Urgent inhibitor issues: targets for expanded research.

Although up to 80% of high-responding inhibitors in patients with severe factor VIII deficiency can be eliminated using heterogeneous regimens for immune tolerance induction, the residual morbidity in this population of haemophilic patients is far from trivial. There is an exigent need for focussed basic, translational and clinical research to extend our understanding of the pathogenesis of haemophilic inhibitor development. In this article, we identify four key research needs, including (i) whether presently available clotting factor concentrates (CFCs) have differential antigenicity, giving rise to clinically relevant immunogenicity; (ii) the interplay of quantitative and qualitative (e.g. age at first exposure) influences of CFCs as well as host-environmental factors (e.g. vaccination effects) on inhibitor development; (iii) the therapeutic role (if any) that concurrent immune tolerance with suppressive or immune-competitive therapeutic strategies play in inhibitor eradication and (iv) pending any major therapeutic advances, alternative or enhanced strategies for treating acute haemorrhage and for preventing chronic haemorrhagic events in these patients.