nodgoРоссийский журнал детской гематологии и онкологии (РЖДГиО)Russian Journal of Pediatric Hematology and Oncology2311-12672413-5496LTD “Graphica”10.21682/2311-1267-2022-9-3-56-64nodgo-858Research ArticleОБЗОРЫ ЛИТЕРАТУРЫLITERATURE REVIEWSЕсть ли место заместительной терапии гемофилии А у детей в настоящем и будущем?Is there any place for replacement therapy of hemophilia A in children in present and future?https://orcid.org/0000-0003-4384-6754ЖарковП. А.ZharkovP. A.

Павел Александрович Жарков, д.м.н., врач-педиатр, врач-гематолог консультативного отделения, заведующий отделом патологии гемостаза.

Web of Science ResearcherID: AAP-9203-2020

117997, Москва, ул. Саморы Машела, 1

Dr. of Sci. (Med.), Pediatrician, Hematologist Outpatient Consultative Unit, Head of the Hemostasis Pathology Department. Web of Science ResearcherID: AAP-9203-2020

1 Samory Mashela St., Moscow, 117997

pavel.zharkov@fccho-moscow.ruФГБУ «Национальный медицинский исследовательский центр детской гематологии, онкологии и иммунологии имени Дмитрия Рогачева» Минздрава РоссииРоссияDmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Health of RussiaRussian Federation202209112022935664Copyright © Жарков П.А., 20222022Жарков П.А.Zharkov P.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.nodgo.org/jour/article/view/858

В последние годы мы наблюдаем революцию в области лечения пациентов с гемофилией А (ГА). Появление новых методов нефакторной и развитие генной терапии ставят перед врачами закономерный вопрос: каковы перспективы классического лечения ГА с применением концентратов факторов? Особенно это касается пациентов с ингибиторной формой ГА (ИГА), для которых до настоящего времени единственной опцией по снижению частоты геморрагических проявлений являлось использование препаратов шунтирующего действия, не позволяющих добиться полного контроля кровотечений. Улучшение результатов лечения больных ИГА было возможно только при полной эрадикации ингибиторов. Наиболее эффективным и безопасным методом, позволяющим избавиться от ингибиторов, является проведение терапии индукции иммунной толерантности (ИИТ). С появлением эмицизумаба и по-настоящему фантастических результатов его применения у пациентов с ИГА все чаще перед врачами встает вопрос о необходимости проведения ИИТ. Особенно остра эта проблема у детей с ИГА.

В данном обзоре представлены основные сведения о современных достижениях в терапии ГА, а также определено место препаратов заместительной терапии в настоящем и будущем.

In recent years, we have seen a revolution in the treatment of patients with hemophilia A. The emergence of new methods of non-factor and the development of gene therapy raise a natural question for doctors: what are the prospects for the classical treatment of hemophilia A using factor concentrates? This is especially true for patients with hemophilia A and inhibitors (HAI), for whom, until now, the only option to reduce the frequency of hemorrhagic manifestations has been the use of bypassing agents that do not allow complete control of bleeding. Improving the results of treatment of patients with HAI was possible only with complete eradication of inhibitors. The most effective and safe method to get rid of inhibitors is immune tolerance induction therapy (ITI). With the advent of emicizumab and the truly fantastic results of its use in patients with HAI, doctors are increasingly faced with the question of the need for ITI. This issue is especially acute in children with HAI.

This review provides basic information about modern advances in the treatment of hemophilia A, and also determines the place of substitution therapy drugs in the present and future.

гемофилия Аингибиториндукция иммунной толерантностилечениефактордетиhemophilia Ainhibitorsimmune tolerance inductiontreatmentfactorchildrenReferencesSrivastava A., Santagostino E., Dougall A., Kitchen S., Sutherland M., Pipe S.W., Carcao M., Mahlangu J., Ragni M.V., Windyga J., Llinás A., Goddard N.J., Mohan R., Poonnoose P.M., Feldman B.M., Lewis S.Z., van den Berg H.M., Pierce G.F. WFH Guidelines for the Management of Hemophilia, 3 rd edition. Haemophilia. 2020;26:1–158. doi: 10.1111/hae.14046.Srivastava A., Santagostino E., Dougall A., Kitchen S., Sutherland M., Pipe S.W., Carcao M., Mahlangu J., Ragni M.V., Windyga J., Llinás A., Goddard N.J., Mohan R., Poonnoose P.M., Feldman B.M., Lewis S.Z., van den Berg H.M., Pierce G.F. WFH Guidelines for the Management of Hemophilia, 3 rd edition. Haemophilia. 2020;26:1–158. doi: 10.1111/hae.14046.Aledort L., Mannucci P.M., Schramm W., Tarantino M. Factor VIII replacement is still the standard of care in haemophilia A. Blood Transfus. 2019;17(6):479–86. doi: 10.2450/2019.0211-19.Aledort L., Mannucci P.M., Schramm W., Tarantino M. Factor VIII replacement is still the standard of care in haemophilia A. Blood Transfus. 