Download PDF
Semin Thromb Hemost 2009; 35(8): 723-734
DOI: 10.1055/s-0029-1245105
© Thieme Medical Publishers

The Multifactorial Etiology of Inhibitor Development in Hemophilia: Genetics and Environment

Samantha C. Gouw1 , H. Marÿke van den Berg2 , 3
  • 1Department of Pediatrics, Wilhelmina Children's Hospital, Utrecht, The Netherlands
  • 2Department of Laboratory Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
  • 3Meander Medical Center, Amersfoort, The Netherlands
Further Information

Publication History

Publication Date:
18 February 2010 (online)

    Permissions and Reprints

ABSTRACT

The most important complication in the treatment of hemophilia A patients today is the development of inhibitory antibodies against infused factor VIII (FVIII). Inhibitor development is caused by a complex interplay between both genetic and environmental factors. The risk of developing inhibitors is greatest in previously untreated patients with severe hemophilia A. Several genetic factors, such as a positive family history of inhibitors, ethnicity, FVIII genotype, and certain polymorphisms in immune modulatory genes, are associated with the risk of inhibitor development. Treatment-related factors, such as intensive treatment with FVIII for bleeds or surgery, are associated with a higher inhibitor risk. However, regular prophylaxis seems to have a protective effect on inhibitor development. Knowledge about the risk factors of inhibitor development is a condition for predicting and in the future possibly even preventing the development of inhibitors in patients with severe hemophilia A. This review summarizes the current knowledge on the potential risk factors of inhibitor development. At present, many uncertainties still remain that will require collaborative investigation.

KEYWORDS

Factor VIII inhibitors - risk factors - prophylaxis - genetic polymorphisms - factor VIII mutation - intensive treatment

