The most serious current complication of factor replacement therapy for hemophilia patients is the development of neutralizing antibodies to the factor termed inhibitors. Patients with high-titer inhibitors frequently develop serious bleeding complications which do not respond to standard factor replacement therapy. Therefore, they must be treated with the so-called bypassing agents, recombinant factor VIIa and activated prothrombin complex concentrates, neither of which is as effective as standard factor replacement in patients without inhibitors. Immune tolerance therapy aimed at eradicating inhibitors is successful in a majority of patients; however, a sizable minority will have life-long inhibitors and often develop debilitating joint disease. The ultimate goal is to develop strategies aimed at preventing inhibitor development though these have not been realized yet. Until this is achieved, additional novel approaches are needed to improve the treatment of bleeding episodes and to better treat arthropathy once it develops. Finally, there is no laboratory monitoring device which can predict the clinical response of patients to bypassing agents. Thus another goal of current research is to develop such a tool which will enable the individualization of bypassing agent.

Darby SC, Keeling DM, Spooner RJ, Wan Kan S, Giangrande PL, Collins PW, Hill FG, Hay CR; UK Haemophilia Centre Doctors’ Organisation: The incidence of factor VIII and factor IX inhibitors in the hemophilia population of the UK and their effect on subsequent mortality, 1977–99. J Thromb Haemost 2004;2:1047–1054.
Gringeri A, Mantovani LG, Scalone L, Mannucci PM; COCIS Study Group: Cost of care and quality of life for patients with hemophilia complicated by inhibitors: the COCIS study group. Blood 2003;102:2358–2363.
Dimichele D: Inhibitors: resolving diagnostic and therapeutic dilemmas. Haemophilia 2002;8:280–287.
Barrow RT, Healey JF, Gailani D, Scandella D, Lollar P: Reduction of the antigenicity of factor VIII toward complex inhibitory antibody plasmas using multiply-substituted hybrid human/porcine factor VIII molecules. Blood 2000;95:564–568.
Van Der Bom JG, Mauser-Bunschoten EP, Fischer K, Van Den Berg HM: Age at first treatment and immune tolerance to factor VIII in severe hemophilia. Thromb Haemost 2003;89:475–479.
Rossi G, Sarkar J, Scandella D: Long-term induction of immune tolerance after blockade of CD40-CD40L interaction in a mouse model of hemophilia A. Blood 2001;97:2750–2757.
Qian J, Collins M, Sharpe AH, Hoyer LW: Prevention and treatment of factor VIII inhibitors in murine hemophilia A. Blood 2000;95:1324–1329.
Madoiwa S, Yamauchi T, Hakamata Y, Kobayashi E, Arai M, Sugo T, Mimuro J, Sakata Y: Induction of immune tolerance by neonatal intravenous injection of human factor VIII in murine hemophilia A. J Thromb Haemost 2004;2:754–762.
Sharathkumar A, Lillicrap D, Blanchette VS, Kern M, Leggo J, Stain AM, Brooker L, Carcao MD: Intensive exposure to factor VIII is a risk factor for inhibitor development in mild hemophilia A. J Thromb Haemost 2003;1:1228–1236.
Ewenstein BM, Hoots WK, Lusher JM, Dimichele D, White GC 2nd, Adelman B, Nadeau K: Inhibition of CD40 ligand (CD154) in the treatment of factor VIII inhibitors. Haematologica 2000;85(10 suppl):35–39.
Auerswald G, Spranger T, Brackmann HH: The role of plasma-derived factor VIII/von Willebrand factor concentrates in the treatment of hemophilia A patients. Haematologica 2003;88:EREP05.
Mathias M, Khair K, Hann I, Liesner R: Rituximab in the treatment of alloimmune factor VIII and IX antibodies in two children with severe haemophilia. Br J Haematol 2004;125:366–368.
Villard S, Lacroix-Desmazes S, Kieber-Emmons T, Piquer D, Grailly S, Benhida A, Kaveri SV, Saint-Remy JM, Granier C: Peptide decoys selected by phage display block in vitro and in vivo activity of a human anti-FVIII inhibitor. Blood 2003;102:949–952.
Hilgartner M, Aledort L, Andes A, Gill J: Efficacy and safety of vapor-heated anti-inhibitor coagulant complex in hemophilia patients. FEIBA Study Group. Transfusion 1990;30:626–630.
Key NS, Aledort LM, Beardsley D, Cooper HA, Davignon G, Ewenstein BM, Gilchrist GS, Gill JC, Glader B, Hoots WK, Kisker CT, Lusher JM, Rosenfield CG, Shapiro AD, Smith H, Taft E: Home treatment of mild to moderate bleeding episodes using recombinant factor VIIa (Novoseven) in haemophiliacs with inhibitors. Thromb Haemost 1998;80:912–918.