2019;17(6):479–86. doi: 10.2450/2019.0211-19.Peyvandi F., Mannucci P.M., Garagiola I., El-Beshlawy A., Elalfy M., Ramanan V., Eshghi P., Hanagavadi S., Varadarajan R., Karimi M., Manglani M.V., Ross C., Young G., Seth T., Apte S., Nayak D.M., Santagostino E., Mancuso M.E., Sandoval Gonzalez A.C., Mahlangu J.N., Bonanad Boix S., Cerqueira M., Ewing N.P., Male C., Owaidah T., Soto Arellano V., Kobrinsky N.L., Majumdar S., Perez Garrido R., Sachdeva A., Simpson M., Thomas M., Zanon E., Antmen B., Kavakli K., Manco-Johnson M.J., Martinez M., Marzouka E., Mazzucconi M.G., Neme D., Palomo Bravo A., Paredes Aguilera R., Prezotti A., Schmitt K., Wicklund B.M., Zulfi kar B., Rosendaal F.R. A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A. N Engl J Med. 2016;374(21):2054–64. doi: 10.1056/NEJMoa1516437. PMID: 27223147.Peyvandi F., Mannucci P.M., Garagiola I., El-Beshlawy A., Elalfy M., Ramanan V., Eshghi P., Hanagavadi S., Varadarajan R., Karimi M., Manglani M.V., Ross C., Young G., Seth T., Apte S., Nayak D.M., Santagostino E., Mancuso M.E., Sandoval Gonzalez A.C., Mahlangu J.N., Bonanad Boix S., Cerqueira M., Ewing N.P., Male C., Owaidah T., Soto Arellano V., Kobrinsky N.L., Majumdar S., Perez Garrido R., Sachdeva A., Simpson M., Thomas M., Zanon E., Antmen B., Kavakli K., Manco-Johnson M.J., Martinez M., Marzouka E., Mazzucconi M.G., Neme D., Palomo Bravo A., Paredes Aguilera R., Prezotti A., Schmitt K., Wicklund B.M., Zulfi kar B., Rosendaal F.R. A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A. N Engl J Med. 2016;374(21):2054–64. doi: 10.1056/NEJMoa1516437. PMID: 27223147.Rota M., Cortesi P.A., Steinitz-Trost K.N., Reininger A.J., Gringeri A., Mantovani L.G. Meta-analysis on incidence of inhibitors in patients with haemophilia A treated with recombinant factor VIII products. Blood Coagul Fibrinolysis. 2017;28(8):627–37. doi: 10.1097/MBC.0000000000000647. PMID: 28678027.Rota M., Cortesi P.A., Steinitz-Trost K.N., Reininger A.J., Gringeri A., Mantovani L.G. Meta-analysis on incidence of inhibitors in patients with haemophilia A treated with recombinant factor VIII products. Blood Coagul Fibrinolysis. 2017;28(8):627–37. doi: 10.1097/MBC.0000000000000647. PMID: 28678027.Wight J., Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia. 2003;9(4):418–35. doi: 10.1046/j.1365-2516.2003.00780.x. PMID: 12828678.Wight J., Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia. 2003;9(4):418–35. doi: 10.1046/j.1365-2516.2003.00780.x. PMID: 12828678.Hassan S., Cannavò A., Gouw S.C., Rosendaal F.R., van der Bom J.G. Factor VIII products and inhibitor development in previously treated patients with severe or moderately severe hemophilia A: a systematic review. J Thromb Haemost. 2018;16(6):1055–68. doi: 10.1111/jth.14124.Hassan S., Cannavò A., Gouw S.C., Rosendaal F.R., van der Bom J.G. Factor VIII products and inhibitor development in previously treated patients with severe or moderately severe hemophilia A: a systematic review. J Thromb Haemost. 2018;16(6):1055–68. doi: 10.1111/jth.14124.Chai-Adisaksopha C., Nevitt S.J., Simpson M.L., Janbain M., Konkle B.A. Bypassing agent prophylaxis in people with hemophilia A or B with inhibitors. Cochrane Database Syst Rev. 2017;9(9):CD011441. doi: 10.1002/14651858.CD011441.pub2.Chai-Adisaksopha C., Nevitt S.J., Simpson M.L., Janbain M., Konkle B.A. Bypassing agent prophylaxis in people with hemophilia A or B with inhibitors. Cochrane Database Syst Rev. 2017;9(9):CD011441. doi: 10.1002/14651858.CD011441.pub2.Жарков П.А., Воронин К.А., Андреева Т.А., Асекретова Т.В., Белкина Ю.Е., Демихов В.Г., Зинина Е.Е., Колясина Т.А., Лебедев В.В., Маркова И.В., Осмульская Н.С., Петров В.Ю., Скобин В.Б., Спичак О.В., Шелехова Т.В., Шерстнев Д.Г. Значительное снижение количества кровотечений у детей с ингибиторной формой гемофилии А в реальной клинической практике применения эмицизумаба. Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2022;21(1):66–71. doi: 10.24287/1726-1708-2022-21-1-66-71Zharkov P.А., Voronin K.A., Andreeva T.A., Asekretova T.V., Belkina Yu.E., Demikhov V.G., Zinina E.E., Kolyasina T.A., Lebedev V.V., Markova I.V., Osmulskaya N.S., Petrov V.Yu., Skobin V.B., Spichak O.V., Shelekhova T.V., Sherstnev D.G. Bleeding rate reduction in children with hemophilia A and inhibitors treated with emicizumab in the real-world clinical setting. Voprosy gematologii/ onkologii i immunopatologii v pediatrii = Pediatric Hematology/ Oncology and Immunopathology. 2022;21(1):66–71. (In Russ.) doi: 10.24287/1726-1708-2022-21-1-66-71.O’Hara J., Sima C.S., Frimpter J., Paliargues F., Chu P., Presch I. Long-term outcomes from prophylactic or episodic treatment of haemophilia A: A systematic review. Haemophilia. 2018;24(5):e301–11. doi: 10.1111/hae.13546.O’Hara J., Sima C.S., Frimpter J., Paliargues F., Chu P., Presch I. Long-term outcomes from prophylactic or episodic treatment of haemophilia A: A systematic review. Haemophilia. 2018;24(5):e301–11. doi: 10.1111/hae.13546.Delgado-Flores C.J., García-Gomero D., Salvador-Salvador S., Montes-Alvis J., Herrera-Cunti C., Taype-Rondan A. Effects of replacement therapies with clotting factors in patients with hemophilia: A systematic review and meta-analysis. PLoS One. 2022;17(1):e0262273. doi: 10.1371/journal.pone.0262273. PMID: 35030189.Delgado-Flores C.J., García-Gomero D., Salvador-Salvador S., Montes-Alvis J., Herrera-Cunti C., Taype-Rondan A. Effects of replacement therapies with clotting factors in patients with hemophilia: A systematic review and meta-analysis. PLoS One. 2022;17(1):e0262273. doi: 10.1371/journal.pone.0262273. PMID: 35030189.Von Mackensen S., Kalnins W., Krucker J., Weiss J., Miesbach W., Albisetti M., Pabinger I., Oldenburg J. Haemophilia patients' unmet needs and their expectations of the new extended half-life factor concentrates. Haemophilia. 2017;23(4):566–74. doi: 10.1111/hae.13221.Von Mackensen S., Kalnins W., Krucker J., Weiss J., Miesbach W., Albisetti M., Pabinger I., Oldenburg J. Haemophilia patients' unmet needs and their expectations of the new extended half-life factor concentrates. Haemophilia. 2017;23(4):566–74. doi: 10.1111/hae.13221.Hermans C., Mancuso M.E., Nolan B., Pasi K.J. Recombinant factor VIII Fc for the treatment of haemophilia A. Eur J Haematol. 