REFERENCES

  • 1 White II G C, Rosendaal F, Aledort L M, Lusher J M, Rothschild C, Ingerslev J. Factor VIII and Factor IX Subcommittee . 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(3) 560
    Article in Thieme ConnectPubMedGoogle Scholar
  • 2 Plug I, Peters M, Mauser-Bunschoten E P et al.. Social participation of patients with hemophilia in the Netherlands.  Blood. 2008;  111(4) 1811-1815
    CrossrefPubMedGoogle Scholar
  • 3 DiMichele D. Inhibitor development in haemophilia B: an orphan disease in need of attention.  Br J Haematol. 2007;  138(3) 305-315
    CrossrefPubMedGoogle Scholar
  • 4 Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review.  Haemophilia. 2003;  9(4) 418-435
    CrossrefPubMedGoogle Scholar
  • 5 Kempton C L, Soucie J M, Abshire T C. Incidence of inhibitors in a cohort of 838 males with hemophilia A previously treated with factor VIII concentrates.  J Thromb Haemost. 2006;  4(12) 2576-2581
    CrossrefPubMedGoogle Scholar
  • 6 Darby S C, Keeling D M, Spooner R J UK Haemophilia Centre Doctors' Organisation et al. 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(7) 1047-1054
    CrossrefPubMedGoogle Scholar
  • 7 Morfini M, Haya S, Tagariello G et al.. European study on orthopaedic status of haemophilia patients with inhibitors.  Haemophilia. 2007;  13(5) 606-612
    CrossrefPubMedGoogle Scholar
  • 8 Gringeri A, Mantovani L G, Scalone L, Mannucci P M. COCIS Study Group . Cost of care and quality of life for patients with hemophilia complicated by inhibitors: the COCIS Study Group.  Blood. 2003;  102(7) 2358-2363
    CrossrefPubMedGoogle Scholar
  • 9 Wight J, Paisley S, Knight C. Immune tolerance induction in patients with haemophilia A with inhibitors: a systematic review.  Haemophilia. 2003;  9(4) 436-463
    CrossrefPubMedGoogle Scholar
  • 10 Donfield S M, Lynn H S, Lail A E, Hoots W K, Berntorp E, Gomperts E D. for the Hemophilia Growth and Development Study Group . Delays in maturation among adolescents with hemophilia and a history of inhibitors.  Blood. 2007;  110(10) 3656-3661
    CrossrefPubMedGoogle Scholar
  • 11 Kershaw G, Jayakodi D, Dunkley S. Laboratory identification of factor inhibitors: the perspective of a large tertiary hemophilia centre.  Semin Thromb Hemost. 2009;  35(8) 760-768
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Verbruggen B, Novakova I, Wessels H, Boezeman J, van den Berg M, Mauser-Bunschoten E. The Nijmegen modification of the Bethesda assay for factor VIII:C inhibitors: improved specificity and reliability.  Thromb Haemost. 1995;  73(2) 247-251
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Peerschke E I, Castellone D D, Ledford-Kraemer M, Van Cott E M, Meijer P. NASCOLA Proficiency Testing Committee . Laboratory assessment of factor VIII inhibitor titer: the North American Specialized Coagulation Laboratory Association experience.  Am J Clin Pathol. 2009;  131(4) 552-558
    CrossrefPubMedGoogle Scholar
  • 14 Schwaab R, Brackmann H H, Meyer C et al.. Haemophilia A: mutation type determines risk of inhibitor formation.  Thromb Haemost. 1995;  74(6) 1402-1406
    PubMedGoogle Scholar
  • 15 Goodeve A C, Williams I, Bray G L, Peake I R. Recombinate PUP Study Group . Relationship between factor VIII mutation type and inhibitor development in a cohort of previously untreated patients treated with recombinant factor VIII (Recombinate).  Thromb Haemost. 2000;  83(6) 844-848
    PubMedGoogle Scholar
  • 16 Astermark J, Oldenburg J, Escobar M, White II G C, Berntorp E. Malmö International Brother Study group . The Malmö International Brother Study (MIBS). Genetic defects and inhibitor development in siblings with severe hemophilia A.  Haematologica. 2005;  90(7) 924-931
    PubMedGoogle Scholar
