Dana Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts, USA; Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
Indiana Hemophilia and Thrombosis Center, Indianapolis, Indianapolis, USA.
J Thromb Haemost. 2023 May;21(5):1248-1257. doi: 10.1016/j.jtha.2023.01.037. Epub 2023 Feb 9.
The natural history and genotype-phenotype correlation of congenital antithrombin (AT) deficiency in children are unknown.
To describe the clinical presentation of congenital AT deficiency in children and evaluate its correlation to specific mutations in SERPINC1.
In 2017, a prospective pediatric database and DNA biorepository for congenital AT deficiency was established. During the pilot phase, the database was opened at 4 tertiary care centers in Canada and US. Approval from research ethics board was obtained at each participating center. Written consent/assent was obtained from guardians/subjects who met eligibility. Demographic/clinical data were uploaded into a database. DNA extraction and SERPINC1 sequencing were centralized for US centers. Standard statistical methods were used to summarize parameters. Probability of VTE-free survival was assessed using the Kaplan-Meier method.
Overall, 43 participants (25 females) from 31 unique kindreds were enrolled. Median age (range) at enrollment was 14.8 years (1-21 years). Median AT activity was 52% (24%-87%), and median AT antigen (n = 20) was 55% (38%-110%). Nineteen (44%) participants had a history of venous thromboembolism (VTE). Median age at VTE diagnosis was 12.8 years (0.1-19.2 years). SERPINC1 sequencing was completed for 31 participants and 21 unique mutations were identified, including 5 novel variants. Probability of 5-year VTE-free survival (95% CI) for carriers of missense mutations (92.0% [95% CI: 71.6%-97.9%]) was significantly higher compared with carriers of null mutations (66.7% [95% CI: 19.5%-90.4%]); p = .0012.
To our knowledge, this is the first pediatric study to document a severe thrombotic phenotype in carriers of null mutations in SERPINC1, when compared with carriers of missense mutations; underscoring the importance of genetic testing.
儿童先天性抗凝血酶（AT）缺乏症的自然病史和基因型-表型相关性尚不清楚。
描述儿童先天性 AT 缺乏症的临床表现，并评估其与 SERPINC1 特定突变的相关性。
2017 年，建立了一个前瞻性儿科数据库和先天性 AT 缺乏症 DNA 生物库。在试点阶段，该数据库在加拿大和美国的 4 个三级保健中心开放。每个参与中心都获得了研究伦理委员会的批准。符合入选标准的监护人/受试者均签署了书面同意书。人口统计学/临床数据被上传到数据库中。美国中心进行了 DNA 提取和 SERPINC1 测序的集中化处理。采用标准统计方法总结参数。采用 Kaplan-Meier 法评估无静脉血栓栓塞（VTE）生存概率。
共有 31 个家系的 43 名（25 名女性）参与者入选。登记时的中位年龄（范围）为 14.8 岁（1-21 岁）。中位 AT 活性为 52%（24%-87%），中位 AT 抗原（n=20）为 55%（38%-110%）。19 名（44%）参与者有静脉血栓栓塞（VTE）病史。VTE 诊断的中位年龄为 12.8 岁（0.1-19.2 岁）。对 31 名参与者进行了 SERPINC1 测序，共发现 21 个独特的突变，包括 5 个新的变异。错义突变携带者的 5 年无 VTE 生存概率（95%CI）[92.0%（95%CI：71.6%-97.9%）]明显高于无义突变携带者[66.7%（95%CI：19.5%-90.4%）]；p=0.0012。
据我们所知，这是第一项描述 SERPINC1 无义突变携带者与错义突变携带者相比存在严重血栓表型的儿科研究；强调了基因检测的重要性。
