Prothrombin Arg541Trp Mutation Leads to Defective PC (Protein C) Pathway Activation and Constitutes a Novel Genetic Risk Factor for Venous Thrombosis
Prothrombin Arg541Trp Mutation Leads to Defective PC (Protein C) Pathway Activation and Constitutes a Novel Genetic Risk Factor for Venous Thrombosis
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凝血酶原 Arg541Trp 突变导致 PC（蛋白 C）通路激活缺陷并构成静脉血栓形成的新遗传风险因素
DOI：
10.1161/atvbaha.119.313373
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
Wang Xuefeng
中科院分区：
文献类型：
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作者：
Wu Xi;Dai Jing;Xu Xiaoqian;Li Fang;Li Lei;Lu Yeling;Xu Qin;Ding Qiulan;Wu Wenman;Wang Xuefeng
目的PC（蛋白C）通路缺陷使患者易发生静脉血栓栓塞（VTE），主要但不完全归因于遗传性PC或PS（蛋白S）缺陷以及V - Leiden因子突变引起的活化的PC耐药。方法与结果在1例急性肠系膜静脉血栓形成患者中，通过凝血酶生成试验发现了一种新的杂合凝血酶原突变p.a g541trp。在另外373名不相关患者的队列中，又发现了2名携带相同突变的静脉血栓栓塞家族史阳性患者，总患病率为0.8%。家族调查显示，3个家系中有11人携带凝血酶原p.a g541trp杂合突变，其中8人（72%）发生过静脉血栓栓塞发作。功能研究表明，该突变适度降低了凝血酶原的促凝活性，对凝血酶抑制剂抗凝血酶的失活有轻微影响。然而，氨基酸残基取代显著损害凝血酶对PC的激活，无论是在不存在可溶性凝血调节蛋白的情况下还是在存在可溶性凝血调节蛋白的情况下，从而使凝血酶原功能偏向于促凝剂。结论综上所述，凝血酶原p.a g541trp突变通过损害PC通路功能，使凝血酶的促凝活性向抗凝功能倾斜，从而构成静脉血栓栓塞新的遗传危险因素。
ObjectiveDefective PC (protein C) pathway predisposes patients to venous thromboembolism (VTE) and is mostly, but not exclusively, attributed to hereditary PC or PS (protein S) deficiencies and activated PC resistance caused by factor V Leiden mutation.Approach and ResultsIn a patient with acute mesenteric venous thrombosis and positive family history of VTE associated with the impaired PC pathway function determined by thrombin generation test, we identified a novel heterozygous prothrombin mutation p.Arg541Trp. Two more patients with positive family history of VTE carrying the same mutation were identified in a cohort of another 373 unrelated patients, making an overall prevalence of 0.8%. Family investigation revealed 11 individuals in the 3 pedigrees harboring the heterozygous prothrombin p.Arg541Trp mutation, and 8 of them (72%) had experienced episodes of VTE. Functional studies indicated the mutation moderately decreased procoagulant activity of prothrombin and had mild impact on the inactivation of thrombin by its inhibitor antithrombin. However, the amino acid residue substitution significantly compromised PC activation by thrombin, both in the absence and presence of soluble thrombomodulin, and thus rendered prothrombin function procoagulant biased.ConclusionsIn summary, the prothrombin p.Arg541Trp mutation constitutes a new genetic risk factor of VTE by impairing function of PC pathway and tilting thrombin’s procoagulant activity over anticoagulant function.