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Semin Thromb Hemost 2018; 44(06): 509-516
DOI: 10.1055/s-0038-1660816
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Genetic Risk Factors and Inhibitor Development in Hemophilia: What Is Known and Searching for the Unknown

Maurizio Margaglione
1   Medical Genetics, Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
,
Mariano Intrieri
2   Department of Medicine and Health Sciences “V. Tiberio,” University of Molise, Campobasso, Italy
› Author Affiliations
Further Information

Publication History

Publication Date:
25 June 2018 (online)

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Abstract

Over the past few decades, important knowledge on why inhibitors develop and better information about significant risk factors have become available. A series of both genetic and nongenetic factors are recognized and clinical score systems were proposed to quantify the risk for each patient. In addition, modulation of the immunological response was acknowledged to play a pivotal role in the occurrence of inhibitors. However, with the exception of mutation testing in severe hemophilia B patients, no single risk factor or clinical score is currently utilized in clinical practice. “Omics” technologies are large-scale hypothesis-generating approaches, which provide the tools to study issues contributing to a complex and multifactorial phenomenon, such as inhibitor development. Newer cutting edge technologies may enable a more accurate estimation of the personal risk profile and provide a reliable tool to accurately measure the risk periodically, thereby enabling strategies to foresee and prevent inhibitor formation.