2021;106(6):745–61. doi: 10.1111/ejh.13610.Hermans C., Mancuso M.E., Nolan B., Pasi K.J. Recombinant factor VIII Fc for the treatment of haemophilia A. Eur J Haematol. 2021;106(6):745–61. doi: 10.1111/ejh.13610.Siekmann J., Turecek P.L. PEGylation of human coagulation factor VIII and other plasma proteins. Polymer-Protein Conjugates. 2020:155–74. doi: 10.1016/B978-0-444-64081-9.00008-5.Siekmann J., Turecek P.L. PEGylation of human coagulation factor VIII and other plasma proteins. Polymer-Protein Conjugates. 2020:155–74. doi: 10.1016/B978-0-444-64081-9.00008-5.Raso S., Hermans C. Lonoctocog alfa (rVIII-SingleChain) for the treatment of haemophilia A. Expert Opin Biol Ther. 2018;18(1):87–94. doi: 10.1080/14712598.2018.1416088.Raso S., Hermans C. Lonoctocog alfa (rVIII-SingleChain) for the treatment of haemophilia A. Expert Opin Biol Ther. 2018;18(1):87–94. doi: 10.1080/14712598.2018.1416088.Morfi ni M. Simoctocog alfa for the treatment of hemophilia A. Expert Opin Biol Ther. 2017;17(12):1573–80. doi: 10.1080/14712598.2017.1391785.Morfi ni M. Simoctocog alfa for the treatment of hemophilia A. Expert Opin Biol Ther. 2017;17(12):1573–80. doi: 10.1080/14712598.2017.1391785.Lissitchkov T., Klukowska A., Pasi J., Kessler C.M., Klamroth R., Liesner R.J., Belyanskaya L., Walter O., Knaub S., Bichler J., Jansen M., Oldenburg J. Efficacy and safety of simoctocog alfa (Nuwiq® ) in patients with severe hemophilia A: a review of clinical trial data from the GENA program. Ther Adv Hematol. 2019;10:2040620719858471. doi: 10.1177/2040620719858471.Lissitchkov T., Klukowska A., Pasi J., Kessler C.M., Klamroth R., Liesner R.J., Belyanskaya L., Walter O., Knaub S., Bichler J., Jansen M., Oldenburg J. Efficacy and safety of simoctocog alfa (Nuwiq® ) in patients with severe hemophilia A: a review of clinical trial data from the GENA program. Ther Adv Hematol. 2019;10:2040620719858471. doi: 10.1177/2040620719858471.Di Minno M.N.D., Di Minno A., Calcaterra I., Cimino E., Dell’Aquila F., Franchini M. Enhanced Half-Life Recombinant Factor VIII Concentrates for Hemophilia A: Insights from Pivotal and Extension Studies. Semin Thromb Hemost. 2021;47(1):32–42. doi: 10.1055/s-0040-1718887.Di Minno M.N.D., Di Minno A., Calcaterra I., Cimino E., Dell’Aquila F., Franchini M. Enhanced Half-Life Recombinant Factor VIII Concentrates for Hemophilia A: Insights from Pivotal and Extension Studies. Semin Thromb Hemost. 2021;47(1):32–42. doi: 10.1055/s-0040-1718887.Klamroth R., Wojciechowski P., Aballéa S., Diamand F., Hakimi Z., Nazir J., Abad-Franch L., Lethagen S., Santagostino E., Tarantino M.D. Efficacy of rFVIIIFc versus Emicizumab for the Treatment of Patients with Hemophilia A without Inhibitors: Matching-Adjusted Indirect Comparison of A-LONG and HAVEN Trials. J Blood Med. 2021;12:115–22. doi: 10.2147/JBM.S288283.Klamroth R., Wojciechowski P., Aballéa S., Diamand F., Hakimi Z., Nazir J., Abad-Franch L., Lethagen S., Santagostino E., Tarantino M.D. Efficacy of rFVIIIFc versus Emicizumab for the Treatment of Patients with Hemophilia A without Inhibitors: Matching-Adjusted Indirect Comparison of A-LONG and HAVEN Trials. J Blood Med. 2021;12:115–22. doi: 10.2147/JBM.S288283.Konkle B.A., Shapiro A.D., Quon D.V., Staber J.M., Kulkarni R., Ragni M.V., Chhabra E.S., Poloskey S., Rice K., Katragadda S., Fruebis J., Benson C.C. BIVV001 Fusion Protein as Factor VIII Replacement Therapy for Hemophilia A. N Engl J Med. 2020;383(11):1018–27. doi: 10.1056/NEJMoa2002699. PMID: 32905674.Konkle B.A., Shapiro A.D., Quon D.V., Staber J.M., Kulkarni R., Ragni M.V., Chhabra E.S., Poloskey S., Rice K., Katragadda S., Fruebis J., Benson C.C. BIVV001 Fusion Protein as Factor VIII Replacement Therapy for Hemophilia A. N Engl J Med. 2020;383(11):1018–27. doi: 10.1056/NEJMoa2002699. PMID: 32905674.Lenting P.J., Denis C.V., Christophe O.D. Emicizumab, a bispecific antibody recognizing coagulation factors IX and X: how does it actually compare to factor VIII? Blood. 2017;130(23):2463–8. doi: 10.1182/blood-2017-08-801662.Lenting P.J., Denis C.V., Christophe O.D. Emicizumab, a bispecific antibody recognizing coagulation factors IX and X: how does it actually compare to factor VIII? Blood. 2017;130(23):2463–8. doi: 10.1182/blood-2017-08-801662.Lauritzen B., Bjelke M., Björkdahl O., Bloem E., Keane K., Kjalke M., Rossen M., Lippert S.L., Weldingh K.N., Skydsgaard M., Kjellev S. A novel next-generation FVIIIa mimetic, Mim8, has a favorable safety profile and displays potent pharmacodynamic effects: Results from safety studies in cynomolgus monkeys. J Thromb Haemost. 2022;20(6):1312–24. doi: 10.1111/jth.15682.Lauritzen B., Bjelke M., Björkdahl O., Bloem E., Keane K., Kjalke M., Rossen M., Lippert S.L., Weldingh K.N., Skydsgaard M., Kjellev S. A novel next-generation FVIIIa mimetic, Mim8, has a favorable safety profile and displays potent pharmacodynamic effects: Results from safety studies in cynomolgus monkeys. J Thromb Haemost. 2022;20(6):1312–24. doi: 10.1111/jth.15682.Lindley C.M., Sawyer W.T., Macik B.G., Lusher J., Harrison J.F., Baird-Cox K., Birch K., Glazer S., Roberts H.R. Pharmacokinetics and pharmacodynamics of recombinant factor VIIa. Clin Pharmacol Ther. 1994;55(6):638–48. doi: 10.1038/clpt.1994.80. PMID: 8004880.Lindley C.M., Sawyer W.T., Macik B.G., Lusher J., Harrison J.F., Baird-Cox K., Birch K., Glazer S., Roberts H.R. Pharmacokinetics and pharmacodynamics of recombinant factor VIIa. Clin Pharmacol Ther. 1994;55(6):638–48. doi: 10.1038/clpt.1994.80. PMID: 8004880.Wang M., Lawrence J.B., Quon D.V., Ducore J., Simpson M.L., Boggio L.N., Mitchell I.S., Yuan G., Alexander W.A., Schved J.F. PERSEPT 1: a phase 3 trial of activated eptacog beta for on-demand treatment of haemophilia inhibitor-related bleeding. Haemophilia. 