Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2023; 22: 58-64
Факторы риска появления патологических ингибиторов свертывания у детей с тяжелой гемофилией А
https://doi.org/10.24287/1726-1708-2023-22-3-58-64Аннотация
Цель исследования: определить роль потенциальных факторов риска возникновения патологических ингибиторов свертывания у ранее не леченных пациентов (РНЛП) (или минимально леченных пациентов) с тяжелой гемофилией А. Настоящее исследование одобрено независимым этическим комитетом и утверждено решением ученого совета ГУ «Республиканский научно-практический центр детской онкологии, гематологии и иммунологии» (Республика Беларусь). В исследование включены 89 мальчиков, состоявших на диспансерном учете в ГУ «Республиканский научнопрактический центр детской онкологии, гематологии и иммунологии» (Республика Беларусь) с 1998 по 2022 г. по поводу тяжелой гемофилии А. Возраст выявления гемофилии, представленный как медиана (10–90-й процентили), составил 8,0 (1,0–21,0) месяца, базовая активность фактора VIII – 0,7% (0,4–0,95%). Первое введение препаратов фактора свертывания крови VIII выполнено в возрасте 11,0 (1,0–31,0) месяца. Из 89 пациентов ингибиторная форма тяжелой гемофилии А диагностирована у 23 детей. Кумулятивная частота возникновения патологических ингибиторов свертывания в целом по группе среди РНЛП составила 31,0 ± 5,6%. Кумулятивная частота ингибиторных форм гемофилии (37,0 ± 6,9%) у пациентов с нулевыми мутациями превышала (log-rank-тест, p = 0,041) аналогичный показатель (6,5 ± 6,0%) у пациентов с ненулевыми мутациями. Использование одного и того же плазменного концентрата фактора свертывания крови (КФСК) VIII, разрешенного с периода новорожденности, в том числе и для профилактического введения, было сопряжено (c2 = 8,53; p = 0,004) со снижением частоты возникновения ингибиторов к фактору VIII до 21,3 ± 8,5% по сравнению частотой 45,2 ± 7,8% в группе пациентов, получавших КФСК различных производителей. Возраст (до 1 года или старше) первого введения КФСК не оказал влияния на формирование патологических ингибиторов свертывания (log-rank-тест, р = 0,746). Такие показатели, как возраст выявления гемофилии (отношение шансов (ОШ) 0,99; 95% доверительный интервал (ДИ) 0,931,024; р = 0,991), базовая активность фактора VIII (ОШ 0,99; 95% ДИ 0,98–1,06; р = 0,09), не были связаны с появлением патологических ингибиторов. Также не были связаны с выявлением ингибиторов результаты первых в жизни ребенка определений отношения величины активированного частичного тромбопластинового времени пациента к величине данного показателя в контроле (ОШ 1,89; 95% ДИ 0,72–5,09; p = 0,21) и показателя восстановления (ОШ 0,74; 95% ДИ 0,27–2,01; p = 0,55). Мы подтвердили, что одним из основных факторов риска возникновения патологических ингибиторов свертывания в ответ на введение КФСК VIII являются аномалии гена F8. Применение плазменного КФСК VIII, рекомендованного для введения РНЛП с периода новорожденности, одного производителя способствовало снижению частоты возникновения ингибиторов по сравнению с пациентами, получавшими КФСК различных производителей.
Список литературы
1. Collins P.W., Palmer B.P., Chalmers E.A., Hart D.P., Liesner R., Rangarajan S., et al.; UK HaemophiliaCentreDoctors’ Organization. Factor VIII brand and the incidence of factorVIII inhibitors in previously untreated UK children with severe haemophilia A, 2000–2011. Blood 2014; 124: 3389–97.
2. Fischer K., Lassila R., Peyvandi F., Calizzani G., Gatt A., Lambert T., et al.; EUHASS Participants. Inhibitor development in haemophilia according to concentrate. Fouryear results from the European Hаemophilia Safety Surveillance (EUHASS) project. Thromb Haemost 2015; 113: 968–75.
3. Peyvandi F., Mannucci P.M., Garagiola I., El-Beshlawy А., Elalfy М., Ramanan V., et al. Randomized trial of Factor VIII and neutralizing antibodies in hemophilia A. N Engl J Med 2016; 374: 2054–64.
4. Keipert C., Drechsel-Bäuerle U., Oberle D., Müller-Olling M., Hilger A. Epidemiological Challenges in Rare Bleeding Disorders: FVIII Inhibitor Incidence in Haemophilia A Patients – A Known Issue of Unknown Origin. Int J Environ Res Public Health 2021; 18: 225. DOI: 10.3390/ijerph18010225
5. Liesner R.J., Abraham A., Altisent C., Belletrutti M.J., Carcao M., Carvalho M., et al. Simoctocog Alfa (Nuwiq) in Previously Untreated Patients with Severe Haemophilia A: Final Results of the NuProtect Study. Thromb Haemost 2021; 121 (11): 1400–8. DOI: 10.1055/s-0040-1722623
6. Lorenzo J.I., Lopez A., Altisent C., Aznar J.A. Incidence of factor VIII inhibitors in severe haemophilia: the importance of patient age. Br J Haematol 2001; 113: 600–3.