Keywords

hemophilia - genetics - inhibitors - variants - genomics
 

  • References

  • 1 Remor E, Young NL, Von Mackensen S, Lopatina EG. Disease-specific quality-of-life measurement tools for haemophilia patients. Haemophilia 2004; 10 (Suppl. 04) 30-34
    PubMedGoogle Scholar
  • 2 Dimichele D. The North American Immune Tolerance Registry: contributions to the thirty-year experience with immune tolerance therapy. Haemophilia 2009; 15 (01) 320-328
    CrossrefPubMedGoogle Scholar
  • 3 Skinner MW. WFH: closing the global gap--achieving optimal care. Haemophilia 2012; 18 (Suppl. 04) 1-12
    PubMedGoogle Scholar
  • 4 Bowen DJ. Haemophilia A and haemophilia B: molecular insights. Mol Pathol 2002; 55 (02) 127-144
    CrossrefPubMedGoogle Scholar
  • 5 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; 119 (12) 2922-2934
    CrossrefPubMedGoogle Scholar
  • 6 Key NS. Inhibitors in congenital coagulation disorders. Br J Haematol 2004; 127 (04) 379-391
    CrossrefPubMedGoogle Scholar
  • 7 Oldenburg J, Pavlova A. Genetic risk factors for inhibitors to factors VIII and IX. Haemophilia 2006; 12 (Suppl. 06) 15-22
    CrossrefPubMedGoogle Scholar
  • 8 Eckhardt CL, van Velzen AS, Peters M. , et al; INSIGHT Study Group. Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A. Blood 2013; 122 (11) 1954-1962
    CrossrefPubMedGoogle Scholar
  • 9 Margaglione M, Castaman G, Morfini M. , et al; AICE-Genetics Study Group. The Italian AICE-Genetics hemophilia A database: results and correlation with clinical phenotype. Haematologica 2008; 93 (05) 722-728
    CrossrefPubMedGoogle Scholar
  • 10 Chitlur M, Warrier I, Rajpurkar M, Lusher JM. Inhibitors in factor IX deficiency a report of the ISTH-SSC international FIX inhibitor registry (1997-2006). Haemophilia 2009; 15 (05) 1027-1031
    CrossrefPubMedGoogle Scholar
  • 11 Warrier I, Lusher JM. Development of anaphylactic shock in haemophilia B patients with inhibitors. Blood Coagul Fibrinolysis 1998; 9 (Suppl. 01) S125-S128
    PubMedGoogle Scholar
  • 12 Rallapalli PM, Kemball-Cook G, Tuddenham EG, Gomez K, Perkins SJ. An interactive mutation database for human coagulation factor IX provides novel insights into the phenotypes and genetics of hemophilia B. J Thromb Haemost 2013; 11 (07) 1329-1340
    CrossrefPubMedGoogle Scholar
  • 13 Oldenburg J, Schröder J, Brackmann HH, Müller-Reible C, Schwaab R, Tuddenham E. Environmental and genetic factors influencing inhibitor development. Semin Hematol 2004; 41 (01) (Suppl. 01) 82-88
    CrossrefPubMedGoogle Scholar
  • 14 Belvini D, Salviato R, Radossi P. , et al; AICE HB Study Group. Molecular genotyping of the Italian cohort of patients with hemophilia B. Haematologica 2005; 90 (05) 635-642
    PubMedGoogle Scholar
  • 15 Saini S, Hamasaki-Katagiri N, Pandey GS. , et al. Genetic determinants of immunogenicity to factor IX during the treatment of haemophilia B. Haemophilia 2015; 21 (02) 210-218
    CrossrefPubMedGoogle Scholar
  • 16 Rocino A, Coppola A, Franchini M. , et al; Italian Association of Haemophilia Centres (AICE) Working Party. Principles of treatment and update of recommendations for the management of haemophilia and congenital bleeding disorders in Italy. Blood Transfus 2014; 12 (04) 575-598
    PubMedGoogle Scholar
  • 17 DiMichele D. Inhibitor development in haemophilia B: an orphan disease in need of attention. Br J Haematol 2007; 138 (03) 305-315
    CrossrefPubMedGoogle Scholar
  • 18 Franchini M, Santoro C, Coppola A. Inhibitor incidence in previously untreated patients with severe haemophilia B: a systematic literature review. Thromb Haemost 2016; 116 (01) 201-203
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Gill JC. The role of genetics in inhibitor formation. Thromb Haemost 1999; 82 (02) 500-504
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Astermark J, Berntorp E, White II GC, Kroner BL. ; MIBS Study Group. The Malmö International Brother Study (MIBS): further support for genetic predisposition to inhibitor development in hemophilia patients. Haemophilia 2001; 7 (03) 267-272
    CrossrefPubMedGoogle Scholar
  • 21 Astermark J, Oldenburg J, Escobar M, White II GC, Berntorp E. ; Malmö International Brother Study study group. The Malmö International Brother Study (MIBS). Genetic defects and inhibitor development in siblings with severe hemophilia A. Haematologica 2005; 90 (07) 924-931
    PubMedGoogle Scholar
  • 22 Klintman J, Hillarp A, Donfield S, Berntorp E, Astermark J. Antibody formation and specificity in Bethesda-negative brother pairs with haemophilia A. Haemophilia 2013; 19 (01) 106-112
    CrossrefPubMedGoogle Scholar
