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Expert Opinion on Orphan Drugs Volume 4, 2016 - Issue 2
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Review

Epidemiological aspects of inhibitor development in hemophilia and strategies of management

Jenny KlintmanLund University, Centre for Thrombosis and Haemostasis, Skåne University Hospital, Malmö, Sweden
&
Erik BerntorpLund University, Centre for Thrombosis and Haemostasis, Skåne University Hospital, Malmö, SwedenCorrespondence[email protected]
Pages 153-168 | Received 03 Sep 2015, Accepted 30 Nov 2015, Published online: 14 Jan 2016

References

  • Mannucci PM, Tuddenham EG. The hemophilias: from royal genes to gene therapy. N Engl J Med. 2001 Jun 7;344(23):1773–1779.
  • Berntorp E, Shapiro AD. Modern haemophilia care. Lancet. 2012 Apr 14;379(9824):1447–1456.
  • White GC, Rosendaal F, Aledort LM, et al. Definitions in hemophilia. Recommendation of the Scientific Subcommittee on Factor VIII and Factor IX of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost. 2001;85:560.
  • Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Guidelines for the management of hemophilia. Haemophilia. 2013;19(1):e1–e47.
  • Astermark J, Petrini P, Tengborn L, et al. Primary prophylaxis in severe haemophilia should be started at an early age but can be individualized. Br J Haematol. 1999 Jun;105(4):1109–1113.
  • DiMichele D. Inhibitor development in haemophilia B: an orphan disease in need of attention. Br J Haematol. 2007 Aug;138(3):305–315.
  • Ghosh K, Shetty S. Immune response to FVIII in hemophilia A: an overview of risk factors. Clin Rev Allergy Immunol. 2009 Oct;37(2):58–66.
  • Lusher JM, Arkin S, Abildgaard CF, et al. Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. Safety, efficacy, and development of inhibitors. Kogenate Previously Untreated Patient Study Group. N Engl J Med. 1993 Feb 18;328(7):453–459.
  • Astermark J, Oldenburg J, Escobar M, et al. The Malmo International Brother Study (MIBS). Genetic defects and inhibitor development in siblings with severe hemophilia A. Haematologica. 2005 Jul;90(7):924–931.

** Large, important sibling study.

  • Gouw SC, Van Den Berg HM, Oldenburg J, et al. F8 gene mutation type and inhibitor development in patients with severe hemophilia A: systematic review and meta-analysis. Blood. 2012 Mar 22;119(12):2922–2934.

** Important information about F8 mutation and inhibitor development.

  • Astermark J, Oldenburg J, Carlson J, et al. Polymorphisms in the TNFA gene and the risk of inhibitor development in patients with hemophilia A. Blood. 2006 Dec 1;108(12):3739–3745.

* First report on TNFA gene and inhibitor development.

  • Astermark J, Oldenburg J, Pavlova A, et al. Polymorphisms in the IL10 but not in the IL1beta and IL4 genes are associated with inhibitor development in patients with hemophilia A. Blood. 2006 Apr 15;107(8):3167–3172.

* First report on IL10 and inhibitor development.

  • Pavlova A, Delev D, Lacroix-Desmazes S, et al. Impact of polymorphisms of the major histocompatibility complex class II, interleukin-10, tumor necrosis factor-alpha and cytotoxic T-lymphocyte antigen-4 genes on inhibitor development in severe hemophilia A. J Thromb Haemost. 2009 Dec;7(12):2006–2015.
  • Gouw SC, Van Den Berg HM, Le Cessie S, et al. Treatment characteristics and the risk of inhibitor development: a multicenter cohort study among previously untreated patients with severe hemophilia A. J Thromb Haemost. 2007 Jul;5(7):1383–1390.
  • Gouw SC, Van Der Bom JG, Van Den Berg HM. Treatment-related risk factors of inhibitor development in previously untreated patients with hemophilia A: the CANAL cohort study. Blood. 2007 Jun 1;109(11):4648–4654.

