Download PDF
Semin Thromb Hemost 2018; 44(06): 568-577
DOI: 10.1055/s-0037-1621717
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Inhibitors in Nonsevere Hemophilia A: What Is Known and Searching for the Unknown

Amal Abdi
1   Department of Pediatric Hematology, Amsterdam Medical Center, Amsterdam, The Netherlands
,
Silvia Linari
2   Department of Oncology, Center for Bleeding Disorders and Coagulation, Careggi University Hospital, Firenze, Italy
,
Lisa Pieri
2   Department of Oncology, Center for Bleeding Disorders and Coagulation, Careggi University Hospital, Firenze, Italy
,
Jan Voorberg
3   Sanquin, Amsterdam, The Netherlands
,
Karin Fijnvandraat
1   Department of Pediatric Hematology, Amsterdam Medical Center, Amsterdam, The Netherlands
,
Giancarlo Castaman
2   Department of Oncology, Center for Bleeding Disorders and Coagulation, Careggi University Hospital, Firenze, Italy
› Author Affiliations
Further Information

Publication History

Publication Date:
13 February 2018 (online)

    Permissions and Reprints

Abstract

Nonsevere hemophilia A (NSHA) is an inherited X-linked bleeding disorder, caused by mutations of the F8 gene, leading to decreases of clotting factor VIII (FVIII) levels to 1 to 40 IU/dL. Desmopressin is the first therapeutic option for NSHA, but 40 to 50% of patients fail to attain adequate postinfusion FVIII levels. Thus, in these cases, FVIII concentrates remain the mainstay of treatment. The development of neutralizing FVIII antibodies (inhibitors) is a major challenge with replacement therapy. In contrast to severe disease, NSHA patients have a lifelong risk of inhibitor development. Recent data indicate that inhibitors are associated with a deterioration of clinical outcome, illustrated by an increase in bleeding and mortality rate. F8 genotype is an important risk factor for inhibitor occurrence together with surgical interventions and a high dose of FVIII concentrate. Adequate prevention and treatment of inhibitors in NSHA patients is limited by a lack of understanding of the underlying immunological mechanisms. Elucidation of the immunology driving inhibitor development is required to identify high-risk patients, to understand the association between clinical risk factors and inhibitor occurrence, and to provide the opportunity to develop new preventive and therapeutic strategies.

Keywords

nonsevere hemophilia A - diagnosis - treatment - inhibitor development - immunological characteristics
 

  • References

  • 1 Bolton-Maggs PH, Pasi KJ. Haemophilias A and B. Lancet 2003; 361 (9371): 1801-1809
    CrossrefPubMedGoogle Scholar
  • 2 Jayandharan GR, Srivastava A. The phenotypic heterogeneity of severe hemophilia. Semin Thromb Hemost 2008; 34 (01) 128-141
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Pavlova A, Oldenburg J. Defining severity of hemophilia: more than factor levels. Semin Thromb Hemost 2013; 39 (07) 702-710
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Castaman G, Fijnvandraat K. Molecular and clinical predictors of inhibitor risk and its prevention and treatment in mild hemophilia A. Blood 2014; 124 (15) 2333-2336
    CrossrefPubMedGoogle Scholar
  • 5 Castaman G. Desmopressin for the treatment of haemophilia. Haemophilia 2008; 14 (Suppl. 01) 15-20
    PubMedGoogle Scholar
