nodgoРоссийский журнал детской гематологии и онкологии (РЖДГиО)Russian Journal of Pediatric Hematology and Oncology2311-12672413-5496LTD “Graphica”10.21682/2311-1267-2021-8-3-123-126nodgo-752Research ArticleКЛИНИЧЕСКИЕ НАБЛЮДЕНИЯCLINICAL CASESКлиническое наблюдение ребенка первого года жизни с тяжелой гемофилией А, получающего профилактическое лечение эмицизумабомClinical case of an infant with severe hemophilia A on emicizumabhttps://orcid.org/0000-0002-5649-325XАндрееваТ. А.AndreevaT. A.

Татьяна Андреевна Андреева,  к.м.н., врач-гематолог, заведующая

Author ID: 954196

SPIN-код: 8529-6758 

191186, Санкт-Петербург, ул. Гороховая, 6

Cand. of Sci. (Med.), Hematologist of the Highest Category, Head

Author ID: 954196

SPIN-code: 8529-6758 

6 Gorokhovaya St., S.-Petersburg, 191186

spbhemophilia@mail.ruhttps://orcid.org/0000-0002-1483-7704ЛавриченкоИ. А.LavrichenkoI. A.

к.м.н., врач-гематолог высшей категории 

191186, Санкт-Петербург, ул. Гороховая, 6

Cand. of Sci. (Med.), Hematologist of the Highest Category 

6 Gorokhovaya St., S.-Petersburg, 191186

lavrin59@mail.ruГородской центр по лечению больных гемофилией СПб ГБУЗ «Государственная поликлиника № 37»РоссияCity Center for the Treatment of Hemophilia Patients, City Polyclinic № 37Russian Federation20211910202183123126Copyright © Андреева Т.А., Лавриченко И.А., 20212021Андреева Т.А., Лавриченко И.А.Andreeva T.A., Lavrichenko I.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/752

Гемофилия А – сцепленное с Х-хромосомой врожденное нарушение свертываемости крови, вызванное недостаточностью или отсутствием фактора свертывания крови VIII. В отличие от взрослых пациентов, у которых суставы являются наиболее частой локализацией кровотечений, у детей первого года жизни кровотечения в область головы составляют 12,8–17,7 % случаев и до 45,5 % из них приходится на внутричерепные кровотечения. Первые 2 года жизни ребенка с гемофилией являются наиболее опасными в отношении внутричерепного кровотечения, и обеспечение полноценного профилактического лечения крайне важно в этот период.Цель исследования – представить первый опыт применения эмицизумаба в качестве первичной профилактики у ребенка первого года жизни.Пациенту 2020 г.р. с тяжелой формой гемофилии А после 2 посттравматических кровотечений, потребовавших госпитализации и заместительной терапии, было решено начать первичную профилактику препаратом эмицизумаб в возрасте 10 месяцев. В течение 8 мес наблюдения на фоне применения эмицизумаба не зарегистрировано ни одного спонтанного кровотечения. Посттравматическое кровотечение не потребовало госпитализации и дополнительной терапии.Представленный клинический случай демонстрирует, что эмицизумаб эффективен и безопасен у пациентов первого года жизни, ранее не получавших профилактического лечения.

Hemophilia A is an X-linked congenital bleeding disorder caused by a deficiency or absence of coagulation factor VIII. In children who are in the first year of life, bleeding into the head accounts for 12.8–17.7 % of cases, and up to 45.5 % of them are intracranial bleeding in contrast to adult patients, in whom joints are the most frequent localization of bleeding. The first 2 years of life are the most dangerous in relation tointracranial bleeding for a child with hemophilia and the provision of full preventive treatment is extremely important for this time.Aim of the study – present the first experience of using emicizumab as primary prophylaxis in a child of the first year of life with hemophilia A. A patient born in 2020 with a severe hemophilia A had two post-traumatic bleeding that required hospitalization and replacement therapy. We decided to start primary prophylaxis with emicizumab at the age of 10 months.There were not spontaneous bleedings during 8 months of emicizumab usage. Post-traumatic bleeding did not require hospitalization and additional therapy.The clinical case demonstrates that emicizumab is effective and safe in infant who have not previously received prophylactic treatment.