** Important study of treatment-related factors and inhibitor development.

  • Knobe KE, Sjorin E, Tengborn LI, et al. Inhibitors in the Swedish population with severe haemophilia A and B: a 20-year survey. Acta Paediatrica (Oslo, Norway: 1992). 2002;91(8):910–914.
  • Morado M, Villar A, Jimenez Yuste V, et al. Prophylactic treatment effects on inhibitor risk: experience in one centre. Haemophilia. 2005 Mar;11(2):79–83.
  • Santagostino E, Mancuso ME, Rocino A, et al. Environmental risk factors for inhibitor development in children with haemophilia A: a case-control study. Br J Haematol. 2005 Aug;130(3):422–427.
  • Gouw SC, Van Den Berg HM, Fischer K, et al. Intensity of factor VIII treatment and inhibitor development in children with severe hemophilia A: the RODIN study. Blood. 2013 May 16;121(20):4046–4055.

* Intensity of treatment reported as risk factor. Has since been confirmed in other studies.

  • Chalmers EA, Brown SA, Keeling D, et al. Early factor VIII exposure and subsequent inhibitor development in children with severe haemophilia A. Haemophilia. 2007 Mar;13(2):149–155.
  • Goudemand J, Rothschild C, Demiguel V, et al. Influence of the type of factor VIII concentrate on the incidence of factor VIII inhibitors in previously untreated patients with severe hemophilia A. Blood. 2006 Jan 1;107(1):46–51.
  • Eckhardt CL, Menke LA, Van Ommen CH, et al. Intensive peri-operative use of factor VIII and the Arg593–>Cys mutation are risk factors for inhibitor development in mild/moderate hemophilia A. J Thromb Haemost. 2009 Jun;7(6):930–937.
  • Benson G, Auerswald G, Elezovic I, et al. Immune tolerance induction in patients with severe hemophilia with inhibitors: expert panel views and recommendations for clinical practice. Eur J Haematol. 2012 May;88(5):371–379.
  • Konkle BA, Ebbesen LS, Erhardtsen E, et al. Randomized, prospective clinical trial of recombinant factor VIIa for secondary prophylaxis in hemophilia patients with inhibitors. J Thromb Haemost. 2007 Sep;5(9):1904–1913.

* Prophylaxis with rFVIIa.

  • Leissinger C, Gringeri A, Antmen B, et al. Anti-inhibitor coagulant complex prophylaxis in hemophilia with inhibitors. N Engl J Med. 2011 Nov 3;365(18):1684–1692.

* Prophylaxis with FEIBA.

  • Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009 Jul 21;6(7):e1000097.
  • Batorova A, Holme P, Gringeri A, et al. Continuous infusion in haemophilia: current practice in Europe. Haemophilia. 2012 Sep;18(5):753–759.
  • Auerswald G, Bade A, Haubold K, et al. No inhibitor development after continuous infusion of factor concentrates in subjects with bleeding disorders undergoing surgery: a prospective study. Haemophilia. 2013 May;19(3):438–444.
  • Hay CR, Palmer B, Chalmers E, et al. Incidence of factor VIII inhibitors throughout life in severe hemophilia A in the United Kingdom. Blood. 2011 Jun 9;117(23):6367–6370.
  • Webert KE, Rivard GE, Teitel J, et al. Low prevalence of inhibitor antibodies in the Canadian haemophilia population. Haemophilia. 2012 May;18(3):e254–9.
  • Eckhardt CL, Van Velzen AS, Peters M, et al. Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A. Blood. 2013 Sep 12;122(11):1954–1962.
  • Kempton CL, Soucie JM, Miller CH, et al. In non-severe hemophilia A the risk of inhibitor after intensive factor treatment is greater in older patients: a case-control study. J Thromb Haemost. 2010 Oct;8(10):2224–2231.
  • Mauser-Bunschoten EP, Den Uijl IE, Schutgens RE, et al. Risk of inhibitor development in mild haemophilia A increases with age. Haemophilia. 2012 Mar;18(2):263–267.
  • Lorenzo JI, Lopez A, Altisent C, et al. Incidence of factor VIII inhibitors in severe haemophilia: the importance of patient age. Br J Haematol. 2001 Jun;113(3):600–603.
  • Auerswald G, Thompson AA, Recht M, et al. Experience of Advate rAHF-PFM in previously untreated patients and minimally treated patients with haemophilia A. Thromb Haemost. 2012 Jun;107(6):1072–1082.
  • Collins PW, Palmer BP, Chalmers EA, et al. Factor VIII brand and the incidence of factor VIII inhibitors in previously untreated UK children with severe hemophilia A, 2000-2011. Blood. 2014 Nov 27;124(23):3389–3397.
  • Franchini M, Lippi G. Von Willebrand factor-containing factor VIII concentrates and inhibitors in haemophilia A. A critical literature review. Thromb Haemost. 2010 Nov 3;104(5):931–940.
  • Gringeri A, Tagliaferri A, Tagariello G, et al. Efficacy and inhibitor development in previously treated patients with haemophilia A switched to a B domain-deleted recombinant factor VIII. Br J Haematol. 2004 Aug;126(3):398–404.
  • Singleton E, Smith J, Kavanagh M, et al. Low risk of inhibitor formation in haemophilia patients after a change in treatment from Chinese hamster ovary cell-produced to baby hamster kidney cell-produced recombinant factor VIII. Thromb Haemost. 2007 Dec;98(6):1188–1192.
  • Mauser-Bunschoten EP, Van Der Bom JG, Bongers M, et al. Purity of factor VIII product and incidence of inhibitors in previously untreated patients with haemophilia A. Haemophilia. 2001 Jul;7(4):364–368.
  • Bacon CL, Singleton E, Brady B, et al. Low risk of inhibitor formation in haemophilia A patients following en masse switch in treatment to a third generation full length plasma and albumin-free recombinant factor VIII product (ADVATE(R)). Haemophilia. 2011 May;17(3):407–411.
  • Strauss T, Lubetsky A, Ravid B, et al. Recombinant factor concentrates may increase inhibitor development: a single centre cohort study. Haemophilia. 2011 Jul;17(4):625–629.
  • Aledort LM, Navickis RJ, Wilkes MM. Can B-domain deletion alter the immunogenicity of recombinant factor VIII? A meta-analysis of prospective clinical studies. J Thromb Haemost. 2011 Nov;9(11):2180–2192.
  • Gouw SC, Van Der Bom JG, Auerswald G, et al. Recombinant versus plasma-derived factor VIII products and the development of inhibitors in previously untreated patients with severe hemophilia A: the CANAL cohort study. Blood. 2007 Jun 1;109(11):4693–4697.
  • Mancuso ME, Mannucci PM, Rocino A, et al Source and purity of factor VIII products as risk factors for inhibitor development in patients with hemophilia A. J Thromb Haemost. 2012 May;10(5):781–790.
  • Gouw SC, Van Der Bom JG, Ljung R, et al. Factor VIII products and inhibitor development in severe hemophilia A. N Engl J Med. 2013 Jan 17;368(3):231–239.

** Study on FVIII product type and risk of inhibitor development. Has created a lot of discussion in the scientific community.

