Attempts to treat patients with hemophilia, the "royal disease"

which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. " Our poor family seems persecuted by this awful disease, the worst I know. " Queen Victoria (1819–1901) of the United Kingdom of Great Britain and Ireland wrote in her diary. She is well known as the most famous carrier of hemophilia, the " royal disease " , and had passed on the disease to several royal families in Europe through her daughters. Since first described in a hemophilia patient by Lawrence and Johnson in 1941 [1], inhibitor development has been the most serious complication of hemophilia A treatment. Inhibitor development occurs in up to 36% of patients with severe hemophilia A [2, 3]. The inhibitor is an alloantibody against factor VIII (FVIII), which if developed during hemophilia treatment, impairs FVIII activity and thus neutralizes the effect of the " factor replacement " therapy, leading to increased complications and therapeutic cost [4]. Some genetic and environmental risk factors for inhibitor development are well known; however, it is still unclear why some, but not other patients, develop inhibitors. The inhibitors in hemophiliacs may be temporary or can be eradicated with immune tolerance induction (ITI) therapy. The recent study (International Immune Tolerance Study) of 115 " good-risk " subjects with severe hemophilia A and high-titer inhibitors showed that there was no difference between the low-dose (50 IU/kg 3 times/week) and high-dose (200 IU/kg/day) regimens in achieving tolerance, with the former taking longer [5]. These data might be important for nations with limited resources. Although the eradication of inhibitors and recommencement of FVIII replacement therapy is a long-term goal in treating inhibitor patients, ITI therapy has limited indications and a success rate of 63–80% [6]. Patients with high-titer inhibitors and intractable bleeding episodes should be given recombinant activated factor VII (r-FVIIa) or activated prothrombin complex concentrate (aPCC), called the hemostatic bypassing agent (to circumvent FVIII in the coagulation pathway), as the first choice therapy. The FEIBA NovoSeven Comparative (FENOC) Study evaluated the hemostatic efficacy of both products on 96 joint bleeds of 48 inhibitor patients and showed nearly equivalent efficacy, with both agents being effective and safe, although a substantial number of patients reported different efficacies for both agents [7]. Nevertheless, 10–20% of bleeding events in hemophiliacs with high-titer inhibitors cannot be controlled by either r-FVIIa or aPCC alone and thus may need sequential combined …