  • 17 Vinciguerra C, Zawadzki C, Dargaud Y et al.. Characterisation of 96 mutations in 128 unrelated severe haemophilia A patients from France. Description of 62 novel mutations.  Thromb Haemost. 2006;  95(4) 593-599
    PubMedGoogle Scholar
  • 18 Tuddenham E G, McVey J H. The genetic basis of inhibitor development in haemophilia A.  Haemophilia. 1998;  4(4) 543-545
    CrossrefPubMedGoogle Scholar
  • 19 Oldenburg J, Brackmann H H, Schwaab R. Risk factors for inhibitor development in hemophilia A.  Haematologica. 2000;  85(Suppl 10) 7-13 discussion 13-14
    PubMedGoogle Scholar
  • 20 Goodeve A C, Peake I R. The molecular basis of hemophilia A: genotype-phenotype relationships and inhibitor development.  Semin Thromb Hemost. 2003;  29(1) 23-30
    PubMedGoogle Scholar
  • 21 Oldenburg J, Schröder J, Schmitt C, Brackmann H H, Schwaab R. Small deletion/insertion mutations within poly-A runs of the factor VIII gene mitigate the severe haemophilia A phenotype.  Thromb Haemost. 1998;  79(2) 452-453
    PubMedGoogle Scholar
  • 22 Frommel D, Allain J P. Genetic predisposition to develop factor VIII antibody in classic hemophilia.  Clin Immunol Immunopathol. 1977;  8(1) 34-38
    CrossrefPubMedGoogle Scholar
  • 23 Shapiro S S. Genetic predisposition to inhibitor formation.  Prog Clin Biol Res. 1984;  150 45-55
    PubMedGoogle Scholar
  • 24 Astermark J, Berntorp E, White G C, Kroner B L. MIBS Study Group . The Malmö International Brother Study (MIBS): further support for genetic predisposition to inhibitor development in hemophilia patients.  Haemophilia. 2001;  7(3) 267-272
    CrossrefPubMedGoogle Scholar
  • 25 Aledort L M, Dimichele D M. Inhibitors occur more frequently in African-American and Latino haemophiliacs.  Haemophilia. 1998;  4(1) 68
    CrossrefPubMedGoogle Scholar
  • 26 Scharrer I, Bray G L, Neutzling O. Incidence of inhibitors in haemophilia A patients—a review of recent studies of recombinant and plasma-derived factor VIII concentrates.  Haemophilia. 1999;  5(3) 145-154
    CrossrefPubMedGoogle Scholar
  • 27 Viel K R, Ameri A, Abshire T C et al.. Inhibitors of factor VIII in black patients with hemophilia.  N Engl J Med. 2009;  360(16) 1618-1627
    CrossrefPubMedGoogle Scholar
  • 28 Hay C R, Ollier W, Pepper L UKHCDO Inhibitor Working Party et al. HLA class II profile: a weak determinant of factor VIII inhibitor development in severe haemophilia A.  Thromb Haemost. 1997;  77(2) 234-237
    PubMedGoogle Scholar
  • 29 Oldenburg J, Picard J K, Schwaab R, Brackmann H H, Tuddenham E G, Simpson E. HLA genotype of patients with severe haemophilia A due to intron 22 inversion with and without inhibitors of factor VIII.  Thromb Haemost. 1997;  77(2) 238-242
    PubMedGoogle Scholar
  • 30 Frommel D, Allain J P, Saint-Paul E et al.. HLA antigens and factor VIII antibody in classic hemophilia. European study group of factor VIII antibody.  Thromb Haemost. 1981;  46(4) 687-689
    PubMedGoogle Scholar
  • 31 Mayr W R, Lechner K, Niessner H, Pabinger-Fasching I. HLA-DR and factor VIII antibodies in hemophilia A.  Thromb Haemost. 1984;  51(2) 293
    PubMedGoogle Scholar
  • 32 Lippert L E, Fisher L M, Schook L B. Relationship of major histocompatibility complex class II genes to inhibitor antibody formation in hemophilia A.  Thromb Haemost. 1990;  64(4) 564-568
    PubMedGoogle Scholar
  • 33 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;  108(12) 3739-3745
    CrossrefPubMedGoogle Scholar
  • 34 Shapiro S S. Markers for the factor VIII antibody response in hemophilia A.  Scand J Haematol Suppl. 1984;  40 181-185
    PubMedGoogle Scholar
  • 35 Alper C A, Raum D D, Awdeh Z L, Shapiro S S, Yunis E J. Major histocompatibility complex (MHC)-linked complement alleles as markers for the development of anti-factor VIII in hemophiliacs.  Prog Clin Biol Res. 1984;  150 141-142
    PubMedGoogle Scholar