7. Van der Bom J.G., Mauser-Bunschoten E.P., Fischer K., van den Berg H.M. Age at first treatment and immune tolerance to factor VIII inseverehemophilia. Thromb Haemost 2003; 89: 475–9.
8. Gouw S.C., van den Berg H.M., Fischer K., Auerswald G., Carcao M., Chalmers E., et al.; PedNet and RODIN Study Group. Intensity of factor VIII treatment and inhibitor development in children with severe hemophilia A: the RODIN study. Blood 2013; 121: 4046–55. DOI: 10.1182/blood-2012-09-457036
9. Hashemi S.M., Fischer K., Gouw SC., et al.; on behalf of PedNetStudy Group. Do vaccinations influence the risk of inhibitor development in patients with severe hemohpilia A? Abstracts of the XXV Congress of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 2015; 13 (Suppl S2): 147.
10. Hay C.R.М., Broun S., Collins P.W., Keeling D.M., Liesner R. The diagnosis and management of factor VIII and IX inhibitots: a guideline from the United Kingdom Hemophilia Centre Doctors Organisation. Br J Haematol 2006; 133: 591–605.
11. Rossetti L.C., Radic C.P., Larripa I.B., De Brasi C.D. Genotyping the Hemophilia Inversion Hotspot by Use of Inverse PCR. Clin Chem 2005; 51 (7): 1154–8.
12. Rossetti L.C., Radic C.P., Larripa I.B., De Brasi C.D. Developing a new generation of tests for genotyping hemophilia-causative rearrangements involving int 22h and int1h hotspots in the factor VIII gene. J Thromb Haemost 2008; 6: 830–6.
13. Любушкин А.В., Гурьянова И.Е., Дмитриев Е.В., Полякова Е.А., Вертелко В.Р., Алейникова О.В. Частота встречаемости инверсии 22 интрона гена фактора VIII среди пациентов детского возраста в Республике Беларусь. Гематология. Трансфузиология. Восточная Европа 2022; 8 (1): 41–8.
14. Bagnall R.D., Waseem N., Green P.M., Giannelli F. Recurrent inversion breaking intron 1 of the factor VIII gene is a frequent cause of severe hemophilia A. Blood 2002; 99 (1): 168–74.
15. Pavlova A., Oldenburg J. Defining severity of hemophilia: more than factor levels. Semin Thromb Hemost 2013; 39 (7): 702–10.
16. Rosendaal F.R., Palla R., Garagiola I., Mannucci P.M., Peyvandi F.; SIPPET Study Group. Genetic risk stratification to reduce inhibitor development in the early treatment of hemophilia A: a SIPPET analysis. Blood 2017; 130 (15): 1757–9. DOI: 10.1182/blood-2017-06-791756
Pediatric Hematology/Oncology and Immunopathology. 2023; 22: 58-64
Risk factors for coagulation inhibitor development in children with severe hemophilia A
https://doi.org/10.24287/1726-1708-2023-22-3-58-64Abstract
Aim of the study: to examine the role of potential risk factors in inhibitor development in previously untreated patients (PUPs) (or minimally treated patients) with severe hemophilia A. The study was approved by the Independent Ethics Committee and the Scientific Council of the Belarusian Research Center for Pediatric Oncology, Hematology and Immunology (the Republic of Belarus). The study included 89 boys who underwent regular follow-up for severe hemophilia A at the Belarusian Research Center for Pediatric Oncology, Hematology and Immunology (the Republic of Belarus) from 1998 to 2022. The median age (10th–90th percentile) at diagnosis of hemophilia was 8.0 (1.0–21.0) months, the baseline factor VIII activity was 0.7% (0.4–0.95%). Age at first exposure to factor VIII concentrate was 11.0 (1.0–31.0) months. Out of 89 patients, 23 children had severe hemophilia A with inhibitors. The cumulative incidence of inhibitors in the whole group of PUPs was 31.0 ± 5.6%. The cumulative incidence of hemophilia A with inhibitors was higher in the patients with null mutations (37.0 ± 6.9%) than in the patients with non-null mutations (6.5 ± 6.0%) (the log-rank test, p = 0.041). The use of plasma-derived FVIII concentrate (approved for use in neonates and for prophylaxis) from one manufacturer was associated (c2 = 8.53; p = 0.004) with a lower incidence of factor VIII inhibitors (up to 21.3 ± 8.5%) compared with the incidence in the group of patients treated with FVIII concentrates from different manufacturers (45.2 ± 7.8%). Age (> 1 year old or < 1 year old) at first exposure to FVIII had no effect on the formation of inhibitors (the log-rank test, p = 0.746). Such factors as age at diagnosis of hemophilia (odds ratio (OR) 0.99; 95% confidence interval (CI) 0.93–1.024; p = 0.991) and baseline factor VIII activity (OR 0.99; 95% CI 0.8–1.06; p = 0.09) were not associated with inhibitor development. The first measurements of activated partial thromboplastin time (APTT) ratio (patient APTT value over the APTT reference value) (OR 1.89; 95% CI 0.72–5.09; p = 0.21) and FVIII recovery in vivo (OR 0.74; 95% CI 0.27–2.01; p = 0.55) were not associated with inhibitor development either. We have confirmed that one of the main risk factors for FVIII inhibitor development is F8 gene mutations. The incidence of inhibitors among the patients who received plasma-derived FVIII concentrates (recommended for use in PUPs in the neonatal period) from one manufacturer was lower than among those who received FVIII from different manufacturers.