гемофилия Атяжелая форма гемофилии Аэмицизумабпациентранее не получавший терапиюдети с гемофилией Аhemophilia Asevere hemophilia Aemicizumabuntreated patientchildren with hemophilia AReferencesBenson G., Auerswald G., Dolan G., Duffy A., Hermans C., Ljung R., Morfini M., Šalek S.Z. Diagnosis and care of patients with mild haemophilia: practical recommendations for clinical management. Blood Transfus 2018;16(6):535–44. doi: 10.2450/2017.0150-17.Benson G., Auerswald G., Dolan G., Duffy A., Hermans C., Ljung R., Morfini M., Šalek S.Z. Diagnosis and care of patients with mild haemophilia: practical recommendations for clinical management. Blood Transfus 2018;16(6):535–44. doi: 10.2450/2017.0150-17.Российские клинические рекомендации по диагностике и лечению пациентов с гемофилией. [Электронный ресурс]: https://cr.rosminzdrav.ru/schema/127 (дата обращения 10.09.2020). [Russian clinical guidelines for the diagnosis and treatment of patients with hemophilia. [Electronic resource]: https://cr.rosminzdrav.ru/schema/127 (appeal date 10.09.2020). (In Russ.)].Российские клинические рекомендации по диагностике и лечению пациентов с гемофилией. [Электронный ресурс]: https://cr.rosminzdrav.ru/schema/127 (дата обращения 10.09.2020). [Russian clinical guidelines for the diagnosis and treatment of patients with hemophilia. [Electronic resource]: https://cr.rosminzdrav.ru/schema/127 (appeal date 10.09.2020). (In Russ.)].Kenet G., Chan A.K.C., Soucie J.M., Kulkarni R. Bleeding disorders in neonates. Haemophilia 2010;16(Suppl 5):168–75. doi: 10.1111/j.1365-2516.2010.02316.x.Kenet G., Chan A.K.C., Soucie J.M., Kulkarni R. Bleeding disorders in neonates. Haemophilia 2010;16(Suppl 5):168–75. doi: 10.1111/j.1365-2516.2010.02316.x.Kulkarni R., Soucie J.M., Lusher J., Presley R., Shapiro A., Gill J., MancoJohnson M., Koerper M., Mathew P., Abshire T., Dimichele D., Hoots K., Janco R., Nugent D., Geraghty S., Evatt B.; the Haemophilia Treatment Center Network Investigators. Sites of initial bleeding episodes, mode of delivery and age of diagnosis in babies with haemophilia diagnosed before the age of 2 years: a report from The Centers for Disease Control and Prevention’s (CDC) Universal Data Collection (UDC) project. Haemophilia 2009;15(6):1281–90. doi: 10.1111/j.1365-2516.2009.02074.x.Kulkarni R., Soucie J.M., Lusher J., Presley R., Shapiro A., Gill J., MancoJohnson M., Koerper M., Mathew P., Abshire T., Dimichele D., Hoots K., Janco R., Nugent D., Geraghty S., Evatt B.; the Haemophilia Treatment Center Network Investigators. Sites of initial bleeding episodes, mode of delivery and age of diagnosis in babies with haemophilia diagnosed before the age of 2 years: a report from The Centers for Disease Control and Prevention’s (CDC) Universal Data Collection (UDC) project. Haemophilia 2009;15(6):1281–90. doi: 10.1111/j.1365-2516.2009.02074.x.Stieltjes N., Calvez T., Demiguel V., Torchet M.F., Briquel M.E., Fressinaud E., Claeyssens S., Coatmelec B., Chambost H.; The French ICH Study Group. Intracranial haemorrhage in French haemophilia patients (1991–2001): clinical presentation, management and prognosis factors for death. Haemophilia 2005;11:452–8. doi: 10.1111/j.1365-2516.2005.01090.x.Stieltjes N., Calvez T., Demiguel V., Torchet M.F., Briquel M.E., Fressinaud E., Claeyssens S., Coatmelec B., Chambost H.; The French ICH Study Group. Intracranial haemorrhage in French haemophilia patients (1991–2001): clinical presentation, management and prognosis factors for death. Haemophilia 2005;11:452–8. doi: 10.1111/j.1365-2516.2005.01090.x.Nuss R., Soucie J.M., Evatt B.; Hemophilia Surveillance System Project Investigators. Changes in the occurrence of and risk factors for hemophilia-associated intracranial hemorrhage. Am J Hematol 2001;68(1):37–42. doi: 10.1002/ajh.1146.Nuss R., Soucie J.M., Evatt B.; Hemophilia Surveillance System Project Investigators. Changes in the occurrence of and risk factors for hemophilia-associated