2017;23(6):832–43. doi: 10.1111/hae.13301.Wang M., Lawrence J.B., Quon D.V., Ducore J., Simpson M.L., Boggio L.N., Mitchell I.S., Yuan G., Alexander W.A., Schved J.F. PERSEPT 1: a phase 3 trial of activated eptacog beta for on-demand treatment of haemophilia inhibitor-related bleeding. Haemophilia. 2017;23(6):832–43. doi: 10.1111/hae.13301.Gruppo R.A., Malan D., Kapocsi J., Nemes L., Hay C.R.M., Boggio L., Chowdary P., Tagariello G., von Drygalski A., Hua F., Scaramozza M., Arkin S.; Marzeptacog alfa (activated) Study Group Investigators. Phase 1, single-dose escalating study of marzeptacog alfa (activated), a recombinant factor VIIa variant, in patients with severe hemophilia. J Thromb Haemost. 2018;16(10):1984–93. doi: 10.1111/jth.14247.Gruppo R.A., Malan D., Kapocsi J., Nemes L., Hay C.R.M., Boggio L., Chowdary P., Tagariello G., von Drygalski A., Hua F., Scaramozza M., Arkin S.; Marzeptacog alfa (activated) Study Group Investigators. Phase 1, single-dose escalating study of marzeptacog alfa (activated), a recombinant factor VIIa variant, in patients with severe hemophilia. J Thromb Haemost. 2018;16(10):1984–93. doi: 10.1111/jth.14247.Abildgaard C.F., Penner J.A., Watson-Williams E.J. Anti-inhibitor Coagulant Complex (Autoplex) for treatment of factor VIII inhibitors in hemophilia. Blood. 1980;56(6):978–84. PMID: 6777002.Abildgaard C.F., Penner J.A., Watson-Williams E.J. Anti-inhibitor Coagulant Complex (Autoplex) for treatment of factor VIII inhibitors in hemophilia. Blood. 1980;56(6):978–84. PMID: 6777002.Eichler H., Angchaisuksiri P., Kavakli K., Knoebl P., Windyga J., Jiménez-Yuste V., Harder Delff P., Chowdary P. Concizumab restores thrombin generation potential in patients with haemophilia: Pharmacokinetic/pharmacodynamic modelling results of concizumab phase 1/1b data. Haemophilia. 2019;25(1):60–6. doi: 10.1111/hae.13627.Eichler H., Angchaisuksiri P., Kavakli K., Knoebl P., Windyga J., Jiménez-Yuste V., Harder Delff P., Chowdary P. Concizumab restores thrombin generation potential in patients with haemophilia: Pharmacokinetic/pharmacodynamic modelling results of concizumab phase 1/1b data. Haemophilia. 2019;25(1):60–6. doi: 10.1111/hae.13627.Pasi K.J., Lissitchkov T., Mamonov V., Mant T., Timofeeva M., Bagot C., Chowdary P., Georgiev P., Gercheva-Kyuchukova L., Madigan K., Van Nguyen H., Yu Q., Mei B., Benson C.C., Ragni M.V. Targeting of antithrombin in hemophilia A or B with investigational siRNA therapeutic fitusiran-Results of the phase 1 inhibitor cohort. J Thromb Haemost. 2021;19(6):1436–46. doi: 10.1111/jth.15270.Pasi K.J., Lissitchkov T., Mamonov V., Mant T., Timofeeva M., Bagot C., Chowdary P., Georgiev P., Gercheva-Kyuchukova L., Madigan K., Van Nguyen H., Yu Q., Mei B., Benson C.C., Ragni M.V. Targeting of antithrombin in hemophilia A or B with investigational siRNA therapeutic fitusiran-Results of the phase 1 inhibitor cohort. J Thromb Haemost. 2021;19(6):1436–46. doi: 10.1111/jth.15270.Hamedani N.S., Rühl H., Zimmermann J.J., Heiseler T., Oldenburg J., Mayer G., Pötzsch B., Müller J. In Vitro Evaluation of Aptamer-Based Reversible Inhibition of Anticoagulant Activated Protein C as a Novel Supportive Hemostatic Approach. Nucleic Acid Ther. 2016;26(6):355–62. doi: 10.1089/nat.2016.0645.Hamedani N.S., Rühl H., Zimmermann J.J., Heiseler T., Oldenburg J., Mayer G., Pötzsch B., Müller J. In Vitro Evaluation of Aptamer-Based Reversible Inhibition of Anticoagulant Activated Protein C as a Novel Supportive Hemostatic Approach. Nucleic Acid Ther. 2016;26(6):355–62. doi: 10.1089/nat.2016.0645.Polderdijk S.G., Adams T.E., Ivanciu L., Camire R.M., Baglin T.P., Huntington J.A. Design and characterization of an APC-specific serpin for the treatment of hemophilia. Blood. 2017;129(1):105–13. doi: 10.1182/blood-2016-05-718635.Polderdijk S.G., Adams T.E., Ivanciu L., Camire R.M., Baglin T.P., Huntington J.A. Design and characterization of an APC-specific serpin for the treatment of hemophilia. Blood. 2017;129(1):105–13. doi: 10.1182/blood-2016-05-718635.Zhao X.Y., Wilmen A., Wang D., Wang X., Bauzon M., Kim J.Y., Linden L., Li L., Egner U., Marquardt T., Moosmayer D., Tebbe J., Glück J.M., Ellinger P., McLean K., Yuan S., Yegneswaran S., Jiang X., Evans V., Gu J.M., Schneider D., Zhu Y., Xu Y., Mallari C., Hesslein A., Wang Y., Schmidt N., Gutberlet K., Ruehl-Fehlert C., Freyberger A., Hermiston T., Patel C., Sim D., Mosnier L.O., Laux V. Targeted inhibition of activated protein C by a non-active-site inhibitory antibody to treat hemophilia. Nat Commun. 2020;11(1):2992. doi: 10.1038/s41467-020-16720-9.Zhao X.Y., Wilmen A., Wang D., Wang X., Bauzon M., Kim J.Y., Linden L., Li L., Egner U., Marquardt T., Moosmayer D., Tebbe J., Glück J.M., Ellinger P., McLean K., Yuan S., Yegneswaran S., Jiang X., Evans V., Gu J.M., Schneider D., Zhu Y., Xu Y., Mallari C., Hesslein A., Wang Y., Schmidt N., Gutberlet K., Ruehl-Fehlert C., Freyberger A., Hermiston T., Patel C., Sim D., Mosnier L.O., Laux V. Targeted inhibition of activated protein C by a non-active-site inhibitory antibody to treat hemophilia. Nat Commun. 