Prediction of factor VIII inhibitor development in the SIPPET cohort by mutational analysis and factor VIII antigen measurement

Abstract

Background The type of F8 mutation is the main predictor of inhibitor development in patients with severe hemophilia A. Mutations expected to allow residual synthesis of factor VIII are likely to play a protective role against alloantibody development by inducing immune tolerance. According to the expected full or partial impairment of FVIII synthesis, F8 variants are commonly classified as null and non-null. Objectives To explore the mutation type-inhibitor risk association in a cohort of 231 patients with severe hemophilia A enrolled in the Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) randomized trial. Methods The genetic defects in these patients, consisting of inversions of intron 22 (n = 110) and intron 1 (n = 6), large deletions (n = 16), and nonsense (n = 38), frameshift (n = 28), missense (n = 19) and splicing (n = 14) variants, of which 34 have been previously unreported, were reclassified according to two additional criteria: the functional effects of missense and splicing alterations as predicted by multiple in silico analyses, and the levels of FVIII antigen in patient plasma. Results A two-fold increase in inhibitor development for in silico null mutations as compared with in silico non-null mutations (hazard ratio [HR] 2.08, 95% confidence interval [CI] 0.84-5.17) and a 3.5-fold increase in inhibitor development for antigen-negative mutations as compared with antigen-positive mutations (HR 3.61, 95% CI 0.89-14.74] were found. Conclusions Our findings confirm an association between the synthesis of minute amounts of FVIII and inhibitor protection, and underline the importance of investigating the residual FVIII antigen levels associated with causative variants in order to understand their clinical relevance.

Safety and efficacy of turoctocog alfa in the prevention and treatment of bleeds in previously untreated paediatric patients with severe haemophilia A: Results from the guardian 4 multinational clinical trial

“…The inhibitor risk for patients with mild/moderate haemophilia is considerably lower compared with those with severe haemophilia (from <5% to >30%, respectively). It is also well known that even in severe patients, null vs non‐null mutations are associated with varying risks of inhibitor development; this underlies the direct inverse correlation between endogenous FVIII levels and inhibitor risk …”

Spectrum of F8 Genotype and Genetic Impact on Inhibitor Development in Patients with Hemophilia A from Multicenter Cohort Studies (J-HIS) in Japan

“…Demographics of severity in the patients enrolled in the present study from J-HIS1 ( were consistent with those in the original J-HIS1 and J-HIS2 cohorts (►Table 1). F8 genotypes identified in 84.7% (50/ 59) of patients with inhibitors from J-HIS1 were null variants classified as a high-risk group in the previous studies 6,21 (►Table 2). This was supportive of the findings in our previous study 18 that family history of inhibitors was…”

“…All the patients enrolled in this study from J-HIS1 were affected by inhibitors but their onset of inhibitor remained uncertain and historical peak titers of them (117 BU/mL) were distinct from those (10.1 BU/mL) in the patients with inhibitors from J-HIS2 (►Table 1) because of the difference in the study design, thereby combination of data of the patients from J-HIS1 and those from J-HIS2 may overestimate the frequency of the variants associated with inhibitor development. In the present study, the spectrum of F8 unique variants in the severe PwHA from the J-HIS2 cohort (n ¼ 188 in 178 families) was compared with those in the previously reported Asian cohorts in China, 22 Korea, 23 and Taiwan, 24 as well as that reported in the SIPPET study, 21 The distribution of variants in J-HIS2 was similar to that in the other Asian cohorts, [22][23][24] the SIPPET study, 21 and the MLOF study, 25 although the frequency of nonsense variants was somewhat lower in J-HIS2. The distribution of F8 variants observed in the nonsevere PwHA in J-HIS2 was also similar to that in the MLOF study (►Fig.…”

In silico study of correlation between missense variations of F8 gene and inhibitor formation in severe hemophilia A

“…In a recent study, Spena et al [36] evaluated the association between F8 gene variants and inhibitor development by analyzing 231 causative variants, grouped as low-risk and high-risk variations according to Gouw et al [35]. Only a small difference was observed in the cumulative inhibitor incidence [32.0% (95% CI=18.9 to 45.1) vs. 37.9% (95% CI=29.9 to 45.9)] for low-and high-risk variations classified corresponding to a hazard ratio of 1.35 (95% CI=0.78-2.35) [36].…”