intracranial hemorrhage. Am J Hematol 2001;68(1):37–42. doi: 10.1002/ajh.1146.Kerr C.B. Intracranial haemorrhage in haemophilia. J Neurol Neurosurg Psychiatry 1964;27(2):166–73. doi: 10.1136/jnnp.27.2.166.Kerr C.B. Intracranial haemorrhage in haemophilia. J Neurol Neurosurg Psychiatry 1964;27(2):166–73. doi: 10.1136/jnnp.27.2.166.Kulkarni R., Presley R.J., Lusher J.M., Shapiro A.D., Gill J.C., MancoJohnson M., Koerper M.A., Abshire T.C., DiMichele D., Hoots W.K., Mathew P., Nugent D.J., Geraghty S., Evatt B.L., Soucie J.M. Complications of haemophilia in babies (first two years of life): a report from the Centers for Disease Control and Prevention Universal Data Collection System. Haemophilia 2017;23:207–14. doi: 10.1111/hae.13081.Kulkarni R., Presley R.J., Lusher J.M., Shapiro A.D., Gill J.C., MancoJohnson M., Koerper M.A., Abshire T.C., DiMichele D., Hoots W.K., Mathew P., Nugent D.J., Geraghty S., Evatt B.L., Soucie J.M. Complications of haemophilia in babies (first two years of life): a report from the Centers for Disease Control and Prevention Universal Data Collection System. Haemophilia 2017;23:207–14. doi: 10.1111/hae.13081.Andersson N.G., Auerswald G., Barnes C., Carcao M., Dunn A.L., Fijnvandraat K., Hoffmann M., Kavakli K., Kenet G., Kobelt R., Kurnik K., Liesner R., Mäkipernaa A., Manco-Johnson M.J., Mancuso M.E., Molinari A.C., Nolan B., Garrido R.P., Petrini P., Platokouki H.E., Shapiro A.D., Wu R., Ljung R. Intracranial haemorrhage in children and adolescents with severe haemophilia A or B – the impact of prophylactic treatment. Br J Haematol 2017;179:298–307. doi: 10.1111/bjh.14844.Andersson N.G., Auerswald G., Barnes C., Carcao M., Dunn A.L., Fijnvandraat K., Hoffmann M., Kavakli K., Kenet G., Kobelt R., Kurnik K., Liesner R., Mäkipernaa A., Manco-Johnson M.J., Mancuso M.E., Molinari A.C., Nolan B., Garrido R.P., Petrini P., Platokouki H.E., Shapiro A.D., Wu R., Ljung R. Intracranial haemorrhage in children and adolescents with severe haemophilia A or B – the impact of prophylactic treatment. Br J Haematol 2017;179:298–307. doi: 10.1111/bjh.14844.Patiroglu T., Ozdemir M.A., Unal E., Torun Y.A., Coskun A., Menku A., Mutlu F.T., Karakukcu M. Intracranial haemorrhage in children with congenital factor deficiencies. Childs Nerv Syst 2011;27:1963–6. doi: 10.1007/s00381-011-1519-5.Patiroglu T., Ozdemir M.A., Unal E., Torun Y.A., Coskun A., Menku A., Mutlu F.T., Karakukcu M. Intracranial haemorrhage in children with congenital factor deficiencies. Childs Nerv Syst 2011;27:1963–6. doi: 10.1007/s00381-011-1519-5.Roshni K., Soucie J.M. Pediatric hemophilia: a review. Semin Thromb Hemost 2011;37(7):737–44. doi: 10.1055/s-0031-1297164.Roshni K., Soucie J.M. Pediatric hemophilia: a review. Semin Thromb Hemost 2011;37(7):737–44. doi: 10.1055/s-0031-1297164.van Dijk K., van der Bom J.G., Bax K.N., van der Zee D.C., van den Berg M.H. Use of implantable venous access devices in children with severe hemophilia: benefits and burden. Haematologica 2004;89(2):189–94. doi: 10.3324/%25x.van Dijk K., van der Bom J.G., Bax K.N., van der Zee D.C., van den Berg M.H. Use of implantable venous access devices in children with severe hemophilia: benefits and burden. Haematologica 2004;89(2):189–94. doi: 10.3324/%25x.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;377:809–18. 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;377:809–18. doi: 10.1056/NEJMoa1703068.Uchida N., Sambe T., Yoneyama K., Fukazawa N., Kawanishi T., Kobayashi S., Shima M. A first-in-human phase 1 study of ACE910, a novel factor VIII-mimetic bispecific antibody, in healthy subjects. Blood 2016;127(13):1633–41. doi: 10.1182/blood-2015-06-650226.Uchida N., Sambe T., Yoneyama K., Fukazawa N., Kawanishi T., Kobayashi S., Shima M. A first-in-human phase 1 study of ACE910, a novel factor VIII-mimetic bispecific antibody, in healthy subjects. Blood 2016;127(13):1633–41. doi: 10.1182/blood-2015-06-650226.Shima M., Hanabusa