  • 36 Simonney N, De Bosch N, Argueyo A, Garcia E, Layrisse Z. HLA antigens in hemophiliacs A with or without factor VIII antibodies in a Venezuelan mestizo population.  Tissue Antigens. 1985;  25(4) 216-219
    CrossrefPubMedGoogle Scholar
  • 37 Papasteriades C, Varla M, Economidou J et al.. High frequency of HLA-DR5 in Greek patients with haemophilia A and haemophilia B.  Tissue Antigens. 1986;  28(2) 84-87
    CrossrefPubMedGoogle Scholar
  • 38 Aly A M, Aledort L M, Lee T D, Hoyer L W. Histocompatibility antigen patterns in haemophilic patients with factor VIII antibodies.  Br J Haematol. 1990;  76(2) 238-241
    CrossrefPubMedGoogle Scholar
  • 39 Ohta H, Takahashi I, Kojima T et al.. Histocompatibility antigens and alleles in Japanese haemophilia A patients with or without factor VIII antibodies.  Tissue Antigens. 1999;  54(1) 91-97
    CrossrefPubMedGoogle Scholar
  • 40 Wieland I, Wermes C, Eifrig B et al.. Inhibitor-Immunology-Study. Different HLA-types seem to be involved in the inhibitor development in haemophilia A.  Hamostaseologie. 2008;  28(suppl 1) S26-S28
    PubMedGoogle Scholar
  • 41 Ragni M V, Ojeifo O, Feng J et al.. Risk factors for inhibitor formation in haemophilia: a prevalent case-control study.  Haemophilia. 2009;  15(5) 1074-1082
    CrossrefPubMedGoogle Scholar
  • 42 Astermark J, Oldenburg J, Pavlova A, Berntorp E, Lefvert A K. MIBS Study Group . Polymorphisms in the IL10 but not in the IL1beta and IL4 genes are associated with inhibitor development in patients with hemophilia A.  Blood. 2006;  107(8) 3167-3172
    CrossrefPubMedGoogle Scholar
  • 43 Astermark J, Wang X, Oldenburg J, Berntorp E, Lefvert A K. MIBS Study Group . Polymorphisms in the CTLA-4 gene and inhibitor development in patients with severe hemophilia A.  J Thromb Haemost. 2007;  5(2) 263-265
    CrossrefPubMedGoogle Scholar
  • 44 Berntorp E, Astermark J, Donfield S M Hemophilia Inhibitor Genetics Study et al. Haemophilia Inhibitor Genetics Study—evaluation of a model for studies of complex diseases using linkage and association methods.  Haemophilia. 2005;  11(4) 427-429
    CrossrefPubMedGoogle Scholar
  • 45 Lorenzo J I, López A, Altisent C, Aznar J A. Incidence of factor VIII inhibitors in severe haemophilia: the importance of patient age.  Br J Haematol. 2001;  113(3) 600-603
    CrossrefPubMedGoogle Scholar
  • 46 van der Bom J G, Mauser-Bunschoten E P, Fischer K, van den Berg H M. Age at first treatment and immune tolerance to factor VIII in severe hemophilia.  Thromb Haemost. 2003;  89(3) 475-479
    PubMedGoogle Scholar
  • 47 Chalmers E A, Brown S A, Keeling D Paediatric Working Party of UKHCDO et al. Early factor VIII exposure and subsequent inhibitor development in children with severe haemophilia A.  Haemophilia. 2007;  13(2) 149-155
    CrossrefPubMedGoogle Scholar
  • 48 Santagostino E, Mancuso M E, Rocino A et al.. Environmental risk factors for inhibitor development in children with haemophilia A: a case-control study.  Br J Haematol. 2005;  130(3) 422-427
    CrossrefPubMedGoogle Scholar
  • 49 Gouw S C, van den Berg H M, le Cessie S, van der Bom J G. Treatment characteristics and the risk of inhibitor development: a multicenter cohort study among previously untreated patients with severe hemophilia A.  J Thromb Haemost. 2007;  5(7) 1383-1390
    CrossrefPubMedGoogle Scholar
  • 50 Gouw S C, van der Bom J G, Marijke van den Berg H. Treatment-related risk factors of inhibitor development in previously untreated patients with hemophilia A: the CANAL cohort study.  Blood. 2007;  109(11) 4648-4654
    CrossrefPubMedGoogle Scholar
  • 51 Matzinger P. Tolerance, danger, and the extended family.  Annu Rev Immunol. 1994;  12 991-1045
    CrossrefPubMedGoogle Scholar
  • 52 Morado M, Villar A, Jiménez Yuste V, Quintana M, Hernandez Navarro F. Prophylactic treatment effects on inhibitor risk: experience in one centre.  Haemophilia. 2005;  11(2) 79-83
