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Review
. 2020 Jan 1;12(1):e2020001.
doi: 10.4084/MJHID.2020.001. eCollection 2020.

Molecular Mechanisms of Inhibitor Development in Hemophilia

Paul Tieu  1 , Anthony Chan  2   3 , Davide Matino  3   4
Affiliations
Review

Molecular Mechanisms of Inhibitor Development in Hemophilia

Paul Tieu et al. Mediterr J Hematol Infect Dis. .

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.

Keywords: Anti-FIX antibodies; Anti-FVIII antibodies; Hemophilia; Inhibitors.

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Conflict of interest statement

Competing interests: The authors declare no conflict of Interest.

Figures

Figure 1
Figure 1
Primary immune response in hemophilia inhibitor development. APC: antigen-presenting cells; MMR: mannose receptor; LRP: lipoprotein receptor-related protein; TCR: T-cell receptor.
Figure 2
Figure 2
Secondary immune response in haemophilia.
See this image and copyright information in PMC

References

    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. doi: 10.1002/(SICI)1096-8652(199812)59:4<288::AID-AJH4>3.0.CO;2-I. - DOI - PubMed
    1. 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. doi: 10.1111/jth.12672. - DOI - PubMed
    1. 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. doi: 10.1182/blood.V86.6.2206.bloodjournal8662206. - DOI - PubMed
    1. 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. doi: 10.1055/s-0038-1649954. - DOI - PubMed
    1. Hay CR. Factor VIII inhibitors in mild and moderate-severity haemophilia A. Haemophilia. 1998;4:558–563. doi: 10.1046/j.1365-2516.1998.440558.x. - DOI - PubMed