2020;11(1):2992. doi: 10.1038/s41467-020-16720-9.Prince R., Bologna L., Manetti M., Melchiorre D., Rosa I., Dewarrat N., Suardi S., Amini P., Fernández J.A., Burnier L., Quarroz C., Reina Caro M.D., Matsumura Y., Kremer Hovinga J.A., Griffin J.H., Simon H.U., Ibba-Manneschi L., Saller F., Calzavarini S., Angelillo-Scherrer A. Targeting anticoagulant protein S to improve hemostasis in hemophilia. Blood. 2018;131(12):1360–71. doi: 10.1182/blood-2017-09-800326.Prince R., Bologna L., Manetti M., Melchiorre D., Rosa I., Dewarrat N., Suardi S., Amini P., Fernández J.A., Burnier L., Quarroz C., Reina Caro M.D., Matsumura Y., Kremer Hovinga J.A., Griffin J.H., Simon H.U., Ibba-Manneschi L., Saller F., Calzavarini S., Angelillo-Scherrer A. Targeting anticoagulant protein S to improve hemostasis in hemophilia. Blood. 2018;131(12):1360–71. doi: 10.1182/blood-2017-09-800326.Инструкция по медицинскому применению препарата Эмицизумаб. [Электронный ресурс] URL: https://www.rlsnet.ru/tn_index_id_96727 (дата обращения 10.2021).Instructions for medical use of the drug Emicizumab. [Electronic resource] URL: https://www.rlsnet.ru/tn_index_id_96727 (appeal date 10.2021). (In Russ.).Mahlangu J., Oldenburg J., Paz-Priel I., Negrier C., Niggli M., Mancuso M.E., Schmitt C., Jiménez-Yuste V., Kempton C., Dhalluin C., Callaghan M.U., Bujan W., Shima M., Adamkewicz J.I., Asikanius E., Levy G.G., Kruse-Jarres R. Emicizumab Prophylaxis in Patients Who Have Hemophilia A without Inhibitors. N Engl J Med. 2018;379(9):811–22. doi: 10.1056/NEJMoa1803550. PMID: 30157389.Mahlangu J., Oldenburg J., Paz-Priel I., Negrier C., Niggli M., Mancuso M.E., Schmitt C., Jiménez-Yuste V., Kempton C., Dhalluin C., Callaghan M.U., Bujan W., Shima M., Adamkewicz J.I., Asikanius E., Levy G.G., Kruse-Jarres R. Emicizumab Prophylaxis in Patients Who Have Hemophilia A without Inhibitors. N Engl J Med. 2018;379(9):811–22. doi: 10.1056/NEJMoa1803550. PMID: 30157389.Young G., Liesner R., Chang T., Sidonio R., Oldenburg J., Jiménez-Yuste V., Mahlangu J., Kruse-Jarres R., Wang M., Uguen M., Doral M.Y., Wright L.Y., Schmitt C., Levy G.G., Shima M., Mancuso M.E. A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors. Blood. 2019;134(24):2127–38. doi: 10.1182/blood.2019001869.Young G., Liesner R., Chang T., Sidonio R., Oldenburg J., Jiménez-Yuste V., Mahlangu J., Kruse-Jarres R., Wang M., Uguen M., Doral M.Y., Wright L.Y., Schmitt C., Levy G.G., Shima M., Mancuso M.E. A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors. Blood. 2019;134(24):2127–38. doi: 10.1182/blood.2019001869.Pipe S.W., Shima M., Lehle M., Shapiro A., Chebon S., Fukutake K., Key N.S., Portron A., Schmitt C., Podolak-Dawidziak M., Selak Bienz N., Hermans C., Campinha-Bacote A., Kiialainen A., Peerlinck K., Levy G.G., Jiménez-Yuste V. Efficacy, safety, and pharmacokinetics of emicizumab prophylaxis given every 4 weeks in people with haemophilia A (HAVEN 4): a multicentre, open-label, non-randomised phase 3 study. Lancet Haematol. 2019;6(6):e295–305. doi: 10.1016/S2352-3026(19)30054-7.Pipe S.W., Shima M., Lehle M., Shapiro A., Chebon S., Fukutake K., Key N.S., Portron A., Schmitt C., Podolak-Dawidziak M., Selak Bienz N., Hermans C., Campinha-Bacote A., Kiialainen A., Peerlinck K., Levy G.G., Jiménez-Yuste V. Efficacy, safety, and pharmacokinetics of emicizumab prophylaxis given every 4 weeks in people with haemophilia A (HAVEN 4): a multicentre, open-label, non-randomised phase 3 study. Lancet Haematol. 2019;6(6):e295–305. doi: 10.1016/S2352-3026(19)30054-7.Клинические рекомендации «Гемофилия» (утверждены Минздравом России), 2018 г. [Электронный ресурс] URL: https://legalacts.ru/doc/klinicheskie-rekomendatsii-gemofilija-utv-minzdravom-rossii/ [Clinical guidelines “Hemophilia” (approved by the Ministry of Health of Russia), 2018.Clinical guidelines “Hemophilia” (approved by the Ministry of Health of Russia), 2018. [Electronic resource] URL: https://legalacts.ru/doc/klinicheskie-rekomendatsii-gemofilija-utv-minzdravom-rossii/ (In Russ.).Watanabe A.H., Lee S.W.H., Chai-Adisaksopha C., Lim M.Y., Chaiyakunapruk N. Budget Impact of Emicizumab for Routine Prophylaxis of Bleeding Episodes in Patients With Hemophilia A With Inhibitors. Value Health Reg Issues. 2022;28:7–13. doi: 10.1016/j.vhri.2021.07.003.Watanabe A.H., Lee S.W.H., Chai-Adisaksopha C., Lim M.Y., Chaiyakunapruk N. Budget Impact of Emicizumab for Routine Prophylaxis of Bleeding Episodes in Patients With Hemophilia A With Inhibitors. Value Health Reg Issues. 2022;28:7–13. doi: 10.1016/j.vhri.2021.07.003.Samelson-Jones B.J., Guelcher C., Kuhn J., Butler R., Massey G., Guerrera M.F., Raffini L. Real-world cost estimates of initiating emicizumab in US patients with haemophilia A. Haemophilia. 2021;27(4):591–8. doi: 10.1111/hae.14347.Samelson-Jones B.J., Guelcher C., Kuhn J., Butler R., Massey G., Guerrera M.F., Raffini L. Real-world cost estimates of initiating emicizumab in US patients with haemophilia A. Haemophilia. 2021;27(4):591–8. doi: 10.1111/hae.14347.Saiyarsarai P., Robabpour Derakhshan A., Khedmati J., Eshghi P., Seyedifar M. A comparison between on-demand usage of rFVIIa vs prophylaxis use of emicizumab in high titer inhibitory hemophilia A patients in Iran: A cost-utility analysis. Medicine (Baltimore). 2021;100(40):e27303. doi: 10.1097/MD.0000000000027303.Saiyarsarai P., Robabpour Derakhshan A., Khedmati J., Eshghi P., Seyedifar M. A comparison between on-demand usage of rFVIIa vs prophylaxis use of emicizumab in high titer inhibitory hemophilia A patients in Iran: A cost-utility analysis. Medicine (Baltimore). 