MOLECULAR MECHANISMS OF INHIBITOR DEVELOPMENT IN HEMOPHILIA Guest Editor: Giancarlo Costaman
Main Article Content
Keywords
Keywords: inhibitors, hemophilia, anti-FVIII antibodies, anti-FIX antibodies
Abstract
The development of neutralizing antibodies in hemophilia is a serious complication of factor replacement therapy. These antibodies, also known as “inhibitors”, significantly increase morbidity within the hemophilia population and lower the quality of life for these patients. People with severe hemophilia A have an overall 25-40% lifetime risk of inhibitor development, compared to that of 5-15% lifetime risk in those with moderate/mild hemophilia A. The risk is lower in hemophilia B population (about 1-5%) and occurrence of inhibitors is almost only seen in patients with severe hemophilia B. The understanding of the pathophysiological mechanism leading to the development of inhibitors in patients with hemophilia has improved considerably over the last 2 decades. Identification of early biomarkers which predict inhibitor development in previously untreated patients with hemophilia will assist in risk identification and possible early intervention strategies. In this review, we aim to summarize the molecular mechanisms of inhibitor development in hemophilia and to identify potential areas in need of further investigation.
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Reference
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[1] Soucie JM, Evatt B, Jackson D. Occurrence of hemophilia in the United States. The Hemophilia Surveillance System Project Investigators. Am J Hematol 1998; 59: 288-294.
[2] Blanchette VS, Key NS, Ljung LR, Manco-Johnson MJ, van den Berg HM, Srivastava A. Definitions in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost 2014; 12: 1935-1939.
[3] Antonarakis SE, Rossiter JP, Young M, Horst J, de MP, Sommer SS, Ketterling RP, Kazazian HH, Jr., Negrier C, Vinciguerra C, Gitschier J, Goossens M, Girodon E, Ghanem N, Plassa F, Lavergne JM, Vidaud M, Costa JM, Laurian Y, Lin SW, Lin SR, Shen MC, Lillicrap D, Taylor SA, Windsor S, Valleix SV, Nafa K, Sultan Y, Delpech M, Vnencak-Jones CL, Phillips JA, III, Ljung RC, Koumbarelis E, Gialeraki A, Mandalaki T, Jenkins PV, Collins PW, Pasi KJ, Goodeve A, Peake I, Preston FE, Schwartz M, Scheibel E, Ingerslev J, Cooper DN, Millar DS, Kakkar VV, Giannelli F, Naylor JA, Tizzano EF, Baiget M, Domenech M, Altisent C, Tusell J, Beneyto M, Lorenzo JI, Gaucher C, Mazurier C, Peerlinck K, Matthijs G, Cassiman JJ, Vermylen J, Mori PG, Acquila M, Caprino D, Inaba H. Factor VIII gene inversions in severe hemophilia A: results of an international consortium study. Blood 1995; 86: 2206-2212.
[4] Schwaab R, Brackmann HH, Meyer C, Seehafer J, Kirchgesser M, Haack A, Olek K, Tuddenham EG, Oldenburg J. Haemophilia A: mutation type determines risk of inhibitor formation. Thromb Haemost 1995; 74: 1402-1406.
[5] Hay CR. Factor VIII inhibitors in mild and moderate-severity haemophilia A. Haemophilia 1998; 4: 558-563.
[6] Gomez K, Klamroth R, Mahlangu J, Mancuso ME, Mingot ME, Ozelo MC. Key issues in inhibitor management in patients with haemophilia. Blood Transfus 2014; 12 Suppl 1: s319-s329.
[7] Astermark J, Oldenburg J, Carlson J, Pavlova A, Kavakli K, Berntorp E, Lefvert AK. Polymorphisms in the TNFA gene and the risk of inhibitor development in patients with hemophilia A. Blood 2006; 108: 3739-3745.
[8] Astermark J, Oldenburg J, Pavlova A, Berntorp E, Lefvert AK. 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: 3167-3172.
[9] Astermark J, Wang X, Oldenburg J, Berntorp E, Lefvert AK. Polymorphisms in the CTLA-4 gene and inhibitor development in patients with severe hemophilia A. J Thromb Haemost 2007; 5: 263-265.
[10] Hollestelle MJ, Thinnes T, Crain K, Stiko A, Kruijt JK, van Berkel TJ, Loskutoff DJ, van Mourik JA. Tissue distribution of factor VIII gene expression in vivo--a closer look. Thromb Haemost 2001; 86: 855-861.
[11] Madoiwa S, Yamauchi T, Kobayashi E, Hakamata Y, Dokai M, Makino N, Kashiwakura Y, Ishiwata A, Ohmori T, Mimuro J, Sakata Y. Induction of factor VIII-specific unresponsiveness by intrathymic factor VIII injection in murine hemophilia A. J Thromb Haemost 2009; 7: 811-824.
[12] Vremec D, Pooley J, Hochrein H, Wu L, Shortman K. CD4 and CD8 expression by dendritic cell subtypes in mouse thymus and spleen. J Immunol 2000; 164: 2978-2986.
[13] Mebius RE, Kraal G. Structure and function of the spleen. Nat Rev Immunol 2005; 5: 606-616.
[14] Navarrete A, Dasgupta S, Delignat S, Caligiuri G, Christophe OD, Bayry J, Nicoletti A, Kaveri SV, Lacroix-Desmazes S. Splenic marginal zone antigen-presenting cells are critical for the primary allo-immune response to therapeutic factor VIII in hemophilia A. J Thromb Haemost 2009; 7: 1816-1823.
[15] Qian J, Burkly LC, Smith EP, Ferrant JL, Hoyer LW, Scott DW, Haudenschild CC. Role of CD154 in the secondary immune response: the reduction of pre-existing splenic germinal centers and anti-factor VIII inhibitor titer. Eur J Immunol 2000; 30: 2548-2554.
[16] Feuerer M, Beckhove P, Garbi N, Mahnke Y, Limmer A, Hommel M, Hammerling GJ, Kyewski B, Hamann A, Umansky V, Schirrmacher V. Bone marrow as a priming site for T-cell responses to blood-borne antigen. Nat Med 2003; 9: 1151-1157.
[17] Stern LJ, Brown JH, Jardetzky TS, Gorga JC, Urban RG, Strominger JL, Wiley DC. Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide. Nature 1994; 368: 215-221.
[18] Celli S, Lemaitre F, Bousso P. Real-time manipulation of T cell-dendritic cell interactions in vivo reveals the importance of prolonged contacts for CD4+ T cell activation. Immunity 2007; 27: 625-634.
[19] Lipscomb MF, Masten BJ. Dendritic cells: immune regulators in health and disease. Physiol Rev 2002; 82: 97-130.
[20] Pfistershammer K, Stockl J, Siekmann J, Turecek PL, Schwarz HP, Reipert BM. Recombinant factor VIII and factor VIII-von Willebrand factor complex do not present danger signals for human dendritic cells. Thromb Haemost 2006; 96: 309-316.
[21] Peerlinck K, Arnout J, Gilles JG, Saint-Remy JM, 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: 115-118.
[22] Peerlinck K, Arnout J, Di GM, Gilles JG, Laub R, Jacquemin M, Saint-Remy JM, Vermylen J. Factor VIII inhibitors in previously treated haemophilia A patients with a double virus-inactivated plasma derived factor VIII concentrate. Thromb Haemost 1997; 77: 80-86.
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