  • 6 Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia 2003; 9 (04) 418-435
    CrossrefPubMedGoogle Scholar
  • 7 Witmer C, Young G. Factor VIII inhibitors in hemophilia A: rationale and latest evidence. Ther Adv Hematol 2013; 4 (01) 59-72
    CrossrefPubMedGoogle Scholar
  • 8 Franchini M, Favaloro EJ, Lippi G. Mild hemophilia A. J Thromb Haemost 2010; 8 (03) 421-432
    Google Scholar
  • 9 Hay CR, Ludlam CA, Colvin BT. , et al; UK Haemophilia Centre Directors Organisation. Factor VIII inhibitors in mild and moderate-severity haemophilia A. Thromb Haemost 1998; 79 (04) 762-766
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Darby SC, Keeling DM, Spooner RJ. , et al; 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 (07) 1047-1054
    CrossrefPubMedGoogle Scholar
  • 11 Eckhardt CL, Loomans JI, van Velzen AS. , et al; INSIGHT Study Group. Inhibitor development and mortality in non-severe hemophilia A. J Thromb Haemost 2015; 13 (07) 1217-1225
    CrossrefPubMedGoogle Scholar
  • 12 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
  • 13 Oldenburg J, El-Maarri O, Schwaab R. Inhibitor development in correlation to factor VIII genotypes. Haemophilia 2002; 8 (Suppl. 02) 23-29
    CrossrefPubMedGoogle Scholar
  • 14 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
  • 15 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
  • 16 Franchini M, Girelli D, Olivieri O. , et al. Tyr2105Cys mutation in exon 22 of FVIII gene is a risk factor for the development of inhibitors in patients with mild/moderate haemophilia A. Haemophilia 2006; 12 (04) 448-451
    CrossrefPubMedGoogle Scholar
  • 17 van Velzen AS, Eckhardt CL, Hart DP. , et al; INSIGHT study group. Inhibitors in nonsevere haemophilia A: outcome and eradication strategies. Thromb Haemost 2015; 114 (01) 46-55
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 van Velzen AS, Eckhardt CL, Streefkerk N. , et al; INSIGHT study group. The incidence and treatment of bleeding episodes in non-severe haemophilia A patients with inhibitors. Thromb Haemost 2016; 115 (03) 543-550
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 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
  • 20 Oldenburg J, Picard JK, Schwaab R, Brackmann HH, Tuddenham EGD, 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 (02) 238-242
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 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 . Doi: 10.1111/j.1538-7836.2009.03636.x
    CrossrefPubMedGoogle Scholar
  • 22 Steinitz KN, van Helden PM, Binder B. , et al. CD4+ T-cell epitopes associated with antibody responses after intravenously and subcutaneously applied human FVIII in humanized hemophilic E17 HLA-DRB1*1501 mice. Blood 2012; 119 (17) 4073-4082 . Doi: 10.1182/blood-2011-08-374645
    CrossrefPubMedGoogle Scholar
  • 23 van Haren SD, Herczenik E, ten Brinke A, Mertens K, Voorberg J, Meijer AB. HLA-DR-presented peptide repertoires derived from human monocyte-derived dendritic cells pulsed with blood coagulation factor VIII. Mol Cell Proteomics 2011; 10 (06) 002246
    PubMedGoogle Scholar
  • 24 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 . Doi: 10.1182/blood-2005-09-3918
    CrossrefPubMedGoogle Scholar
  • 25 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 . Doi: 10.1182/blood-2006-05-024711