  • Halimeh S, Bidlingmaier C, Heller C, et al. Risk factors for high-titer inhibitor development in children with hemophilia A: results of a cohort study. Biomed Res Int. 2013;2013:901975.
  • Calvez T, Chambost H, Claeyssens-Donadel S, et al. Recombinant factor VIII products and inhibitor development in previously untreated boys with severe hemophilia A. Blood. 2014 Nov 27;124(23):3398–3408.
  • Fischer K, Iorio A, Hollingsworth R, et al. FVIII inhibitor development according to concentrate: data from the EUHASS registry excluding overlap with other studies. Haemophilia. 2015:1–3. DOI:10.1111/hae.12764. [Epub ahead of print].
  • Fischer K, Lassila R, Peyvandi F, et al. Inhibitor development in haemophilia according to concentrate. Four-year results from the European HAemophilia Safety Surveillance (EUHASS) project. Thromb Haemost. 2015 May;113(5):968–975.
  • Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol. 2007 January 1;81(1):1–5.
  • Eckhardt CL, Kamphuisen PW, Fijnvandraat K. Inhibitors of factor VIII in hemophilia. N Engl J Med. 2009 Jul 16;361(3):309. author reply 10.
  • Kurnik K, Bidlingmaier C, Engl W, et al. New early prophylaxis regimen that avoids immunological danger signals can reduce FVIII inhibitor development. Haemophilia. 2010 Mar;16(2):256–262.

** Study that reported on low inhibitor incidence if early prophylaxis avoids danger signals. Has created a lot of scientific discussions.

  • Ragni MV, Ojeifo O, Feng J, et al. Risk factors for inhibitor formation in haemophilia: a prevalent case-control study. Haemophilia. 2009 Sep;15(5):1074–1082.
  • Rothschild C, Laurian Y, Satre EP, et al. French previously untreated patients with severe hemophilia A after exposure to recombinant factor VIII: incidence of inhibitor and evaluation of immune tolerance. Thromb Haemost. 1998 Nov;80(5):779–783.
  • Astermark J, Berntorp E, White GC, et al. The Malmo International Brother Study (MIBS): further support for genetic predisposition to inhibitor development in hemophilia patients. Haemophilia: Official J World Fed Hemophilia. 2001 May;7(3):267–272.
  • Carpenter SL, Michael Soucie J, Sterner S, et al. Increased prevalence of inhibitors in Hispanic patients with severe haemophilia A enrolled in the Universal Data Collection database. Haemophilia. 2012 May;18(3):e260–5.
  • Viel KR, Ameri A, Abshire TC, et al. Inhibitors of factor VIII in black patients with hemophilia. N Engl J Med. 2009 Apr 16;360(16):1618–1627.
  • Peyvandi F, Lotta LA, Mannucci PM. Inhibitors of factor VIII in hemophilia. N Engl J Med. 2009 Jul 16;361(3):309. author reply 10.
  • Schwarz J, Astermark J, Menius ED, et al. F8 haplotype and inhibitor risk: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort. Haemophilia. 2013 Jan;19(1):113–118.
  • Wang XF, Zhao YQ, Yang RC, et al. The prevalence of factor VIII inhibitors and genetic aspects of inhibitor development in Chinese patients with haemophilia A. Haemophilia. 2010 Jul 1;16(4):632–639.
  • Boekhorst J, Lari GR, D’Oiron R, et al. Factor VIII genotype and inhibitor development in patients with haemophilia A: highest risk in patients with splice site mutations. Haemophilia. 2008 Jul;14(4):729–735.
  • Gouw SC, Van Der Bom JG, Van Den Berg HM, et al. Influence of the type of F8 gene mutation on inhibitor development in a single centre cohort of severe haemophilia A patients. Haemophilia. 2011 Mar;17(2):275–281.
  • Miller CH, Benson J, Ellingsen D, et al. F8 and F9 mutations in US haemophilia patients: correlation with history of inhibitor and race/ethnicity. Haemophilia. 2012 May;18(3):375–382.
  • Rossetti LC, Szurkalo I, Radic CP, et al. Factor VIII genotype characterization of haemophilia A affected patients with transient and permanent inhibitors: a comprehensive Argentine study of inhibitor risks. Haemophilia. 2013 Jul;19(4):511–518.
  • Repesse Y, Peyron I, Dimitrov JD, et al. Development of inhibitory antibodies to therapeutic factor VIII in severe hemophilia A is associated with microsatellite polymorphisms in the HMOX1 promoter. Haematologica. 2013 Oct;98(10):1650–1655.
  • Fukuda K, Naka H, Morichika S, et al. Inversions of the factor VIII gene in Japanese patients with severe hemophilia A. Int J Hematol. 2004 Apr;79(3):303–306.
  • Astermark J, Donfield SM, Gomperts ED, et al. The polygenic nature of inhibitors in hemophilia A: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort. Blood. 2013 Feb 21;121(8):1446–1454.