    CrossrefPubMedGoogle Scholar
  • 53 Hawiger D, Inaba K, Dorsett Y et al.. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo.  J Exp Med. 2001;  194(6) 769-779
    CrossrefPubMedGoogle Scholar
  • 54 Rosendaal F R, Nieuwenhuis H K, van den Berg H M Dutch Hemophilia Study Group et al. A sudden increase in factor VIII inhibitor development in multitransfused hemophilia A patients in The Netherlands.  Blood. 1993;  81(8) 2180-2186
    PubMedGoogle Scholar
  • 55 Peerlinck K, Arnout J, Gilles J G, Saint-Remy J M, Vermylen J. A higher than expected incidence of factor VIII inhibitors in multitransfused haemophilia A patients treated with an intermediate purity pasteurized factor VIII concentrate.  Thromb Haemost. 1993;  69(2) 115-118
    PubMedGoogle Scholar
  • 56 Mauser-Bunschoten E P, Rosendaal F R, Nieuwenhuis H K, Roosendaal G, Briët E, van den Berg H M. Clinical course of factor VIII inhibitors developed after exposure to a pasteurised Dutch concentrate compared to classic inhibitors in hemophilia A.  Thromb Haemost. 1994;  71(6) 703-706
    PubMedGoogle Scholar
  • 57 Briët E, Rosendaal F R. Inhibitors in hemophilia A: are some products safer?.  Semin Hematol. 1994;  31(2, suppl 4) 11-15
    PubMedGoogle Scholar
  • 58 Scharrer I, Ehrlich H J. Reported inhibitor incidence in FVIII PUP studies: comparing apples with oranges?.  Haemophilia. 2004;  10(2) 197-198
    CrossrefPubMedGoogle Scholar
  • 59 Ettingshausen C E, Kreuz W. Recombinant vs. plasma-derived products, especially those with intact VWF, regarding inhibitor development.  Haemophilia. 2006;  12(suppl 6) 102-106
    PubMedGoogle Scholar
  • 60 Kreuz W, Ettingshausen C E, Auerswald G, et al.. Epidemiology of inhibitors and current treatment strategies.  Haematologica. 2003;  88(6) EREP04
    PubMedGoogle Scholar
  • 61 Goudemand J, Rothschild C, Demiguel V FVIII-LFB and Recombinant FVIII study groups 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;  107(1) 46-51
    CrossrefPubMedGoogle Scholar
  • 62 Gouw S C, van der Bom J G, Auerswald G, Ettinghausen C E, Tedgård U, van den Berg H M. 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;  109(11) 4693-4697
    CrossrefPubMedGoogle Scholar
  • 63 Suzuki T, Arai M, Amano K, Kagawa K, Fukutake K. Factor VIII inhibitor antibodies with C2 domain specificity are less inhibitory to factor VIII complexed with von Willebrand factor.  Thromb Haemost. 1996;  76(5) 749-754
    PubMedGoogle Scholar
  • 64 Jacquemin M G, Saint-Remy J M. Factor VIII immunogenicity.  Haemophilia. 1998;  4(4) 552-557
    CrossrefPubMedGoogle Scholar
  • 65 Dasgupta S, Repessé Y, Bayry J et al.. VWF protects FVIII from endocytosis by dendritic cells and subsequent presentation to immune effectors.  Blood. 2007;  109(2) 610-612
    CrossrefPubMedGoogle Scholar
  • 66 Wadhwa M, Dilger P, Tubbs J, Mire-Sluis A, Barrowcliffe T, Thorpe R. Identification of transforming growth factor-beta as a contaminant in factor VIII concentrates: a possible link with immunosuppressive effects in hemophiliacs.  Blood. 1994;  84(6) 2021-2030
    PubMedGoogle Scholar
  • 67 Hodge G, Han P. Effect of factor VIII concentrate on antigen-presenting cell (APC)/T-cell interactions in vitro: relevance to inhibitor formation and tolerance induction.  Br J Haematol. 2000;  109(1) 195-200
    CrossrefPubMedGoogle Scholar
  • 68 Hodge G, Flower R, Han P. Effect of factor VIII concentrate on leucocyte cytokine production: characterization of TGF-beta as an immunomodulatory component in plasma-derived factor VIII concentrate.  Br J Haematol. 1999;  106(3) 784-791
    CrossrefPubMedGoogle Scholar
  • 69 Peerlinck K, Arnout J, Di Giambattista M et al.. Factor VIII inhibitors in previously treated haemophilia A patients with a double virus-inactivated plasma derived factor VIII concentrate.  Thromb Haemost. 1997;  77(1) 80-86