H., Taki M., Matsushita T., Sato T., Fukutake K., Fukazawa N., Yoneyama K., Yoshida H., Nogami K. Factor VIII-Mimetic Function of Humanized Bispecific Antibody in Hemophilia A. N Engl J Med 2016;374(21):2044–53. doi: 10.1056/NEJMoa1511769.Shima M., Hanabusa H., Taki M., Matsushita T., Sato T., Fukutake K., Fukazawa N., Yoneyama K., Yoshida H., Nogami K. Factor VIII-Mimetic Function of Humanized Bispecific Antibody in Hemophilia A. N Engl J Med 2016;374(21):2044–53. doi: 10.1056/NEJMoa1511769.Kitazawa T., Igawa T., Sampei Z., Muto A., Kojima T., Soeda T., Yoshihashi K., Okuyama-Nishida Y., Saito H., Tsunoda H., Suzuki T., Adachi H., Miyazaki T., Ishii S., Kamata-Sakurai M., Iida T., Harada A., Esaki K., Funaki M., Moriyama C., Tanaka E., Kikuchi Y., Wakabayashi T., Wada M., Goto M., Toyoda T., Ueyama A., Suzuki S., Haraya K., Tachibana T., Kawabe Y., Shima M., Yoshioka A., Hattori K. A bispecific antibody to factors IXa and X restores factor VIII hemostatic activity in a hemophilia A model. Nat Med 2012;18(10):1570–4. doi: 10.1038/nm.2942.Kitazawa T., Igawa T., Sampei Z., Muto A., Kojima T., Soeda T., Yoshihashi K., Okuyama-Nishida Y., Saito H., Tsunoda H., Suzuki T., Adachi H., Miyazaki T., Ishii S., Kamata-Sakurai M., Iida T., Harada A., Esaki K., Funaki M., Moriyama C., Tanaka E., Kikuchi Y., Wakabayashi T., Wada M., Goto M., Toyoda T., Ueyama A., Suzuki S., Haraya K., Tachibana T., Kawabe Y., Shima M., Yoshioka A., Hattori K. A bispecific antibody to factors IXa and X restores factor VIII hemostatic activity in a hemophilia A model. Nat Med 2012;18(10):1570–4. doi: 10.1038/nm.2942.Инструкция по медицинскому применению препарата Эмицизумаб. [Электронный ресурс]: https://www.rlsnet.ru/tn_index_id_96727.htm#farmakokinetika (дата обращения 10.09.2020). [Instructions for medical use of the drug Emicizumab. [Electronic resource]: https://www.rlsnet.ru/tn_index_id_96727.htm#farmakokinetika (appeal date 10.09.2020). (In Russ.)].Инструкция по медицинскому применению препарата Эмицизумаб. [Электронный ресурс]: https://www.rlsnet.ru/tn_index_id_96727.htm#farmakokinetika (дата обращения 10.09.2020). [Instructions for medical use of the drug Emicizumab. [Electronic resource]: https://www.rlsnet.ru/tn_index_id_96727.htm#farmakokinetika (appeal date 10.09.2020). (In Russ.)].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.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.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.Pipe S.W., Shima M., Lehle M., Shapiro A., Chebon S., Fukutake K., Key N.S., Portron A., Schmitt C., Podolak-Dawidziak M., Bienz N.S., 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., Bienz N.S., 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.A Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Subcutaneous Emicizumab in Participants From Birth to 12 Months of Age With Hemophilia A Without Inhibitors (HAVEN 7). [Electronic resource]: https://www.clinicaltrials.gov/ct2/show/NCT04431726?term=emicizumab&draw=2&rank=6 (appeal date 10.09.2020).A Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Subcutaneous Emicizumab in Participants From Birth to 12 Months of Age With Hemophilia A Without Inhibitors (HAVEN 7). [Electronic resource]: https://www.clinicaltrials.gov/ct2/show/NCT04431726?term=emicizumab&draw=2&rank=6 (appeal date 10.09.2020).Srivastava A., Santagostino E., Dougall A., Kitchen S., Sutherland M., Pipe S.W., Carca 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 panelists and co-authors. WFH Guidelines for the Management of Hemophilia, 3rd edition. Haemophilia 2020;26 Suppl 6:1–158. doi: 10.1111/hae.14046.Srivastava A., Santagostino E., Dougall A., Kitchen S., Sutherland M., Pipe S.W., Carca 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 panelists and co-authors. WFH Guidelines for the Management of Hemophilia, 3rd edition. Haemophilia 2020;26 Suppl 6:1–158. doi: 10.1111/hae.14046.

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