** Study showing the complex genetic nature behind inhibitor development.

  • Astermark J, Wang X, Oldenburg J, et al. Polymorphisms in the CTLA-4 gene and inhibitor development in patients with severe hemophilia A. J Thromb Haemost: JTH. 2007 Feb;5(2):263–265.

* First report on CTLA-4 gene and inhibitor development.

  • Bafunno V, Santacroce R, Chetta M, et al. Polymorphisms in genes involved in autoimmune disease and the risk of FVIII inhibitor development in Italian patients with haemophilia A. Haemophilia. 2010 May;16(3):469–473.
  • Pinto P, Ghosh K, Shetty S. Immune regulatory gene polymorphisms as predisposing risk factors for the development of factor VIII inhibitors in Indian severe haemophilia A patients. Haemophilia. 2012 Sep;18(5):794–797.
  • Antunes SV, Tangada S, Stasyshyn O, et al. Randomized comparison of prophylaxis and on-demand regimens with FEIBA NF in the treatment of haemophilia A and B with inhibitors. Haemophilia. 2014 Jan;20(1):65–72.
  • Astermark J, Donfield SM, DiMichele DM, et al. A randomized comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA NovoSeven Comparative (FENOC) Study. Blood. 2007 Jan 15;109(2):546–551.

* Important study comparing FEIBA and NovoSeven head to head.

  • Hay CR, DiMichele DM. The principal results of the International Immune Tolerance Study: a randomized dose comparison. Blood. 2012 Feb 9;119(6):1335–1344.