    PubMedGoogle Scholar
  • 70 Raut S, Weller L, Barrowcliffe T W. Phospholipid binding of factor VIII in different therapeutic concentrates.  Br J Haematol. 1999;  107(2) 323-329
    CrossrefPubMedGoogle Scholar
  • 71 Rosendaal F R. Factor VIII inhibitors on a DS-treated and pasteurized concentrate associated with specific batches and batch characteristics.  Thromb Haemost. 1997;  77 590 , Abstract OC-2407
    PubMedGoogle Scholar
  • 72 Mannucci P M, Gringeri A, Peyvandi F, Santagostino E. Factor VIII products and inhibitor development: the SIPPET study (survey of inhibitors in plasma-product exposed toddlers).  Haemophilia. 2007;  13(suppl 5) 65-68
    CrossrefPubMedGoogle Scholar
  • 73 Baglin T, Beacham E. Is a change of factor VIII product a risk factor for the development of a factor VIII inhibitor?.  Thromb Haemost. 1998;  80(6) 1036-1037
    PubMedGoogle Scholar
  • 74 von Auer C, Oldenburg J, von Depka M et al.. Inhibitor development in patients with hemophilia A after continuous infusion of FVIII concentrates.  Ann N Y Acad Sci. 2005;  1051 498-505
    CrossrefPubMedGoogle Scholar
  • 75 Yee T T, Lee C A. Oral immune tolerance induction to factor VIII via breast milk, a possibility?.  Haemophilia. 2000;  6(5) 591
    CrossrefPubMedGoogle Scholar
  • 76 Jansen I M, Fischer K, Van Der Bom J G, Van Den Berg H M. No protective effect of breastfeeding on inhibitor formation in severe hemophilia.  Pediatr Hematol Oncol. 2005;  22(7) 575-580
    CrossrefPubMedGoogle Scholar
  • 77 Knobe K E, Tengborn L I, Petrini P, Ljung R C. Breastfeeding does not influence the development of inhibitors in haemophilia.  Haemophilia. 2002;  8(5) 657-659
    CrossrefPubMedGoogle Scholar
  • 78 McMillan C W, Shapiro S S, Whitehurst D, Hoyer L W, Rao A V, Lazerson J. The natural history of factor VIII:C inhibitors in patients with hemophilia A: a national cooperative study. II. Observations on the initial development of factor VIII:C inhibitors.  Blood. 1988;  71(2) 344-348
    PubMedGoogle Scholar
  • 79 Maclean P, Young D, Chalmers E. A case control study to examine treatment related factors in the development of inhibitors in haemophilia A.  Haemophilia. 2008;  14(Suppl 2) 44
    CrossrefPubMedGoogle Scholar
  • 80 Oldenburg J, Schwaab R, Brackmann H H. Induction of immune tolerance in haemophilia A inhibitor patients by the ‘Bonn Protocol’: predictive parameter for therapy duration and outcome.  Vox Sang. 1999;  77(Suppl 1) 49-54
    CrossrefPubMedGoogle Scholar
  • 81 Dimichele D M, Hay C R. The international immune tolerance study: a multicenter prospective randomized trial in progress.  J Thromb Haemost. 2006;  4(10) 2271-2273
    CrossrefPubMedGoogle Scholar
  • 82 Peng A, Gaitonde P, Kosloski M P et al.. Effect of route of administration of human recombinant factor VIII on its immunogenicity in hemophilia A mice.  J Pharm Sci. 2009;  98(12) 4480-4484
    CrossrefPubMedGoogle Scholar
  • 83 Ter Avest P C, Fischer K, Mancuso M E et al.. Risk stratification for inhibitor development at first treatment for severe hemophilia A: a tool for clinical practice.  J Thromb Haemost. 2008;  6(12) 2048-2054
    CrossrefPubMedGoogle Scholar
  • 84 Kurnik K, Thomas A E. European Paediatric Network for Haemophilia Management (PedNet) . Meeting report: ninth and tenth workshops of the European Paediatric Network for Haemophilia Management (PedNet).  Haemophilia. 2007;  13(5) 658-662
    CrossrefPubMedGoogle Scholar
  • 85 Reipert B M, Sasgary M, Ahmad R U, Auer W, Turecek P L, Schwarz H P. Blockade of CD40/CD40 ligand interactions prevents induction of factor VIII inhibitors in hemophilic mice but does not induce lasting immune tolerance.  Thromb Haemost. 2001;  86(6) 1345-1352
    PubMedGoogle Scholar