References
1. Collins P.W., Palmer B.P., Chalmers E.A., Hart D.P., Liesner R., Rangarajan S., et al.; UK HaemophiliaCentreDoctors’ Organization. Factor VIII brand and the incidence of factorVIII inhibitors in previously untreated UK children with severe haemophilia A, 2000–2011. Blood 2014; 124: 3389–97.
2. Fischer K., Lassila R., Peyvandi F., Calizzani G., Gatt A., Lambert T., et al.; EUHASS Participants. Inhibitor development in haemophilia according to concentrate. Fouryear results from the European Haemophilia Safety Surveillance (EUHASS) project. Thromb Haemost 2015; 113: 968–75.
3. Peyvandi F., Mannucci P.M., Garagiola I., El-Beshlawy A., Elalfy M., Ramanan V., et al. Randomized trial of Factor VIII and neutralizing antibodies in hemophilia A. N Engl J Med 2016; 374: 2054–64.
4. Keipert C., Drechsel-Bäuerle U., Oberle D., Müller-Olling M., Hilger A. Epidemiological Challenges in Rare Bleeding Disorders: FVIII Inhibitor Incidence in Haemophilia A Patients – A Known Issue of Unknown Origin. Int J Environ Res Public Health 2021; 18: 225. DOI: 10.3390/ijerph18010225
5. Liesner R.J., Abraham A., Altisent C., Belletrutti M.J., Carcao M., Carvalho M., et al. Simoctocog Alfa (Nuwiq) in Previously Untreated Patients with Severe Haemophilia A: Final Results of the NuProtect Study. Thromb Haemost 2021; 121 (11): 1400–8. DOI: 10.1055/s-0040-1722623
6. Lorenzo J.I., Lopez A., Altisent C., Aznar J.A. Incidence of factor VIII inhibitors in severe haemophilia: the importance of patient age. Br J Haematol 2001; 113: 600–3.
7. Van der Bom J.G., Mauser-Bunschoten E.P., Fischer K., van den Berg H.M. Age at first treatment and immune tolerance to factor VIII inseverehemophilia. Thromb Haemost 2003; 89: 475–9.
8. Gouw S.C., van den Berg H.M., Fischer K., Auerswald G., Carcao M., Chalmers E., et al.; PedNet and RODIN Study Group. Intensity of factor VIII treatment and inhibitor development in children with severe hemophilia A: the RODIN study. Blood 2013; 121: 4046–55. DOI: 10.1182/blood-2012-09-457036
9. Hashemi S.M., Fischer K., Gouw SC., et al.; on behalf of PedNetStudy Group. Do vaccinations influence the risk of inhibitor development in patients with severe hemohpilia A? Abstracts of the XXV Congress of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 2015; 13 (Suppl S2): 147.
10. Hay C.R.M., Broun S., Collins P.W., Keeling D.M., Liesner R. The diagnosis and management of factor VIII and IX inhibitots: a guideline from the United Kingdom Hemophilia Centre Doctors Organisation. Br J Haematol 2006; 133: 591–605.
11. Rossetti L.C., Radic C.P., Larripa I.B., De Brasi C.D. Genotyping the Hemophilia Inversion Hotspot by Use of Inverse PCR. Clin Chem 2005; 51 (7): 1154–8.
12. Rossetti L.C., Radic C.P., Larripa I.B., De Brasi C.D. Developing a new generation of tests for genotyping hemophilia-causative rearrangements involving int 22h and int1h hotspots in the factor VIII gene. J Thromb Haemost 2008; 6: 830–6.
13. Lyubushkin A.V., Gur'yanova I.E., Dmitriev E.V., Polyakova E.A., Vertelko V.R., Aleinikova O.V. Chastota vstrechaemosti inversii 22 introna gena faktora VIII sredi patsientov detskogo vozrasta v Respublike Belarus'. Gematologiya. Transfuziologiya. Vostochnaya Evropa 2022; 8 (1): 41–8.
14. Bagnall R.D., Waseem N., Green P.M., Giannelli F. Recurrent inversion breaking intron 1 of the factor VIII gene is a frequent cause of severe hemophilia A. Blood 2002; 99 (1): 168–74.
15. Pavlova A., Oldenburg J. Defining severity of hemophilia: more than factor levels. Semin Thromb Hemost 2013; 39 (7): 702–10.
16. Rosendaal F.R., Palla R., Garagiola I., Mannucci P.M., Peyvandi F.; SIPPET Study Group. Genetic risk stratification to reduce inhibitor development in the early treatment of hemophilia A: a SIPPET analysis. Blood 2017; 130 (15): 1757–9. DOI: 10.1182/blood-2017-06-791756