2021;100(40):e27303. doi: 10.1097/MD.0000000000027303.Polack B., Trossaërt M., Cousin M., Baffert S., Pruvot A., Godard C. Cost-effectiveness of emicizumab vs bypassing agents in the prevention of bleeding episodes in haemophilia A patients with anti-FVIII inhibitors in France. Haemophilia. 2021;27(1):e1–11. doi: 10.1111/hae.14129.Polack B., Trossaërt M., Cousin M., Baffert S., Pruvot A., Godard C. Cost-effectiveness of emicizumab vs bypassing agents in the prevention of bleeding episodes in haemophilia A patients with anti-FVIII inhibitors in France. Haemophilia. 2021;27(1):e1–11. doi: 10.1111/hae.14129.Cortesi P.A., Castaman G., Trifi rò G., Creazzola S.S., Improta G., Mazzaglia G., Molinari A.C., Mantovani L.G. Cost-Effectiveness and Budget Impact of Emicizumab Prophylaxis in Haemophilia A Patients with Inhibitors. Thromb Haemost. 2020;120(2):216–28. doi: 10.1055/s-0039-3401822.Cortesi P.A., Castaman G., Trifi rò G., Creazzola S.S., Improta G., Mazzaglia G., Molinari A.C., Mantovani L.G. Cost-Effectiveness and Budget Impact of Emicizumab Prophylaxis in Haemophilia A Patients with Inhibitors. Thromb Haemost. 2020;120(2):216–28. doi: 10.1055/s-0039-3401822.Lee H., Cho H., Han J.W., Kim A.Y., Park S., Lee M., Cho S., Baik D., Kang H.Y. Cost-utility analysis of emicizumab prophylaxis in haemophilia A patients with factor VIII inhibitors in Korea. Haemophilia. 2021;27(1):e12–21. doi: 10.1111/hae.14143.Lee H., Cho H., Han J.W., Kim A.Y., Park S., Lee M., Cho S., Baik D., Kang H.Y. Cost-utility analysis of emicizumab prophylaxis in haemophilia A patients with factor VIII inhibitors in Korea. Haemophilia. 2021;27(1):e12–21. doi: 10.1111/hae.14143.Schmitt C., Adamkewicz J.I., Xu J., Petry C., Catalani O., Young G., Negrier C., Callaghan M.U., Levy G.G. Pharmacokinetics and Pharmacodynamics of Emicizumab in Persons with Hemophilia A with Factor VIII Inhibitors: HAVEN 1 Study. Thromb Haemost. 2021;121(3):351–60. doi: 10.1055/s-0040-1717114.Schmitt C., Adamkewicz J.I., Xu J., Petry C., Catalani O., Young G., Negrier C., Callaghan M.U., Levy G.G. Pharmacokinetics and Pharmacodynamics of Emicizumab in Persons with Hemophilia A with Factor VIII Inhibitors: HAVEN 1 Study. Thromb Haemost. 2021;121(3):351–60. doi: 10.1055/s-0040-1717114.Yoneyama K., Schmitt C., Kotani N., Levy G.G., Kasai R., Iida S., Shima M., Kawanishi T. A Pharmacometric Approach to Substitute for a Conventional Dose-Finding Study in Rare Diseases: Example of Phase III Dose Selection for Emicizumab in Hemophilia A. Clin Pharmacokinet. 2018;57(9):1123–34. doi: 10.1007/s40262-017-0616-3.Yoneyama K., Schmitt C., Kotani N., Levy G.G., Kasai R., Iida S., Shima M., Kawanishi T. A Pharmacometric Approach to Substitute for a Conventional Dose-Finding Study in Rare Diseases: Example of Phase III Dose Selection for Emicizumab in Hemophilia A. Clin Pharmacokinet. 2018;57(9):1123–34. doi: 10.1007/s40262-017-0616-3.Ferrière S., Peyron I., Christophe O.D., Kawecki C., Casari C., Muczynski V., Nathwani A., Kauskot A., Lenting P.J., Denis C.V. A hemophilia A mouse model for the in vivo assessment of emicizumab function. Blood. 2020;136(6):740–8. doi: 10.1182/blood.2019004334. PMID: 32369559.Ferrière S., Peyron I., Christophe O.D., Kawecki C., Casari C., Muczynski V., Nathwani A., Kauskot A., Lenting P.J., Denis C.V. A hemophilia A mouse model for the in vivo assessment of emicizumab function. Blood. 2020;136(6):740–8. doi: 10.1182/blood.2019004334. PMID: 32369559.Oldenburg J., Mahlangu J.N., Kim B., Schmitt C., Callaghan M.U., Young G., Santagostino E., Kruse-Jarres R., Negrier C., Kessler C., Valente N., Asikanius E., Levy G.G., Windyga J., Shima M. Emicizumab Prophylaxis in Hemophilia A with Inhibitors. N Engl J Med. 2017;377(9):809–18. doi: 10.1056/NEJMoa1703068.Oldenburg J., Mahlangu J.N., Kim B., Schmitt C., Callaghan M.U., Young G., Santagostino E., Kruse-Jarres R., Negrier C., Kessler C., Valente N., Asikanius E., Levy G.G., Windyga J., Shima M. Emicizumab Prophylaxis in Hemophilia A with Inhibitors. N Engl J Med. 2017;377(9):809–18. doi: 10.1056/NEJMoa1703068.Hartmann R., Feenstra T., Valentino L., Dockal M., Scheiflinger F. In vitro studies show synergistic effects of a procoagulant bispecific antibody and bypassing agents. J Thromb Haemost. 2018. doi: 10.1111/jth.14203.Hartmann R., Feenstra T., Valentino L., Dockal M., Scheiflinger F. In vitro studies show synergistic effects of a procoagulant bispecific antibody and bypassing agents. J Thromb Haemost. 2018. doi: 10.1111/jth.14203.Schultz N.H., Glosli H., Bjørnsen S., Holme P.A. The effect of emicizumab and bypassing agents in patients with hemophilia –An in vitro study. Res Pract Thromb Haemost. 2021;5(5):e12561. doi: 10.1002/rth2.12561.Schultz N.H., Glosli H., Bjørnsen S., Holme P.A. The effect of emicizumab and bypassing agents in patients with hemophilia –An in vitro study. Res Pract Thromb Haemost. 2021;5(5):e12561. doi: 10.1002/rth2.12561.Kjalke M., Kjelgaard-Hansen M., Andersen S., Hilden I. Thrombin generation potential in the presence of concizumab and rFVIIa, APCC, rFVIII, or rFIX: In vitro and ex vivo analyses. J Thromb Haemost. 2021;19(7):1687–96. doi: 10.1111/jth.15323.Kjalke M., Kjelgaard-Hansen M., Andersen S., Hilden I. Thrombin generation potential in the presence of concizumab and rFVIIa, APCC, rFVIII, or rFIX: In vitro and ex vivo analyses. J Thromb Haemost. 