  • 86 Qian J, Collins M, Sharpe A H, Hoyer L W. Prevention and treatment of factor VIII inhibitors in murine hemophilia A.  Blood. 2000;  95(4) 1324-1329
    PubMedGoogle Scholar
  • 87 Peng B, Ye P, Blazar B R et al.. Transient blockade of the inducible costimulator pathway generates long-term tolerance to factor VIII after nonviral gene transfer into hemophilia A mice.  Blood. 2008;  112(5) 1662-1672
    CrossrefPubMedGoogle Scholar
  • 88 Qadura M, Othman M, Waters B et al.. Reduction of the immune response to factor VIII mediated through tolerogenic factor VIII presentation by immature dendritic cells.  J Thromb Haemost. 2008;  6(12) 2095-2104
    CrossrefPubMedGoogle Scholar
  • 89 Waters B, Qadura M, Burnett E et al.. Anti-CD3 prevents factor VIII inhibitor development in hemophilia A mice by a regulatory CD4 + CD25 + -dependent mechanism and by shifting cytokine production to favor a Th1 response.  Blood. 2009;  113(1) 193-203
    CrossrefPubMedGoogle Scholar
  • 90 Lei T C, Scott D W. Induction of tolerance to factor VIII inhibitors by gene therapy with immunodominant A2 and C2 domains presented by B cells as Ig fusion proteins.  Blood. 2005;  105(12) 4865-4870
    CrossrefPubMedGoogle Scholar
  • 91 Schellekens H. Immunogenicity of therapeutic proteins: clinical implications and future prospects.  Clin Ther. 2002;  24(11) 1720-1740, discussion 1719
    CrossrefPubMedGoogle Scholar
  • 92 Dasgupta S, Navarrete A M, Bayry J et al.. A role for exposed mannosylations in presentation of human therapeutic self-proteins to CD4 + T lymphocytes.  Proc Natl Acad Sci U S A. 2007;  104(21) 8965-8970
    CrossrefPubMedGoogle Scholar
  • 93 van den Berg H M, Chalmers E A. Clinical prediction models for inhibitor development in severe hemophilia A.  J Thromb Haemost. 2009;  7(Suppl 1) 98-102
    CrossrefPubMedGoogle Scholar
  • 94 Hay C R, Ludlam C A, Colvin B T et al.. Factor VIII inhibitors in mild and moderate-severity haemophilia A. UK Haemophilia Centre Directors Organisation.  Thromb Haemost. 1998;  79(4) 762-766
    PubMedGoogle Scholar
  • 95 Kemball-Cook G, Tuddenham E G, Wacey A I. The factor VIII Structure and Mutation Resource Site: HAMSTeRS version 4.  Nucleic Acids Res. 1998;  26(1) 216-219
    CrossrefPubMedGoogle Scholar
  • 96 D'Oiron R, Pipe S W, Jacquemin M. Mild/moderate haemophilia A: new insights into molecular mechanisms and inhibitor development.  Haemophilia. 2008;  14(Suppl 3) 138-146
    CrossrefPubMedGoogle Scholar
  • 97 Sharathkumar A, Lillicrap D, Blanchette V S et al.. Intensive exposure to factor VIII is a risk factor for inhibitor development in mild hemophilia A.  J Thromb Haemost. 2003;  1(6) 1228-1236
    CrossrefPubMedGoogle Scholar
  • 98 Eckhardt C L, Menke L A, van Ommen C H 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;  7(6) 930-937
    CrossrefPubMedGoogle Scholar
  • 99 Belvini D, Salviato R, Radossi P AICE HB Study Group et al. Molecular genotyping of the Italian cohort of patients with hemophilia B.  Haematologica. 2005;  90(5) 635-642
    PubMedGoogle Scholar
  • 100 Chitlur M, Warrier I, Rajpurkar M, Lusher J M. Inhibitors in factor IX deficiency a report of the ISTH-SSC international FIX inhibitor registry (1997–2006).  Haemophilia. 2009;  15(5) 1027-1031
    CrossrefPubMedGoogle Scholar
  • 101 Thorland E C, Drost J B, Lusher J M et al.. Anaphylactic response to factor IX replacement therapy in haemophilia B patients: complete gene deletions confer the highest risk.  Haemophilia. 1999;  5(2) 101-105
    CrossrefPubMedGoogle Scholar
  • 102 Warrier I, Ewenstein B M, Koerper M A et al.. Factor IX inhibitors and anaphylaxis in hemophilia B.  J Pediatr Hematol Oncol. 1997;  19(1) 23-27
    CrossrefPubMedGoogle Scholar

Samantha C GouwM.D. 

Department of Pediatrics, University Medical Center Utrecht

PO Box 85090, 3508 AB Utrecht, The Netherlands

Email: s.c.gouw@umcutrecht.nl

      >