一项对大量中国血栓形成倾向家系队列中的抗凝血酶缺乏症的全面研究：发现4种SERPINC1致病变体仅损害渐进性活性。
A comprehensive study of antithrombin deficiency in a large cohort of Chinese thrombophilia pedigrees: uncovering 4 SERPINC1 pathogenic variants merely impaired progressive activities.
作者信息
Chen Changming, Wu Xi, Li Lei, Xiang Yue, Zhang Huayang, Song Ying, Ding Qiulan, Wang Xuefeng, Hu Xiaobo, Dai Jing
机构信息
Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Department of Clinical Hematology and Osology, Shanghai Center of Clinical Laboratory, Shanghai, China.
出版信息
J Thromb Haemost. 2025 Aug;23(8):2508-2521. doi: 10.1016/j.jtha.2025.04.022. Epub 2025 May 6.
BACKGROUND
Congenital antithrombin (AT) deficiency, primarily caused by variants in SERPINC1, is associated with a high risk of venous thromboembolism. Existing diagnostic procedures, mainly based on functional assays, may miss certain pathogenic variants.
OBJECTIVES
To comprehensively evaluate AT deficiency prevalence in the Chinese thrombophilia population and identify SERPINC1 variants overlooked by traditional diagnostic procedures.
METHODS
We conducted functional assays and genetic analysis simultaneously in 842 Chinese thrombophilia pedigrees. Supplementary functional assays (progressive assay and thrombin generation test) and in vitro enzymatic assays were used to detect AT defects, assess thrombotic risk, and investigate the pathogenic mechanisms of selected variants.
RESULTS
We identified 72 cases with decreased AT activity (<80%), of which 66 cases carried 61 different SERPINC1 variants, while 6 lacked identifiable variants. Additionally, 11 variants were found in 15 cases with normal AT antigen and activity, including 3 known pathogenic variants (p.N224H, p.E227K, and p.M313T) in 5 cases, 4 variants (p.K289E, p.R293W, p.R294C, and p.V295M) associated with impaired AT progressive activity in 7 cases, and 4 likely benign variants (p.V9I, p.S236L, p.G276A, and p.V387I). Thus, the prevalence of AT deficiency was 8.6% (72/842) by functional assays, and could reach 10.0% (84/842) when incorporating genetic analysis. Pathogenic SERPINC1 variants were found in 9.3% (78/842) of venous thromboembolism patients.
CONCLUSION
We identified a new AT type II reactive-site subtype, characterized by impaired progressive activity but normal heparin cofactor activity, which is overlooked in heparin-containing functional assays. These findings support that AT deficiency is underestimated and highlight the need to optimize current diagnostic algorithm for AT deficiency.
背景
先天性抗凝血酶（AT）缺乏症主要由SERPINC1基因变异引起，与静脉血栓栓塞的高风险相关。现有的诊断程序主要基于功能检测，可能会遗漏某些致病变异。
目的
全面评估中国血栓形成倾向人群中AT缺乏症的患病率，并识别传统诊断程序遗漏的SERPINC1基因变异。
方法
我们对842个中国血栓形成倾向家系同时进行了功能检测和基因分析。使用补充功能检测（逐步检测和凝血酶生成试验）和体外酶活性检测来检测AT缺陷、评估血栓形成风险并研究选定变异的致病机制。
结果
我们鉴定出72例AT活性降低（<80%）的病例，其中66例携带61种不同的SERPINC1基因变异，而6例未发现可识别的变异。此外，在15例AT抗原和活性正常的病例中发现了11种变异，包括5例中的3种已知致病变异（p.N224H、p.E227K和p.M313T）、7例中与AT逐步活性受损相关的4种变异（p.K289E、p.R293W、p.R294C和p.V295M）以及4种可能为良性的变异（p.V9I、p.S236L、p.G276A和p.V387I）。因此，通过功能检测，AT缺乏症的患病率为8.6%（72/842），纳入基因分析时患病率可达10.0%（84/842）。在9.3%（78/842）的静脉血栓栓塞患者中发现了致病的SERPINC1基因变异。
结论
我们鉴定出一种新的AT II型反应位点亚型，其特征是逐步活性受损但肝素辅因子活性正常，在含肝素的功能检测中被忽视。这些发现支持AT缺乏症被低估，并强调需要优化当前AT缺乏症的诊断算法。
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