    CrossrefPubMedGoogle Scholar
  • 26 Astermark J, Wang X, Oldenburg J, Berntorp E, Lefvert AK, Group MS. ; 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 . Doi: 10.1111/j.1538-7836.2007.02290.x
    CrossrefPubMedGoogle Scholar
  • 27 van Velzen AS, Eckhardt CL, Peters M. , et al. Intensity of factor VIII treatment and the development of inhibitors in non-severe hemophilia A patients: results of the INSIGHT case-control study. J Thromb Haemost 2017; 15 (07) 1422-1429 . Doi: 10.1111/jth.13711
    CrossrefPubMedGoogle Scholar
  • 28 Goudemand J, Rothschild C, Demiguel V. , et al; FVIII-LFB and Recombinant FVIII study groups. 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 (01) 46-51 . Doi: 10.1182/blood-2005-04-1371
    CrossrefPubMedGoogle Scholar
  • 29 Chalmers EA, Brown SA, Keeling D. , et al; Paediatric Working Party of UKHCDO. Early factor VIII exposure and subsequent inhibitor development in children with severe haemophilia A. Haemophilia 2007; 13 (02) 149-155 . Doi: 10.1111/j.1365-2516.2006.01418.x
    CrossrefPubMedGoogle Scholar
  • 30 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 . Doi: 10.1111/j.1538-7836.2010.03823.x
    CrossrefPubMedGoogle Scholar
  • 31 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 . Doi: 10.1055/s-0033-1356715
    Article in Thieme ConnectPubMedGoogle Scholar
  • 32 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 . Doi: 10.1160/TH14-07-0621
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Mannucci PM, Garagiola I. Factor VIII products in haemophilia A: one size fits all?. Thromb Haemost 2015; 113 (05) 911-914 . Doi: 10.1160/TH15-04-0273
    Article in Thieme ConnectPubMedGoogle Scholar
  • 34 Gouw SC, van der Bom JG, Auerswald G, Ettinghausen CE, Tedgård U, van den Berg HM. 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 . Doi: 10.1182/blood-2006-11-056317
    CrossrefPubMedGoogle Scholar
  • 35 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 . Doi: 10.1056/NEJMoa1208024
    CrossrefPubMedGoogle Scholar
  • 36 Fischer K, Lassila R, Peyvandi F. , et al; EUHASS participants. Inhibitor development in haemophilia according to concentrate. Four-year results from the European HAemophilia Safety Surveillance (EUHASS) project. Thromb Haemost 2015; 113 (05) 968-975 . Doi: 10.1160/TH14-10-0826
    Article in Thieme ConnectPubMedGoogle Scholar
  • 37 Peyvandi F, Ettingshausen CE, Goudemand J, Jiménez-Yuste V, Santagostino E, Makris M. New findings on inhibitor development: from registries to clinical studies. Haemophilia 2017; 23 (Suppl. 01) 4-13 . Doi: 10.1111/hae.13137
    CrossrefPubMedGoogle Scholar
  • 38 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 . Doi: 10.1056/NEJMoa1516437
    CrossrefPubMedGoogle Scholar
  • 39 Peyvandi F, Mannucci PM, Palla R, Rosendaal FR. SIPPET: methodology, analysis and generalizability. Haemophilia 2017; 23 (03) 353-361 . Doi: 10.1111/hae.13203
    CrossrefPubMedGoogle Scholar
  • 40 Hartholt RB, Peyron I, Voorberg J. Hunting down factor VIII in the immunopeptidome. Cell Immunol 2016; 301: 59-64 . Doi: 10.1016/j.cellimm.2015.11.001
    CrossrefPubMedGoogle Scholar
  • 41 Voorberg J, Fijnvandraat K. Inhibitor development in mild hemophilia A. Hemophilia 2013; 7 (01) 3-10
    PubMedGoogle Scholar