** Well-controlled ITI study that has contributed important knowledge.

  • Kavakli K, Makris M, Zulfikar B, et al. Home treatment of haemarthroses using a single dose regimen of recombinant activated factor VII in patients with haemophilia and inhibitors. A multi-centre, randomised, double-blind, cross-over trial. Thromb Haemost. 2006 Apr;95(4):600–605.
  • Pruthi RK, Mathew P, Valentino LA, et al Haemostatic efficacy and safety of bolus and continuous infusion of recombinant factor VIIa are comparable in haemophilia patients with inhibitors undergoing major surgery. Results from an open-label, randomized, multicenter trial. Thromb Haemost. 2007 Oct;98(4):726–732.
  • Santagostino E, Mancuso ME, Rocino A, et al. A prospective randomized trial of high and standard dosages of recombinant factor VIIa for treatment of hemarthroses in hemophiliacs with inhibitors. J Thromb Haemost. 2006 Feb;4(2):367–371.
  • Shapiro AD, Gilchrist GS, Hoots WK, et al. Prospective, randomised trial of two doses of rFVIIa (NovoSeven) in haemophilia patients with inhibitors undergoing surgery. Thromb Haemost. 1998 Nov;80(5):773–778.
  • Young G, Shafer FE, Rojas P, et al. Single 270 microg kg(−1)-dose rFVIIa vs. standard 90 microg kg(−1)-dose rFVIIa and APCC for home treatment of joint bleeds in haemophilia patients with inhibitors: a randomized comparison. Haemophilia. 2008 Mar;14(2):287–294.
  • Chambost H, Santagostino E, Laffan M, et al. Real-world outcomes with recombinant factor VIIa treatment of acute bleeds in haemophilia patients with inhibitors: results from the international ONE registry. Haemophilia. 2013 Jul;19(4):571–577.
  • Key NS, Aledort LM, Beardsley D, et al. Home treatment of mild to moderate bleeding episodes using recombinant factor VIIa (Novoseven) in haemophiliacs with inhibitors. Thromb Haemost. 1998 Dec;80(6):912–918.
  • Negrier C, Lienhart A, Numerof R, et al. SURgical interventions with FEIBA (SURF): international registry of surgery in haemophilia patients with inhibitory antibodies. Haemophilia. 2013 May;19(3):e143–50.
  • Valentino LA. Assessing the benefits of FEIBA prophylaxis in haemophilia patients with inhibitors. Haemophilia. 2010 Mar;16(2):263–271.
  • Zhou ZY, Hay JW. Efficacy of bypassing agents in patients with hemophilia and inhibitors: a systematic review and meta-analysis. Clin Ther. 2012 Feb;34(2):434–445.
  • Balkan C, Karapinar D, Aydogdu S, et al. Surgery in patients with haemophilia and high responding inhibitors: Izmir experience. Haemophilia. 2010 Nov;16(6):902–909.
  • Barnes C, Rivard GE, Poon MC, et al. Canadian multi-institutional survey of immune tolerance therapy (ITT) – experience with the use of recombinant factor VIII for ITT. Haemophilia. 2006 Jan;12(1):1–6.
  • Callaghan MU, Rajpurkar M, Chitlur M, et al. Immune tolerance induction in 31 children with haemophilia A: is ITI less successful in African Americans? Haemophilia. 2011 May;17(3):483–489.
  • Damiano ML, Hutter JJ Jr. Immune tolerance for haemophilia patients with inhibitors: analysis of the western United States experience. The Tri-Regional Nursing Group. Haemophilia. 2000 Sep;6(5):526–532.
  • Dimichele D, Negrier C. A retrospective postlicensure survey of FEIBA efficacy and safety. Haemophilia. 2006 Jul;12(4):352–362.
  • DiMichele DM, Kroner BL. The North American Immune Tolerance Registry: practices, outcomes, outcome predictors. Thromb Haemost. 2002 Jan;87(1):52–57.
  • Haya S, Lopez MF, Aznar JA, et al. Immune tolerance treatment in haemophilia patients with inhibitors: the Spanish Registry. Haemophilia. 2001 Mar;7(2):154–159.
  • Kurth M, Puetz J, Kouides P, et al. The use of a single von Willebrand factor-containing, plasma-derived FVIII product in hemophilia A immune tolerance induction: the US experience. J Thromb Haemost. 2011 Nov;9(11):2229–2234.
  • Kurth MA, Dimichele D, Sexauer C, et al. Immune tolerance therapy utilizing factor VIII/von Willebrand factor concentrate in haemophilia A patients with high titre factor VIII inhibitors. Haemophilia. 2008 Jan;14(1):50–55.
  • Lin PC, Liao YM, Tsai SP, et.al. Immune tolerance induction therapy for patients with hemophilia A and FVIII inhibitors particularly using low-dose regimens. Pediatr Blood Cancer. 2011 Dec 1;57(6):1029–1033.
