophilia A patients. Factor VIII gene mutation type was divided in large mutations (deletions of over 200 base pairs or nonsense mutations), inversions and small mutation types (deletions of less than 200 base pairs, missense mutations, PAK5 and other mutations, including splice site defects or promoter mutations) [16,17].

Success rates were compared using Chi square tests. Cox multivariate regression techniques were used to analyse contribution (hazard ratio’s) of risk factors to ITI outcome over time. Several risk factors were analysed: number of exposure days at inhibitor development, intensive treatment before inhibitor development, inhibitor titre before and during ITI, dosage (25 or 50 IU FVIII kg−1) at start of ITI and surgery during ITI. Kaplan–Meier survival curves were used to estimate probabilities of inhibitor disappearance over time. These curves were compared with log rank tests. Approval for this retrospective study was obtained from the institutional review board of the University Medical Centre Utrecht. Data were collected anonymously. Between 1981 and 2007, inhibitors were detected in 24 children with severe haemophilia A. Three patients were excluded. Two of them, with pre-ITI titres of 6.3 and 137 BU mL−1 were treated with high dose ITI because of participation in the International Immune Tolerance Study. One patient, with a pre-ITI titre of 44 BU mL−1, was excluded as he was on low dose ITI for 1 week only, before he switched to high dose ITI because of a severe bleeding tendency. A total of 21 patients were included in the study. In one patient, FVIII infusions were postponed for 32 months because of problems with venous access.