  • 42 Lai JD, Moorehead PC, Sponagle K. , et al. Concurrent influenza vaccination reduces anti-FVIII antibody responses in murine hemophilia A. Blood 2016; 127 (26) 3439-3449 . Doi: 10.1182/blood-2015-11-679282
    CrossrefPubMedGoogle Scholar
  • 43 Lai JD, Georgescu MT, Hough C, Lillicrap D. To clear or to fear: an innate perspective on factor VIII immunity. Cell Immunol 2016; 301: 82-89 . Doi: 10.1016/j.cellimm.2015.10.011
    CrossrefPubMedGoogle Scholar
  • 44 Georgescu MT, Lai JD, Hough C, Lillicrap D. War and peace: factor VIII and the adaptive immune response. Cell Immunol 2016; 301: 2-7 . Doi: 10.1016/j.cellimm.2015.11.008
    CrossrefPubMedGoogle Scholar
  • 45 van Velzen AS, Eckhardt CL, Peters M. , et al. Product type and the risk of inhibitor development in nonsevere hemophilia A patients. Abstract presented at the Annual Meeting of the International Society of Thrombosis and Haemostasis; July 11 2017; Berlin
    PubMedGoogle Scholar
  • 46 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; 8 (10) 2224-2231 . Doi: 10.1111/j.1538-7836.2010.04013.x
    CrossrefPubMedGoogle Scholar
  • 47 Mauser-Bunschoten EP, Den Uijl IEM, Schutgens REG, Roosendaal G, Fischer K. Risk of inhibitor development in mild haemophilia A increases with age. Haemophilia 2012; 18 (02) 263-267 . Doi: 10.1111/j.1365-2516.2011.02629.x
    CrossrefPubMedGoogle Scholar
  • 48 Arnold CR, Wolf J, Brunner S, Herndler-Brandstetter D, Grubeck-Loebenstein B. Gain and loss of T cell subsets in old age--age-related reshaping of the T cell repertoire. J Clin Immunol 2011; 31 (02) 137-146 . Doi: 10.1007/s10875-010-9499-x
    CrossrefPubMedGoogle Scholar
  • 49 Frasca D, Diaz A, Romero M, Landin AM, Blomberg BB. Age effects on B cells and humoral immunity in humans. Ageing Res Rev 2011; 10 (03) 330-335 . Doi: 10.1016/j.arr.2010.08.004
    CrossrefPubMedGoogle Scholar
  • 50 Nikolich-Žugich J, Li G, Uhrlaub JL, Renkema KR, Smithey MJ. Age-related changes in CD8 T cell homeostasis and immunity to infection. Semin Immunol 2012; 24 (05) 356-364 . Doi: 10.1016/j.smim.2012.04.009
    CrossrefPubMedGoogle Scholar
  • 51 Haynes L, Lefebvre JS. Age-related deficiencies in antigen-specific CD4 T cell responses: lessons from mouse models. Aging Dis 2011; 2 (05) 374-381
    PubMedGoogle Scholar
  • 52 Kogut I, Scholz JL, Cancro MP, Cambier JC. B cell maintenance and function in aging. Semin Immunol 2012; 24 (05) 342-349 . Doi: 10.1016/j.smim.2012.04.004
    CrossrefPubMedGoogle Scholar
  • 53 Canaro M, Goranova-Marinova V, Berntorp E. The ageing patient with haemophilia. Eur J Haematol 2015; 94 (Suppl. 77) 17-22 . Doi: 10.1111/ejh.12497
    CrossrefPubMedGoogle Scholar
  • 54 Matzinger P. The danger model: a renewed sense of self. Science 2002; 296 (5566): 301-305 . Doi: 10.1126/science.1071059
    CrossrefPubMedGoogle Scholar
  • 55 Houghton AN. Cancer antigens: immune recognition of self and altered self. J Exp Med 1994; 180 (01) 1-4 . Doi: 10.1084/jem.180.1.1
    CrossrefPubMedGoogle Scholar
  • 56 Pradeu T, Jaeger S, Vivier E. The speed of change: towards a discontinuity theory of immunity?. Nat Rev Immunol 2013; 13 (10) 764-769 . Doi: 10.1038/nri3521
    CrossrefPubMedGoogle Scholar
  • 57 Pradeu T, Vivier E. The discontinuity theory of immunity. Sci Immunol 2016; 1 (01) 1-4 . Doi: 10.1126/sciimmunol.aag0479