2021;19(7):1687–96. doi: 10.1111/jth.15323.Rota M., Cortesi P.A., Crea R., Gringeri A., Mantovani L.G. Thromboembolic event rate in patients exposed to anti-inhibitor coagulant complex: a meta-analysis of 40-year published data. Blood Adv. 2017;1(26):2637–42. doi: 10.1182/bloodadvances.2017011536.Rota M., Cortesi P.A., Crea R., Gringeri A., Mantovani L.G. Thromboembolic event rate in patients exposed to anti-inhibitor coagulant complex: a meta-analysis of 40-year published data. Blood Adv. 2017;1(26):2637–42. doi: 10.1182/bloodadvances.2017011536.Rajpurkar M., Croteau S.E., Boggio L., Cooper D.L. Thrombotic events with recombinant activated factor VII (rFVIIa) in approved indications are rare and associated with older age, cardiovascular disease, and concomitant use of activated prothrombin complex concentrates (aPCC). J Blood Med. 2019;10:335–40. doi: 10.2147/JBM.S219573.Rajpurkar M., Croteau S.E., Boggio L., Cooper D.L. Thrombotic events with recombinant activated factor VII (rFVIIa) in approved indications are rare and associated with older age, cardiovascular disease, and concomitant use of activated prothrombin complex concentrates (aPCC). J Blood Med. 2019;10:335–40. doi: 10.2147/JBM.S219573.Jiménez-Yuste V., Auerswald G., Benson G., Dolan G., Hermans C., Lambert T., Ljung R., Morfi ni M., Santagostino E., Zupančić Šalek S. Practical considerations for nonfactor-replacement therapies in the treatment of haemophilia with inhibitors. Haemophilia. 2021;27(3):340–50. doi: 10.1111/hae.14167.Jiménez-Yuste V., Auerswald G., Benson G., Dolan G., Hermans C., Lambert T., Ljung R., Morfi ni M., Santagostino E., Zupančić Šalek S. Practical considerations for nonfactor-replacement therapies in the treatment of haemophilia with inhibitors. Haemophilia. 2021;27(3):340–50. doi: 10.1111/hae.14167.Batty P., Lillicrap D. Gene therapy for hemophilia: Current status and laboratory consequences. Int J Lab Hematol. 2021;43 Suppl 1:117–23. doi: 10.1111/ijlh.13605.Batty P., Lillicrap D. Gene therapy for hemophilia: Current status and laboratory consequences. Int J Lab Hematol. 2021;43 Suppl 1:117–23. doi: 10.1111/ijlh.13605.Pasi K.J., Laffan M., Rangarajan S., Robinson T.M., Mitchell N., Lester W., Symington E., Madan B., Yang X., Kim B., Pierce G.F., Wong W.Y. Persistence of haemostatic response following gene therapy with valoctocogene roxaparvovec in severe haemophilia A. Haemophilia. 2021;27(6):947–56. doi: 10.1111/hae.14391.Pasi K.J., Laffan M., Rangarajan S., Robinson T.M., Mitchell N., Lester W., Symington E., Madan B., Yang X., Kim B., Pierce G.F., Wong W.Y. Persistence of haemostatic response following gene therapy with valoctocogene roxaparvovec in severe haemophilia A. Haemophilia. 2021;27(6):947–56. doi: 10.1111/hae.14391.Hay C.R., Palmer B., Chalmers E., Liesner R., Maclean R., Rangarajan S., Williams M., Collins P.W.; United Kingdom Haemophilia Centre Doctors’ Organisation (UKHCDO). Incidence of factor VIII inhibitors throughout life in severe hemophilia A in the United Kingdom. Blood. 2011;117(23):6367–70. doi: 10.1182/blood-2010-09-308668.Hay C.R., Palmer B., Chalmers E., Liesner R., Maclean R., Rangarajan S., Williams M., Collins P.W.; United Kingdom Haemophilia Centre Doctors’ Organisation (UKHCDO). Incidence of factor VIII inhibitors throughout life in severe hemophilia A in the United Kingdom. Blood. 2011;117(23):6367–70. doi: 10.1182/blood-2010-09-308668.Delavenne X., Dargaud Y. Pharmacokinetics for haemophilia treaters: Meaning of PK parameters, interpretation pitfalls, and use in the clinic. Thromb Res. 2020;192:52–60. doi: 10.1016/j.thromres.2020.05.005.Delavenne X., Dargaud Y. Pharmacokinetics for haemophilia treaters: Meaning of PK parameters, interpretation pitfalls, and use in the clinic. Thromb Res. 2020;192:52–60. doi: 10.1016/j.thromres.2020.05.005.Young G., Sørensen B., Dargaud Y., Negrier C., Brummel-Ziedins K., Key N.S. Thrombin generation and whole blood viscoelastic assays in the management of hemophilia: current state of art and future perspectives. Blood. 2013;121(11):1944–50. doi: 10.1182/blood-2012-08-378935.Young G., Sørensen B., Dargaud Y., Negrier C., Brummel-Ziedins K., Key N.S. Thrombin generation and whole blood viscoelastic assays in the management of hemophilia: current state of art and future perspectives. Blood. 2013;121(11):1944–50. doi: 10.1182/blood-2012-08-378935.Fischer K., Lassila R., Peyvandi F., Calizzani G., Gatt A., Lambert T., Windyga J., Iorio A., Gilman E., Makris M.; EUHASS participants. Inhibitor development in haemophilia according to concentrate. Four-year results from the European HAemophilia Safety Surveillance (EUHASS) project. Thromb Haemost. 2015;113(5):968–75. doi: 10.1160/TH14-10-0826.Fischer K., Lassila R., Peyvandi F., Calizzani G., Gatt A., Lambert T., Windyga J., Iorio A., Gilman E., Makris M.; EUHASS participants. Inhibitor development in haemophilia according to concentrate. Four-year results from the European HAemophilia Safety Surveillance (EUHASS) project. Thromb Haemost. 2015;113(5):968–75. doi: 10.1160/TH14-10-0826.Gouw S.C., van den Berg H.M., Fischer K., Auerswald G., Carcao M., Chalmers E., Chambost H., Kurnik K., Liesner R., Petrini P., Platokouki H., Altisent C., Oldenburg J., Nolan B., Garrido R.P., Mancuso M.E., Rafowicz A., Williams M., Clausen N., Middelburg R.A., Ljung R., van der Bom J.G.; 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):4046–55. doi: 10.1182/blood-2012-09-457036.Gouw S.C., van den Berg H.M., Fischer K., Auerswald G., Carcao M., Chalmers E., Chambost H., Kurnik K., Liesner R., Petrini P., Platokouki H., Altisent C., Oldenburg J., Nolan B., Garrido R.P., Mancuso M.E., Rafowicz A., Williams M., Clausen N., Middelburg R.A., Ljung R., van der Bom J.G.; 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):4046–55. doi: 10.1182/blood-2012-09-457036.Oldenburg J., Jiménez-Yuste V., Peiró-Jordán R., Aledort L.M., Santagostino E. Primary and rescue immune tolerance induction in children and adults: a multicentre international study with a VWF-containing plasma-derived FVIII concentrate. Haemophilia. 