The majority of the white individuals in this study (>90%) had haplotype H1 while the rest carried H2. The black population in this study showed far greater diversity, with haplotypes H1 to H5 being represented in approximately 35%, 37%, 22%, 4% and 1% of the sampled individuals, respectively. Figure 2b shows the prevalence of inhibitor development in a cohort of 76 evaluable (of 78 total) black American HA patients as well as the specific background F8 haplotypes on which

their mutations arose; the distribution of patient haplotypes was comparable with that observed in a separately studied healthy black population [13]. Two previously unknown F8 ns-SNPs (A1229C encoding Gln334Pro and G4007A encoding Arg1260Lys) (Fig. 2a), which were also identified in the cohort of 76 black HA patients, defined two additional F8 haplotypes referred see more to as H7 and H8 (Fig. 2b). The recombinant FVIII products currently used for HA replacement CCI-779 chemical structure therapy correspond to

either haplotype H1 or H2, the most common haplotypes in all populations investigated so far [13]. As a result, patients with an H1 or H2 background haplotype treated with the currently available recombinant products can receive a matched (or more accurately a ‘least mismatched’) FVIII protein, i.e. one that differs from their defective endogenous FVIII protein (if any is produced) only at the sites encoded by their HA-causing F8 mutations. Patients infused with plasma-derived products may also be receiving FVIII proteins that are matched to a greater or lesser extent to their endogenous FVIII sequence, depending on their background F8 haplotypes and the Selleckchem Paclitaxel haplotypes of the donors who contributed to the plasma pool. Our earlier study [13] indicated

that approximately one in four of the 76 black American subjects with HA had a background haplotype other than H1 or H2. The currently available recombinant FVIII proteins are thus mismatched at one or more of the sites encoded by ns-SNPs, in addition to the site corresponding to the haemophilic F8 mutation (Fig. 2). Although D1241E, the ns-SNP site that differentiates haplotypes H1 and H2, is removed in B-domain deleted FVIII (Fig. 2c), an additional amino acid sequence mismatch exists between the endogenous dysfunctional FVIII proteins in patients and this recombinant product at its non-naturally occurring B-domain junction [30]. Currently available B-domain deleted products only contain FVIII amino acid sequence, yet their synthetic junctional sites are ‘foreign’ and, as such, could be immunogenic in patients with a permissive major-histocompatibility complex (MHC). These recent findings provide one plausible mechanistic explanation for reports that black HA patients are approximately twice as likely as white HA patients to produce inhibitors against therapeutic FVIII proteins [9–12].