    CrossrefPubMedGoogle Scholar
  • 58 Whelan SFJ, Hofbauer CJ, Horling FM. , et al. Distinct characteristics of antibody responses against factor VIII in healthy individuals and in different cohorts of hemophilia A patients. Blood 2013; 121 (06) 1039-1048 . Doi: 10.1182/blood-2012-07-444877
    CrossrefPubMedGoogle Scholar
  • 59 van Helden PMW, van den Berg HM, Gouw SC. , et al. IgG subclasses of anti-FVIII antibodies during immune tolerance induction in patients with hemophilia A. Br J Haematol 2008; 142 (04) 644-652 . Doi: 10.1111/j.1365-2141.2008.07232.x
    CrossrefPubMedGoogle Scholar
  • 60 Ananyeva NM, Lacroix-Desmazes S, Hauser CA. , et al. Inhibitors in hemophilia A: mechanisms of inhibition, management and perspectives. Blood Coagul Fibrinolysis 2004; 15 (02) 109-124 . Doi: 10.1097/01.mbc.0000114382.15192.a7
    CrossrefPubMedGoogle Scholar
  • 61 Hofbauer CJ, Whelan SFJ, Hirschler M. , et al. Affinity of FVIII-specific antibodies reveals major differences between neutralizing and nonneutralizing antibodies in humans. Blood 2015; 125 (07) 1180-1188 . Doi: 10.1182/blood-2014-09-598268.The
    CrossrefPubMedGoogle Scholar
  • 62 Hofbauer CJ, Kepa S, Schemper M. , et al. FVIII-binding IgG modulates FVIII half-life in patients with severe and moderate hemophilia A without inhibitors. Blood 2016; 128 (02) 293-296 . Doi: 10.1182/blood-2015-10-675512
    CrossrefPubMedGoogle Scholar
  • 63 Cannavò A, Valsecchi C, Garagiola I. , et al; SIPPET study group. Nonneutralizing antibodies against factor VIII and risk of inhibitor development in severe hemophilia A. Blood 2017; 129 (10) 1245-1250 . Doi: 10.1182/blood-2016-06-720086
    CrossrefPubMedGoogle Scholar
  • 64 Bray GL, Kroner BL, Arkin S. , et al. Loss of high-responder inhibitors in patients with severe hemophilia A and human immunodeficiency virus type 1 infection: a report from the Multi-Center Hemophilia Cohort Study. Am J Hematol 1993; 42 (04) 375-379 . Doi: 10.1002/ajh.2830420408
    CrossrefPubMedGoogle Scholar
  • 65 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
    CrossrefPubMedGoogle Scholar
  • 66 Roche PA, Furuta K. The ins and outs of MHC class II-mediated antigen processing and presentation. Nat Rev Immunol 2015; 15 (04) 203-216 . Doi: 10.1038/nri3818
    CrossrefPubMedGoogle Scholar
  • 67 Saenko EL, Yakhyaev AV, Mikhailenko I, Strickland DK, Sarafanov AG. Role of the low density lipoprotein-related protein receptor in mediation of factor VIII catabolism. J Biol Chem 1999; 274 (53) 37685-37692 . Doi: 10.1074/jbc.274.53.37685
    CrossrefPubMedGoogle Scholar
  • 68 Lenting PJ, Neels JG, van den Berg BM. , et al. The light chain of factor VIII comprises a binding site for low density lipoprotein receptor-related protein. J Biol Chem 1999; 274 (34) 23734-23739 . Doi: 10.1074/JBC.274.34.23734
    CrossrefPubMedGoogle Scholar
  • 69 Bovenschen N, van Stempvoort G, Voorberg J, Mertens K, Meijer AB. Proteolytic cleavage of factor VIII heavy chain is required to expose the binding-site for low-density lipoprotein receptor-related protein within the A2 domain. J Thromb Haemost 2006; 4 (07) 1487-1493 . Doi: 10.1111/j.1538-7836.2006.01965.x
    CrossrefPubMedGoogle Scholar