  • Mariani G, Kroner B. Immune tolerance in hemophilia with factor VIII inhibitors: predictors of success. Haematologica. 2001 Nov;86(11):1186–1193.
  • Nakar C, Cooper DL, DiMichele D. Recombinant activated factor VII safety and efficacy in the treatment of cranial haemorrhage in patients with congenital haemophilia with inhibitors: an analysis of the Hemophilia and Thrombosis Research Society Registry (2004-2008). Haemophilia. 2010 Jul 1;16(4):625–631.
  • Oldenburg J, Jimenez-Yuste V, Peiro-Jordan R, et al. Primary and rescue immune tolerance induction in children and adults: a multicentre international study with a VWF-containing plasma-derived FVIII concentrate. Haemophilia. 2014 Jan;20(1):83–91.
  • Oldenburg J, Schwaab R, Brackmann HH. Induction of immune tolerance in haemophilia A inhibitor patients by the ‘Bonn Protocol’: predictive parameter for therapy duration and outcome. Vox Sanguinis. 1999;77(Suppl 1):49–54.
  • Parameswaran R, Shapiro AD, Gill JC, et al. Dose effect and efficacy of rFVIIa in the treatment of haemophilia patients with inhibitors: analysis from the Hemophilia and Thrombosis Research Society Registry. Haemophilia. 2005 Mar;11(2):100–106.
  • Polyanskaya T, Zorenko V, Karpov E, et al. Experience of recombinant activated factor VII usage during surgery in patients with haemophilia with inhibitors. Haemophilia. 2012 Nov;18(6):997–1002.
  • Quintana-Molina M, Martinez-Bahamonde F, Gonzalez-Garcia E, et.al Surgery in haemophilic patients with inhibitor: 20 years of experience. Haemophilia. 2004 Sep;10(Suppl 2):30–40.
  • Rocino A, Santagostino E, Mancuso ME, et al. Immune tolerance induction with recombinant factor VIII in hemophilia A patients with high responding inhibitors. Haematologica. 2006 Apr;91(4):558–561.
  • Rodriguez-Merchan EC, Jimenez-Yuste V, Gomez-Cardero P, et al. Surgery in haemophilia patients with inhibitors, with special emphasis on orthopaedics: Madrid experience. Haemophilia. 2010 May;16(102):84–88.
  • Rodriguez-Merchan EC, Wiedel JD, Wallny T, et al. Elective orthopaedic surgery for inhibitor patients. Haemophilia. 2003 Sep;9(5):625–631.
  • Ter Avest PC, Fischer K, Gouw SC, et al. Successful low dose immune tolerance induction in severe haemophilia A with inhibitors below 40 Bethesda Units. Haemophilia. 2010 May;16(102):71–79.
  • Unuvar A, Kavakli K, Baytan B, et al. Low-dose immune tolerance induction for paediatric haemophilia patients with factor VIII inhibitors. Haemophilia. 2008 Mar;14(2):315–322.
  • Young G, Auerswald G, Jimenez-Yuste V, et al. PRO-PACT: retrospective observational study on the prophylactic use of recombinant factor VIIa in hemophilia patients with inhibitors. Thromb Res. 2012 Dec;130(6):864–870.
  • Young G, Cooper DL, Gut RZ. Dosing and effectiveness of recombinant activated factor VII (rFVIIA) in congenital haemophilia with inhibitors by bleed type and location: the experience of the Haemophilia and Thrombosis Research Society (HTRS) Registry (2004-2008). Haemophilia. 2012 Nov;18(6):990–996.
  • Zulfikar B, Aydogan G, Salcioglu Z, et.al Efficacy of FEIBA for acute bleeding and surgical haemostasis in haemophilia A patients with inhibitors: a multicentre registry in Turkey. Haemophilia. 2012 May;18(3):383–391.
  • Coppola A, Margaglione M, Santagostino E, et al., et al. Factor VIII gene (F8) mutations as predictors of outcome in immune tolerance induction of hemophilia A patients with high-responding inhibitors. J Thromb Haemost: JTH. 2009 Nov;7(11):1809–1815.
  • Auerswald G, Kurnik K, Aledort LM, et al. The EPIC study: a lesson to learn. Haemophilia. 2015; 21(5):622–628.
  • Mannucci PM, Gringeri A, Peyvandi F, et al. Factor VIII products and inhibitor development: the SIPPET study (survey of inhibitors in plasma-product exposed toddlers). Haemophilia. 2007 Dec;13(Suppl 5):65–68.
  • Gomperts E. Recombinant B domain deleted porcine factor VIII for the treatment of bleeding episodes in adults with acquired hemophilia A. Expert Rev Hematol. 2015 Aug;8(4):427–432.
  • Kruse-Jarres R, St-Louis J, Greist A, et al., et al. Efficacy and safety of OBI-1, an antihaemophilic factor VIII (recombinant), porcine sequence, in subjects with acquired haemophilia A. Haemophilia: Official J World Fed Hemophilia. 2015 Mar;21(2):162–170.

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