Wu Xi, Li Lei, Lu Zhengjing, Hu Xiaobo, Lu Yeling, Liu Yu, Xu Guanqun, Ding Qiulan, Wang Xuefeng, Wu Wenman, Jin Peipei, Dai Jing
Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shanghai Center for Clinical Laboratory, Shanghai, China.
Thromb Haemost. 2025 Jan;125(1):69-81. doi: 10.1055/a-2350-8338. Epub 2024 Jun 24.
Venous thromboembolism (VTE) is predisposed by thrombotic mutations in patients with hereditary thrombophilia. Although prothrombin deficiencies caused by homozygous or compound heterozygous mutations are associated with bleeding diathesis, rare cases have shown a correlation between heterozygous prothrombin mutations and thrombosis.
We surveyed genetic variants involved in thrombosis and hemostasis in 347 patients with unprovoked VTE or having a positive family history of thrombosis. For patients identified with heterozygous prothrombin mutations, we conducted family investigations and performed a thrombin generation test (TGT) to elucidate the thrombotic risk. Novel mutants were expressed and subjected to functional assays to clarify the underlying thrombotic mechanisms.
Heterozygous prothrombin mutations were identified in 3.5% of patients (12/347), including three novel mutations Phe382Ser, Phe382Leu, and Asp597Tyr found in one patient each, as well as previously reported Arg541Trp mutation in four patients and Arg596Gln mutation in five patients. A total of 42 mutation carriers were identified within the 12 pedigrees, among whom 64.3% (27/42) had experienced thrombotic events. TGT results demonstrated hypercoagulability for carriers of the five mutations, with Arg596Gln showing the highest thrombin generation potential followed by Arg541Trp. The Phe382-associated mutations severely impaired thrombomodulin-binding ability of thrombin, resulting in obviously reduced protein C (PC) activation. The Asp597Tyr mutation exhibited a mild reduction in both inactivation by antithrombin and PC activation reactions.
The presence of heterozygous prothrombin mutations represents a potential genetic predisposition for VTE. All thrombosis-associated mutations potentiate coagulation activity by either conferring antithrombin resistance and/or impairing PC pathway activity.
遗传性易栓症患者的血栓形成性突变易引发静脉血栓栓塞（VTE）。虽然纯合子或复合杂合子突变导致的凝血酶原缺乏与出血素质相关，但罕见病例显示杂合子凝血酶原突变与血栓形成之间存在关联。
我们对347例无诱因VTE或有血栓形成家族史阳性的患者进行了参与血栓形成和止血的基因变异调查。对于鉴定出杂合子凝血酶原突变的患者，我们进行了家系调查并进行了凝血酶生成试验（TGT）以阐明血栓形成风险。表达新的突变体并进行功能测定以阐明潜在的血栓形成机制。
3.5%的患者（12/347）鉴定出杂合子凝血酶原突变，包括分别在1例患者中发现的3种新突变Phe382Ser、Phe382Leu和Asp597Tyr，以及先前报道的4例患者中的Arg541Trp突变和5例患者中的Arg596Gln突变。在12个家系中共鉴定出42名突变携带者，其中64.3%（27/42）经历过血栓形成事件。TGT结果显示5种突变的携带者具有高凝性，Arg596Gln的凝血酶生成潜力最高，其次是Arg541Trp。与Phe382相关的突变严重损害了凝血酶与血栓调节蛋白的结合能力，导致蛋白C（PC）激活明显减少。Asp597Tyr突变在抗凝血酶灭活和PC激活反应中均表现出轻度降低。
杂合子凝血酶原突变的存在代表了VTE的潜在遗传易感性。所有与血栓形成相关的突变通过赋予抗凝血酶抗性和/或损害PC途径活性来增强凝血活性。