  • 70 Bovenschen N, Herz J, Grimbergen JM. , et al. Elevated plasma factor VIII in a mouse model of low-density lipoprotein receptor-related protein deficiency. Blood 2003; 101 (10) 3933-3939 . Doi: 10.1182/blood-2002-07-2081.Supported
    CrossrefPubMedGoogle Scholar
  • 71 Bloem E, van den Biggelaar M, Wroblewska A. , et al. Factor VIII C1 domain spikes 2092-2093 and 2158-2159 comprise regions that modulate cofactor function and cellular uptake. J Biol Chem 2013; 288 (41) 29670-29679 . Doi: 10.1074/jbc.M113.473116
    CrossrefPubMedGoogle Scholar
  • 72 Sarafanov AG, Ananyeva NM, Shima M, Saenko EL. Cell surface heparan sulfate proteoglycans participate in factor VIII catabolism mediated by low density lipoprotein receptor-related protein. J Biol Chem 2001; 276 (15) 11970-11979 . Doi: 10.1074/jbc.M008046200
    CrossrefPubMedGoogle Scholar
  • 73 Bovenschen N, Mertens K, Hu L, Havekes LM, van Vlijmen BJM. LDL receptor cooperates with LDL receptor-related protein in regulating plasma levels of coagulation factor VIII in vivo. Blood 2005; 106 (03) 906-912 . Doi: 10.1182/blood-2004-11-4230
    CrossrefPubMedGoogle Scholar
  • 74 Sarafanov AG, Makogonenko EM, Pechik IV. , et al. Identification of coagulation factor VIII A2 domain residues forming the binding epitope for low-density lipoprotein receptor-related protein. Biochemistry 2006; 45 (06) 1829-1840 . Doi: 10.1021/bi0520380
    CrossrefPubMedGoogle Scholar
  • 75 Bovenschen N, van Dijk KW, Havekes LM, Mertens K, van Vlijmen BJM. Clearance of coagulation factor VIII in very low-density lipoprotein receptor knockout mice. Br J Haematol 2004; 126 (05) 722-725 . Doi: 10.1111/j.1365-2141.2004.05093.x
    CrossrefPubMedGoogle Scholar
  • 76 Bovenschen N, Rijken DC, Havekes LM, van Vlijmen BJM, Mertens K. The B domain of coagulation factor VIII interacts with the asialoglycoprotein receptor. J Thromb Haemost 2005; 3 (06) 1257-1265 . Doi: 10.1111/j.1538-7836.2005.01389.x
    CrossrefPubMedGoogle Scholar
  • 77 Pegon JN, Kurdi M, Casari C. , et al. Factor VIII and von Willebrand factor are ligands for the carbohydrate-receptor Siglec-5. Haematologica 2012; 97 (12) 1855-1863 . Doi: 10.3324/haematol.2012.063297
    CrossrefPubMedGoogle Scholar
  • 78 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 . Doi: 10.1073/pnas.0702120104
    CrossrefPubMedGoogle Scholar
  • 79 Herczenik E, van Haren SD, Wroblewska A. , et al. Uptake of blood coagulation factor VIII by dendritic cells is mediated via its C1 domain. J Allergy Clin Immunol 2012; 129 (02) 501-509 , 509.e1–509.e5. Doi: 10.1016/j.jaci.2011.08.029
    CrossrefPubMedGoogle Scholar
  • 80 Repessé Y, Dasgupta S, Navarrete AM, Delignat S, Kaveri SV, Lacroix-Desmazes S. Mannose-sensitive receptors mediate the uptake of factor VIII therapeutics by human dendritic cells. J Allergy Clin Immunol 2012; 129 (04) 1172-1173 , author reply 1174–1175. Doi: 10.1016/j.jaci.2012.01.048
    CrossrefPubMedGoogle Scholar
  • 81 Qian J, Borovok M, Bi L, Kazazian Jr HH, Hoyer LW. Inhibitor antibody development and T cell response to human factor VIII in murine hemophilia A. Thromb Haemost 1999; 81 (02) 240-244
    Article in Thieme ConnectPubMedGoogle Scholar
  • 82 Corthay A. How do regulatory T cells work?. Scand J Immunol 2009; 70 (04) 326-336 . Doi: 10.1111/j.1365-3083.2009.02308.x
    PubMedGoogle Scholar
