Incidence of factor VIII inhibitors in severe haemophilia: the importance of patient age

Abstract

Summary. The potential effect of age at the start of replacement therapy on the development of factor VIII (FVIII) inhibitors was assessed in 62 severe (FVIII , 2 IU/dl) haemophilia A patients who started FVIII therapy at one of two haemophilia centres. Inhibitors were tested on an annual basis. Persistent or high-titre inhibitors were detected in 15 patients (24%). Kaplan±Meier cumulative incidence at 3 years from first FVIII exposure was 41% (95% CI 22±67%) in patients starting therapy before the age of 6 months, 29% (95% CI 13±57%) in patients starting therapy between 6 and 12 months of age, and 12% (95% CI 4±34%) in those starting therapy beyond 1 year of age (P 0´03). By multivariate analysis, the influence of age was shown to be independent of other variables, including calendar year at the onset of therapy and baseline FVIII plasma levels. In conclusion, patient age at initial treatment appears to influence inhibitor formation. If confirmed, this finding would have a major impact on the management of haemophilia.

Environmental risk factors for inhibitor development in children with haemophilia A: a case–control study

“…Both of the previous studies arbitrarily defined the strata of age at first FVIII exposure (>12, 12-7, £6 months), however, no significant trend was observed in this study by computing age at first FVIII exposure according to the same age strata (older than 12 months: reference; 12-7 months: OR 1AE1, 95% CI 0AE5-2AE6; 6 months or younger: OR 2AE2, 95% CI 0AE8-6AE2). Apart from the different study design, the main difference between this and previous studies is represented by the type of FVIII products used at the time of treatment onset: rFVIII in our series, low/intermediatepurity concentrates in the oldest patients and high-purity or recombinant products in the youngest patients of the two aforementioned series (Lorenzo et al, 2001;van der Bom et al, 2003). Furthermore, such confounders as the type of FVIII gene mutations and other environmental conditions were not taken into account in the previous studies (Lorenzo et al, 2001;van der Bom et al, 2003).…”

“…Apart from the different study design, the main difference between this and previous studies is represented by the type of FVIII products used at the time of treatment onset: rFVIII in our series, low/intermediatepurity concentrates in the oldest patients and high-purity or recombinant products in the youngest patients of the two aforementioned series (Lorenzo et al, 2001;van der Bom et al, 2003). Furthermore, such confounders as the type of FVIII gene mutations and other environmental conditions were not taken into account in the previous studies (Lorenzo et al, 2001;van der Bom et al, 2003).…”

“…The inhibitor risk was not significantly affected by these conditions. Previous studies carried out in two cohorts of Spanish and Dutch haemophiliacs (Lorenzo et al, 2001;van der Bom et al, 2003) showed an inverse relationship between the age at treatment onset and the likelihood of inhibitor development. A similar trend was found in this study comparing cases and controls on the basis of the distribution tertiles of age at first FVIII exposure in controls (>16, 16-11 and <11 months), however differences were not statistically significant after adjusting for genetic factors.…”

“…Potential environmental factors are the different types of FVIII products used for replacement therapy, but the relative risks of recombinant and plasma-derived FVIII products in inhibitor development are still a matter of debate. Other therapy-related factors potentially involved in the development of inhibitors are mode of treatment delivery by continuous infusion (Sharathkumar et al, 2003), high-dose regimens (Sharathkumar et al, 2003) and very young age at treatment onset (Lorenzo et al, 2001;van der Bom et al, 2003). No data are available on other putative environmental factors for inhibitor formation, such as FVIII treatment in the context of severe bleeding or surgery and during infections, vaccinations or other challenges of the immune system.…”

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

“…In a Spanish cohort of 62 children with severe (FVIII Ͻ 2 IU/dL) hemophilia A, 24% of whom developed persistent inhibitors, a statistically significant difference (P ϭ .03) in the cumulative incidence of laboratory-detected inhibitor formation based on age at first exposure was demonstrated. 4 A cohort study from the Netherlands of 81 infants with severe hemophilia A confirmed this trend, assessing the incidence at 100 exposure days. 5 This trend was again demonstrated in a larger multicenter review of 366 patients with severe hemophilia A in the Netherlands (the CANAL cohort study), but disappeared when adjusting for confounding factors, especially intensity at first treatment.…”