  • 23 Aledort LM, Dimichele DM. Inhibitors occur more frequently in African-American and Latino haemophiliacs. Haemophilia 1998; 4 (01) 68
    CrossrefPubMedGoogle Scholar
  • 24 Scharrer I, Bray GL, 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 (03) 145-154
    CrossrefPubMedGoogle Scholar
  • 25 Ragni MV, Ojeifo O, Feng J. , et al; Hemophilia Inhibitor Study. Risk factors for inhibitor formation in haemophilia: a prevalent case-control study. Haemophilia 2009; 15 (05) 1074-1082
    CrossrefPubMedGoogle Scholar
  • 26 Carpenter SL, Michael Soucie J, Sterner S, Presley R. ; Hemophilia Treatment Center Network (HTCN) Investigators. Increased prevalence of inhibitors in Hispanic patients with severe haemophilia A enrolled in the Universal Data Collection database. Haemophilia 2012; 18 (03) e260-e265
    CrossrefPubMedGoogle Scholar
  • 27 Miller CH, Benson J, Ellingsen D. , et al; Hemophilia Inhibitor Research Study Investigators. F8 and F9 mutations in US haemophilia patients: correlation with history of inhibitor and race/ethnicity. Haemophilia 2012; 18 (03) 375-382
    CrossrefPubMedGoogle Scholar
  • 28 Viel KR, Ameri A, Abshire TC. , et al. Inhibitors of factor VIII in black patients with hemophilia. N Engl J Med 2009; 360 (16) 1618-1627
    CrossrefPubMedGoogle Scholar
  • 29 Schwarz J, Astermark J, Menius ED. , et al; Hemophilia Inhibitor Genetics Study Combined Cohort. F8 haplotype and inhibitor risk: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort. Haemophilia 2013; 19 (01) 113-118
    CrossrefPubMedGoogle Scholar
  • 30 Astermark J, Oldenburg J, Pavlova A, Berntorp E, Lefvert AK. ; 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 (08) 3167-3172
    CrossrefPubMedGoogle Scholar
  • 31 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
  • 32 Astermark J, Wang X, Oldenburg J, Berntorp E, Lefvert AK. ; MIBS Study Group. Polymorphisms in the CTLA-4 gene and inhibitor development in patients with severe hemophilia A. J Thromb Haemost 2007; 5 (02) 263-265
    CrossrefPubMedGoogle Scholar
  • 33 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; 7 (12) 2006-2015
    CrossrefPubMedGoogle Scholar
  • 34 Lozier JN, Rosenberg PS, Goedert JJ, Menashe I. A case-control study reveals immunoregulatory gene haplotypes that influence inhibitor risk in severe haemophilia A. Haemophilia 2011; 17 (04) 641-649
    CrossrefPubMedGoogle Scholar
  • 35 Astermark J, Donfield SM, Gomperts ED. , et al; Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort. The polygenic nature of inhibitors in hemophilia A: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort. Blood 2013; 121 (08) 1446-1454
    CrossrefPubMedGoogle Scholar
  • 36 Franchini M, Coppola A, Mengoli C. , et al; Ad Hoc Study Group. Blood group O protects against inhibitor development in severe hemophilia A patients. Semin Thromb Hemost 2017; 43 (01) 69-74
    PubMedGoogle Scholar
  • 37 Hay CR, Ollier W, Pepper L. , et al; UKHCDO Inhibitor Working Party. HLA class II profile: a weak determinant of factor VIII inhibitor development in severe haemophilia A. Thromb Haemost 1997; 77 (02) 234-237
    Article in Thieme ConnectPubMedGoogle Scholar
  • 38 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. 01) S26-S28
    Article in Thieme ConnectPubMedGoogle Scholar
  • 39 Xi M, Makris M, Marcucci M, Santagostino E, Mannucci PM, Iorio A. Inhibitor development in previously treated hemophilia A patients: a systematic review, meta-analysis, and meta-regression. J Thromb Haemost 2013; 11 (09) 1655-1662
    CrossrefPubMedGoogle Scholar
  • 40 Gallucci S, Matzinger P. Danger signals: SOS to the immune system. Curr Opin Immunol 2001; 13 (01) 114-119
    CrossrefPubMedGoogle Scholar
  • 41 Matzinger P. The danger model: a renewed sense of self. Science 2002; 296 (5566): 301-305
    CrossrefPubMedGoogle Scholar
  • 42 Kono H, Rock KL. How dying cells alert the immune system to danger. Nat Rev Immunol 2008; 8 (04) 279-289
    CrossrefPubMedGoogle Scholar
  • 43 Gouw SC, van den Berg HM, le Cessie S, van der Bom JG. 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 (07) 1383-1390
    CrossrefPubMedGoogle Scholar
  • 44 Gouw SC, van der Bom JG, 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
  • 45 Maclean PS, Richards M, Williams M. , et al; Paediatric Working Party of UKHCDO. Treatment related factors and inhibitor development in children with severe haemophilia A. Haemophilia 2011; 17 (02) 282-287
    CrossrefPubMedGoogle Scholar
  • 46 Marcucci M, Mancuso ME, Santagostino E. , et al. Type and intensity of FVIII exposure on inhibitor development in PUPs with haemophilia A. A patient-level meta-analysis. Thromb Haemost 2015; 113 (05) 958-967
