Product type and other environmental risk factors for inhibitor development in severe hemophilia A

ESSENTIALS: Treatment complications in hemophilia A: inhibitors development. Type of FVIII products: the latest updates on plasma‐derived or recombinant FVIII immunogenicity. SIPPET study, the first randomized study contrasting plasma‐derived FVIII and recombinant FVIII products. The impact of other environmental risk factors in the etiology of inhibitor formation, such as age at first treatment, regimen and intensity of treatment, severe bleeds, surgery, concomitant infections, or vaccinations. The development of FVIII inhibitory antibodies is currently the most challenging complication of treatment, affecting ~30% of severe hemophilia A patients. These inhibitors inactivate FVIII, rendering the treatment ineffective, causing disability and increasing morbidity and mortality. Inhibitor development results from a complex multicausal immune response involving both genetic and environmental risk factors. One of the most important modifiable risk factors is the source of FVIII products, eg, plasma‐derived or recombinant FVIII. Other environmental risk factors, such as age at first treatment, regimen, and intensity of treatment, could contribute to inhibitor development. Severe bleeds, surgery, concomitant infections, or vaccinations may all be events initiating danger signaling resulting in an immune reaction towards administered FVIII. All in all, the etiology of inhibitor development still remains unclear. The risk factors have been stratified into genetic and environmental, but there are no definitive data to determine the impact of each of them.