Seremetis S: Dose optimization of recombinant factor VIIa in the treatment of acute bleeding in haemophilia-associated inhibitors. Blood Coagul Fibrinolysis 2003;14(suppl 1):S29–S30.
Kenet G, Lubetsky A, Luboshitz J, Martinowitz U: A new approach to treatment of bleeding episodes in young hemophilia patients: a single bolus megadose of recombinant activated factor VII (NovoSeven). J Thromb Haemost 2003;1:450–455.
Key NS, Christie B, Henderson N, Nelsestuen GL: Possible synergy between recombinant factor VIIa and prothrombin complex concentrate in hemophilia therapy. Thromb Haemost 2002;88:60–65.
Schneiderman J, Nugent DJ, Young G: Sequential therapy with activated prothrombin complex concentrate and recombinant factor VIIa in patients with severe haemophilia and inhibitors. Haemophilia 2004;10:347–351.
Hilgartner MW, Makipernaa A, Dimichele DM: Long-term FEIBA prophylaxis does not prevent progression of existing joint disease. Haemophilia 2003;9:261–268.
Saxon BR, Shanks D, Jory CB, Williams V: Effective prophylaxis with daily recombinant factor VIIa (rFVIIa-Novoseven) in a child with high titre inhibitors and a target joint. Thromb Haemost 2001;86:1126–1127.
Young G, McDaniel M, Nugent DJ: Prophylactic recombinant factor VIIa in haemophilia patients with inhibitors. Haemophilia 2005; 11:203–207.
Persson E, Kjalke M, Olsen OH: Rational design of coagulation factor VIIa variants with substantially increased intrinsic activity. Proc Natl Acad Sci USA 2001;98:13583–13588.
Tomokiyo K, Nakatomi Y, Araki T, Teshima K, Nakano H, Nakagaki T, Miyamoto S, Funatsu A, Iwanaga S: A novel therapeutic approach combining human plasma-derived factors VIIa and X for haemophiliacs with inhibitors: evidence of a higher thrombin generation rate in vitro and more sustained haemostatic activity in vivo than obtained with factor VIIa alone. Vox Sang 2003;85:290–299.
Parker ET, Craddock HN, Barrow RT, Lollar P: Comparative immunogenicity of recombinant B domain-deleted porcine factor VIII and Hyate:C in hemophilia A mice presensitized to human factor VIII. J Thromb Haemost 2004;2:605–611.
Bragadottir G, Onundarson PT: Factor-sparing use of the COX-2 inhibitor rofecoxib in haemophilic arthropathy. Haemophilia 2002;8:832–833.
Rattray BN, Nugent DJ, Young G: Rofecoxib as adjunctive therapy for haemophilic arthropathy. Haemophilia 2005;11:240–244.
Sramek A, Kriek M, Rosendaal FR: Decreased mortality of ischaemic heart disease among carriers of haemophilia. Lancet 2003;362:351–354.
Rosendaal FR, Varekamp I, Smit C, Brocker-Vriends AH, Van Dijck H, Vandenbroucke JP, Hermans J, Suurmeijer TP, Briet E: Mortality and causes of death in Dutch haemophiliacs, 1973–86. Br J Haematol 1989;71:71–76.
Graham DJ: Risk of acute cardiac events among patients treated with cyclooxygenase-2 selective and non-selective nonsteroidal antiinflammatory drugs (abstract 571). 20th Annual Meeting of the International Society for Pharmacoepidemiology Conference on Pharmacoepidemiology, Bordeaux, 2004.
White WB, Faich G, Borer JS, Makuch RW: Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib. Am J Cardiol 2003;92:411–418.
Siegel HJ, Luck JV Jr, Siegel ME, Quinones C: Phosphate-32 colloid radiosynovectomy in hemophilia: outcome of 125 procedures. Clin Orthop 2001;392:409–417.
Srivastava A: Dose and response in haemophilia – optimization of factor replacement. Br J Haematol 2004;127:12–25.
Key NS, Nelsestuen GL: Views on methods for monitoring recombinant factor VIIa in inhibitor patients. Semin Hematol 2004;41(suppl 1):51–54.
Ingerslev J, Christiansen K, Calatzis A, Holm M, Sabroe Ebbesen L: Management and monitoring of recombinant activated factor VII. Blood Coagul Fibrinolysis 2000;11(suppl 1):S25–S30.
Nugent DJ, Lovejoy A, Nakagawa P, Young G: Successful use of thromboelastography to determine dosing frequency of rFVIIa and FXIII. Blood 2003;102(suppl 1):307a.
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