    Article in Thieme ConnectPubMedGoogle Scholar
  • 47 Gouw SC, van den Berg HM, Fischer K. , et al; PedNet and Research of Determinants of INhibitor Development (RODIN) Study Group. Intensity of factor VIII treatment and inhibitor development in children with severe hemophilia A: the RODIN study. Blood 2013; 121 (20) 4046-4055
    CrossrefPubMedGoogle Scholar
  • 48 Hironaka T, Furukawa K, Esmon PC. , et al. Comparative study of the sugar chains of factor VIII purified from human plasma and from the culture media of recombinant baby hamster kidney cells. J Biol Chem 1992; 267 (12) 8012-8020
    CrossrefPubMedGoogle Scholar
  • 49 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 (02) 610-612
    CrossrefPubMedGoogle Scholar
  • 50 Qadura M, Waters B, Burnett E. , et al. Recombinant and plasma-derived factor VIII products induce distinct splenic cytokine microenvironments in hemophilia A mice. Blood 2009; 114 (04) 871-880
    CrossrefPubMedGoogle Scholar
  • 51 Grancha S, Navajas R, Marañón C, Paradela A, Albar JP, Jorquera JI. Incomplete tyrosine 1680 sulphation in recombinant FVIII concentrates. Haemophilia 2011; 17 (04) 709-710
    CrossrefPubMedGoogle Scholar
  • 52 Iorio A, Halimeh S, Holzhauer S. , et al. Rate of inhibitor development in previously untreated hemophilia A patients treated with plasma-derived or recombinant factor VIII concentrates: a systematic review. J Thromb Haemost 2010; 8 (06) 1256-1265
    CrossrefPubMedGoogle Scholar
  • 53 Franchini M, Coppola A, Rocino A. , et al; Italian Association of Hemophilia Centers (AICE) Working Group. Systematic review of the role of FVIII concentrates in inhibitor development in previously untreated patients with severe hemophilia a: a 2013 update. Semin Thromb Hemost 2013; 39 (07) 752-766
    Article in Thieme ConnectPubMedGoogle Scholar
  • 54 Gouw SC, van der Bom JG, Ljung R. , et al; PedNet and RODIN Study Group. Factor VIII products and inhibitor development in severe hemophilia A. N Engl J Med 2013; 368 (03) 231-239
    CrossrefPubMedGoogle Scholar
  • 55 Calvez T, Chambost H, Claeyssens-Donadel S. , et al; FranceCoag Network. Recombinant factor VIII products and inhibitor development in previously untreated boys with severe hemophilia A. Blood 2014; 124 (23) 3398-3408
    CrossrefPubMedGoogle Scholar
  • 56 Collins PW, Palmer BP, Chalmers EA. , et al; UK Haemophilia Centre Doctors' Organization. Factor VIII brand and the incidence of factor VIII inhibitors in previously untreated UK children with severe hemophilia A, 2000-2011. Blood 2014; 124 (23) 3389-3397
    CrossrefPubMedGoogle Scholar
  • 57 Calvez T, Chambost H, d'Oiron R. , et al; for FranceCoag Collaborators. Analyses of the FranceCoag cohort support differences in immunogenicity among one plasma-derived and two recombinant factor VIII brands in boys with severe hemophilia A. Haematologica 2018; 103 (01) 179-189
    CrossrefPubMedGoogle Scholar
  • 58 Peyvandi F, Mannucci PM, Garagiola I. , et al. A randomized trial of factor VIII and neutralizing antibodies in hemophilia A. N Engl J Med 2016; 374 (21) 2054-2064
    CrossrefPubMedGoogle Scholar
  • 59 Crittenden LB. An interpretation of familial aggregation based on multiple genetic and environmental factors. Ann N Y Acad Sci 1961; 91: 769-780
    CrossrefPubMedGoogle Scholar
  • 60 Falconer DS. The inheritance of liability to certain diseases estimated from the incidence among relatives. Ann Hum Genet 1965; 29: 51-76
    CrossrefPubMedGoogle Scholar
  • 61 Smith C. Recurrence risks for multifactorial inheritance. Am J Hum Genet 1971; 23 (06) 578-588
    PubMedGoogle Scholar
  • 62 ter Avest PC, Fischer K, Mancuso ME. , et al; CANAL Study Group. 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
  • 63 van den Berg HM, Chalmers EA. Clinical prediction models for inhibitor development in severe hemophilia A. J Thromb Haemost 2009; 7 (Suppl. 01) 98-102
    CrossrefPubMedGoogle Scholar
  • 64 Qian J, Collins M, Sharpe AH, Hoyer LW. Prevention and treatment of factor VIII inhibitors in murine hemophilia A. Blood 2000; 95 (04) 1324-1329
    PubMedGoogle Scholar
  • 65 Pratt KP, Thompson AR. B-cell and T-cell epitopes in anti-factor VIII immune responses. Clin Rev Allergy Immunol 2009; 37 (02) 80-95
    CrossrefPubMedGoogle Scholar
  • 66 Schones DE, Zhao K. Genome-wide approaches to studying chromatin modifications. Nat Rev Genet 2008; 9 (03) 179-191
    CrossrefPubMedGoogle Scholar
  • 67 Hon G, Wang W, Ren B. Discovery and annotation of functional chromatin signatures in the human genome. PLOS Comput Biol 2009; 5 (11) e1000566
    CrossrefPubMedGoogle Scholar