  • 83 Sakaguchi S, Yamaguchi T, Nomura T, Ono M, Regulatory T. Regulatory T cells and immune tolerance. Cell 2008; 133 (05) 775-787 . Doi: 10.1016/j.cell.2008.05.009
    CrossrefPubMedGoogle Scholar
  • 84 d'Oiron R, Pipe SW, Jacquemin M. Mild/moderate haemophilia A: new insights into molecular mechanisms and inhibitor development. Haemophilia 2008; 14 (Suppl. 03) 138-146 . Doi: 10.1111/j.1365-2516.2008.01730.x
    CrossrefPubMedGoogle Scholar
  • 85 Gouw SC, Van Der Bom JG, Van Den Berg HM, Zewald RA, Ploos Van Amstel JK, Mauser-Bunschoten EP. Influence of the type of F8 gene mutation on inhibitor development in a single centre cohort of severe haemophilia A patients. Haemophilia 2011; 17 (02) 275-281 . Doi: 10.1111/j.1365-2516.2010.02420.x
    CrossrefPubMedGoogle Scholar
  • 86 Wroblewska A, Reipert BM, Pratt KP, Voorberg J. Dangerous liaisons: how the immune system deals with factor VIII. J Thromb Haemost 2013; 11 (01) 47-55 . Doi: 10.1111/jth.12065
    CrossrefPubMedGoogle Scholar
  • 87 James EA, Kwok WW, Ettinger RA, Thompson AR, Pratt KP. T-cell responses over time in a mild hemophilia A inhibitor subject: epitope identification and transient immunogenicity of the corresponding self-peptide. J Thromb Haemost 2007; 5 (12) 2399-2407 . Doi: 10.1111/j.1538-7836.2007.02762.x
    CrossrefPubMedGoogle Scholar
  • 88 Pashov AD, Calvez T, Gilardin L. , et al. In silico calculated affinity of FVIII-derived peptides for HLA class II alleles predicts inhibitor development in haemophilia A patients with missense mutations in the F8 gene. Haemophilia 2014; 20 (02) 176-184 . Doi: 10.1111/hae.12276
    CrossrefPubMedGoogle Scholar
  • 89 Castaman G, Eckhardt C, van Velzen A, Linari S, Fijnvandraat K. Emerging issues in diagnosis, biology, and inhibitor risk in mild hemophilia A. Semin Thromb Hemost 2016; 42 (05) 507-512 . Doi: 10.1055/s-0036-1571309
    Article in Thieme ConnectPubMedGoogle Scholar
  • 90 Hausl C, Ahmad RU, Sasgary M. , et al. High-dose factor VIII inhibits factor VIII-specific memory B cells in hemophilia A with factor VIII inhibitors. Blood 2005; 106 (10) 3415-3422 . Doi: 10.1182/blood-2005-03-1182
    CrossrefPubMedGoogle Scholar
  • 91 Kempton CL, Allen G, Hord J. , et al. Eradication of factor VIII inhibitors in patients with mild and moderate hemophilia A. Am J Hematol 2012; 87 (09) 933-936 . Doi: 10.1002/ajh.23269
    CrossrefPubMedGoogle Scholar
  • 92 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 (01) 193-203 . Doi: 10.1182/blood-2008-04-151597
    CrossrefPubMedGoogle Scholar
  • 93 Kim YC, Zhang AH, Su Y. , et al. Engineered antigen-specific human regulatory T cells: immunosuppression of FVIII-specific T- and B-cell responses. Blood 2015; 125 (07) 1107-1115 . Doi: 10.1182/blood-2014-04-566786
    CrossrefPubMedGoogle Scholar
  • 94 Macauley MS, Pfrengle F, Rademacher C. , et al. Antigenic liposomes displaying CD22 ligands induce antigen-specific B cell apoptosis. J Clin Invest 2013; 123 (07) 3074-3083 . Doi: 10.1172/JCI69187DS1
    CrossrefPubMedGoogle Scholar
  • 95 Lei TC, Scott DW. 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 . Doi: 10.1182/blood-2004-11-4274.Supported
    CrossrefPubMedGoogle Scholar
  • 96 Hausl C, Maier E, Schwarz HP. , et al. Long-term persistence of anti-factor VIII antibody-secreting cells in hemophilic mice after treatment with human factor VIII. Thromb Haemost 2002; 87 (05) 840-845