2014;20(1):83–91. doi: 10.1111/hae.12263.Oldenburg J., Jiménez-Yuste V., Peiró-Jordán R., Aledort L.M., Santagostino E. Primary and rescue immune tolerance induction in children and adults: a multicentre international study with a VWF-containing plasma-derived FVIII concentrate. Haemophilia. 2014;20(1):83–91. doi: 10.1111/hae.12263.Kreuz W., Escuriola Ettingshausen C., Vdovin V., Zozulya N., Plyushch O., Svirin P., Andreeva T., Bubanská E., Campos M., Benedik-Dolničar M., Jiménez-Yuste V., Kitanovski L., Klukowska A., Momot A., Osmulskaya N., Prieto M., Šalek S.Z., Velasco F., Pavlova A., Oldenburg J., Knaub S., Jansen M., Belyanskaya L., Walter O.; ObsITI study group; ObsITI committee. First prospective report on immune tolerance in poor risk haemophilia A inhibitor patients with a single factor VIII/von Willebrand factor concentrate in an observational immune tolerance induction study. Haemophilia. 2016;22(1):87–95. doi: 10.1111/hae.12774.Kreuz W., Escuriola Ettingshausen C., Vdovin V., Zozulya N., Plyushch O., Svirin P., Andreeva T., Bubanská E., Campos M., Benedik-Dolničar M., Jiménez-Yuste V., Kitanovski L., Klukowska A., Momot A., Osmulskaya N., Prieto M., Šalek S.Z., Velasco F., Pavlova A., Oldenburg J., Knaub S., Jansen M., Belyanskaya L., Walter O.; ObsITI study group; ObsITI committee. First prospective report on immune tolerance in poor risk haemophilia A inhibitor patients with a single factor VIII/von Willebrand factor concentrate in an observational immune tolerance induction study. Haemophilia. 2016;22(1):87–95. doi: 10.1111/hae.12774.Escuriola Ettingshausen C., Kreuz W. A review of immune tolerance induction with Haemate P in haemophilia A. Haemophilia. 2014;20(3):333–9. doi: 10.1111/hae.12288.Escuriola Ettingshausen C., Kreuz W. A review of immune tolerance induction with Haemate P in haemophilia A. Haemophilia. 2014;20(3):333–9. doi: 10.1111/hae.12288.Rothschild C., D’Oiron R., Borel-Derlon A., Gruel Y., Navarro R., Negrier C. Use of Haemate( ® ) P as immune tolerance induction in patients with severe haemophilia A who failed previous induction attempts: a multicentre observational study. Haemophilia. 2013;19(2):281–6. doi: 10.1111/hae.12018.Rothschild C., D’Oiron R., Borel-Derlon A., Gruel Y., Navarro R., Negrier C. Use of Haemate( ® ) P as immune tolerance induction in patients with severe haemophilia A who failed previous induction attempts: a multicentre observational study. Haemophilia. 2013;19(2):281–6. doi: 10.1111/hae.12018.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):749–54. PMID: 8950785.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):749–54. PMID: 8950785.Kallas A., Talpsep T. Von Willebrand factor in factor VIII concentrates protects against neutralization by factor VIII antibodies of haemophilia A patients. Haemophilia. 2001;7(4):375–80. doi: 10.1046/j.1365-2516.2001.00530.x. PMID: 11442642.Kallas A., Talpsep T. Von Willebrand factor in factor VIII concentrates protects against neutralization by factor VIII antibodies of haemophilia A patients. Haemophilia. 2001;7(4):375–80. doi: 10.1046/j.1365-2516.2001.00530.x. PMID: 11442642.Astermark J., Voorberg J., Lenk H., DiMichele D., Shapiro A., Tjönnfjord G., Berntorp E. Impact of inhibitor epitope profile on the neutralizing effect against plasma-derived and recombinant factor VIII concentrates in vitro. Haemophilia. 2003;9(5):567–72. doi: 10.1046/j.1365-2516.2003.00802.x. PMID: 14511295.Astermark J., Voorberg J., Lenk H., DiMichele D., Shapiro A., Tjönnfjord G., Berntorp E. Impact of inhibitor epitope profile on the neutralizing effect against plasma-derived and recombinant factor VIII concentrates in vitro. Haemophilia. 2003;9(5):567–72. doi: 10.1046/j.1365-2516.2003.00802.x. PMID: 14511295.Brackmann H.H., White G.C. 2nd , Berntorp E., Andersen T., Escuriola-Ettingshausen C. Immune tolerance induction: What have we learned over time? Haemophilia. 2018;24 Suppl 3:3–14. doi: 10.1111/hae.13445. PMID: 29543371.Brackmann H.H., White G.C. 2nd , Berntorp E., Andersen T., Escuriola-Ettingshausen C. Immune tolerance induction: What have we learned over time? Haemophilia. 2018;24 Suppl 3:3–14. doi: 10.1111/hae.13445. PMID: 29543371.Hay C.R., DiMichele D.M.; International Immune Tolerance Study. The principal results of the International Immune Tolerance Study: a randomized dose comparison. Blood. 2012;119(6):1335–44. doi: 10.1182/blood-2011-08-369132.Hay C.R., DiMichele D.M.; International Immune Tolerance Study. The principal results of the International Immune Tolerance Study: a randomized dose comparison. Blood. 2012;119(6):1335–44. doi: 10.1182/blood-2011-08-369132.Batsuli G., Zimowski K.L., Tickle K., Meeks S.L., Sidonio R.F. Jr. Immune tolerance induction in paediatric patients with haemophilia A and inhibitors receiving emicizumab prophylaxis. Haemophilia. 2019;25(5):789–96. doi: 10.1111/hae.13819.Batsuli G., Zimowski K.L., Tickle K., Meeks S.L., Sidonio R.F. Jr. Immune tolerance induction in paediatric patients with haemophilia A and inhibitors receiving emicizumab prophylaxis. Haemophilia. 2019;25(5):789–96. doi: 10.1111/hae.13819.

The authors declare that there are no conflicts of interest present.