{"title":"重症A型血友病患儿凝血抑制剂发展的危险因素","authors":"E. V. Dmitriev, A. V. Liubushkin","doi":"10.24287/1726-1708-2023-22-3-58-64","DOIUrl":null,"url":null,"abstract":"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.","PeriodicalId":38370,"journal":{"name":"Pediatric Hematology/Oncology and Immunopathology","volume":"22 1","pages":"0"},"PeriodicalIF":0.0000,"publicationDate":"2023-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Risk factors for coagulation inhibitor development in children with severe hemophilia A\",\"authors\":\"E. V. Dmitriev, A. V. Liubushkin\",\"doi\":\"10.24287/1726-1708-2023-22-3-58-64\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"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. 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引用次数: 0
摘要
该研究的目的:研究潜在危险因素在未接受治疗的严重a型血友病患者(PUPs)(或最低限度治疗的患者)抑制剂发展中的作用。该研究已获得白俄罗斯儿科肿瘤学、血液学和免疫学研究中心(白俄罗斯共和国)独立伦理委员会和科学委员会的批准。该研究包括89名男孩,他们从1998年到2022年在白俄罗斯儿童肿瘤学、血液学和免疫学研究中心(白俄罗斯共和国)接受了严重血友病A的定期随访。血友病诊断时的中位年龄(第10 - 90百分位)为8.0(1.0-21.0)个月,基线因子VIII活性为0.7%(0.4-0.95%)。首次接触因子VIII浓缩物的年龄为11.0(1.0-31.0)个月。在89例患者中,23名儿童患有严重的A型血友病。全组PUPs中抑制剂的累积发生率为31.0±5.6%。无突变患者的A型血友病累积发病率(37.0±6.9%)高于无突变患者(6.5±6.0%)(log-rank检验,p = 0.041)。使用来自一家制造商的血浆源性FVIII浓缩物(批准用于新生儿和预防)是相关的(c2 = 8.53;p = 0.004),因子VIII抑制剂的发生率(高达21.3±8.5%)低于使用不同厂家FVIII浓缩液治疗组的发生率(45.2±7.8%)。年龄(在1岁或;1岁)首次暴露于FVIII对抑制剂的形成没有影响(log-rank检验,p = 0.746)。诊断血友病时的年龄等因素(优势比0.99;95%置信区间(CI) 0.93-1.024;p = 0.991)和基线因子VIII活性(OR 0.99;95% ci 0.8-1.06;P = 0.09)与抑制剂的发展无关。第一次测量活化部分凝血活素时间(APTT)比(患者APTT值与APTT参考值)(OR 1.89;95% ci 0.72-5.09;p = 0.21)和体内FVIII回收率(OR 0.74;95% ci 0.27-2.01;P = 0.55)也与抑制剂的发展无关。我们已经证实FVIII抑制剂发展的主要危险因素之一是F8基因突变。在接受同一厂家血浆源性FVIII浓缩液(推荐用于新生儿期PUPs)的患者中,抑制剂的发生率低于接受不同厂家FVIII的患者。
Risk factors for coagulation inhibitor development in children with severe hemophilia A
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.