    Article in Thieme ConnectPubMedGoogle Scholar
  • 97 Manz RA, Thiel A, Radbruch A. Lifetime of plasma cells in the bone marrow. Nature 1997; 388 (6638): 133-134 . Doi: 10.1038/40540
    CrossrefPubMedGoogle Scholar
  • 98 Chen D, Frezza M, Schmitt S, Kanwar J, Dou QP. Bortezomib as the first proteasome inhibitor anticancer drug: current status and future perspectives. Curr Cancer Drug Targets 2011; 11 (03) 239-253 . Doi: 10.2174/156800911794519752
    CrossrefPubMedGoogle Scholar
  • 99 Obeng EA, Carlson LM, Gutman DM, Harrington Jr WJ, Lee KP, Boise LH. Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood 2006; 107 (12) 4907-4916 . Doi: 10.1182/blood-2005-08-3531
    CrossrefPubMedGoogle Scholar
  • 100 Hideshima T, Richardson PG, Anderson KC. Mechanism of action of proteasome inhibitors and deacetylase inhibitors and the biological basis of synergy in multiple myeloma. Mol Cancer Ther 2011; 10 (11) 2034-2042 . Doi: 10.1158/1535-7163.MCT-11-0433
    CrossrefPubMedGoogle Scholar
  • 101 Meslier Y, André S, Dimitrov JD. , et al. Bortezomib delays the onset of factor VIII inhibitors in experimental hemophilia A, but fails to eliminate established anti-factor VIII IgG-producing cells. J Thromb Haemost 2011; 9 (04) 719-728 . Doi: 10.1111/j.1538-7836.2011.04200.x
    CrossrefPubMedGoogle Scholar
  • 102 Blat D, Zigmond E, Alteber Z, Waks T, Eshhar Z. Suppression of murine colitis and its associated cancer by carcinoembryonic antigen-specific regulatory T cells. Mol Ther 2014; 22 (05) 1018-1028 . Doi: 10.1038/mt.2014.41
    CrossrefPubMedGoogle Scholar
  • 103 Vonderheide RH, June CH. Engineering T cells for cancer: our synthetic future. Immunol Rev 2014; 257 (01) 7-13 . Doi: 10.1111/imr.12143
    CrossrefPubMedGoogle Scholar
  • 104 Grupp SA, Kalos M, Barrett D. , et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 2013; 368 (16) 1509-1518
    CrossrefPubMedGoogle Scholar
  • 105 Kalos M, June CH, Adoptive T. Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology. Immunity 2013; 39 (01) 49-60 . Doi: 10.1016/j.immuni.2013.07.002
    CrossrefPubMedGoogle Scholar
  • 106 Moorehead PC, van Velzen A, Sponagle K, Steinitz KN, Reipert BM, Lillicrap D. Co-administration of factor VIII and dexamethasone prevents anti- factor VIII antibody development in a mouse model of hemophilia A. In: Abstracts of the XXIV Congress of the International Society of Thrombosis and Haemostasis. J Thromb Haemost 2013; 11: 208-209
    CrossrefPubMedGoogle Scholar
  • 107 Moorehead PC, Georgescu MT, van Velzen AS. , et al. Administration of dexamethasone during initial exposure to factor VIII induces durable and antigen-specific tolerance to factor VIII in hemophilia a mice with a humanized major histocompatibility complex II transgene. In: Proceedings of the 2014 ASH Annual Meeting. Blood 2014; 124: 1489
    PubMedGoogle Scholar
  • 108 Georgescu MT, Moorehead PC, Sponagle K, Reipert BM, Hough C, Lillicrap D. Administration of dexamethasone during initial exposure to factor VIII prevents the development of anti-factor VIII antibodies and increases the proportion of thymic but not splenic regulatory T cells in the exon 16 knockout C57Bl6 hemophilia A mouse mode, In: Proceedings of the 2014 ASH Annual Meeting. Blood 2014; 124: 237
    PubMedGoogle Scholar