The epidemiology of factor VIII inhibitors

Risk factors for inhibitor development include specific factor VIII (FVIII) genotypes, a family history of inhibitor development amongst first-degree relatives, certain HLA haplotypes and non-caucasian ethnicity. Patients with major FVIII deletions or rearrangements have a higher risk of inhibitor development than those with small deletions or missense mutations. Studies of HLA-DR amongst northern European patients with the intron 22 inversion indicate that certain HLA haplotypes may also confer either increased or decreased inhibitor risk. However, although brothers of patients with inhibitor have a high risk of inhibitor development, concordance is not 100%, and other constitutional factors must also operate. Disputed risk factors for inhibitor development include early age at first FVIII exposure, the use of recombinant rather than plasma-derived FVIII and product switching. Two studies suggest that inhibitor risk is increased by very early FVIII exposure (P = 0.03), but this is disputed by a third study; larger studies addressing the question are ongoing. Studies investigating the relative inhibitor risk of plasma-derived vs. recombinant FVIII have been similarly inconclusive and will be reviewed. Other environmental or treatment variables such as concomitant infection or vaccination are suspected to influence inhibitor risk but have not yet been fully investigated.