OBJECTIVE Defective 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 Results: In 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. CONCLUSIONS In 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.

中文翻译：

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凝血酶原Arg541Trp突变导致有缺陷的PC（蛋白C）途径活化，并构成静脉血栓形成的新型遗传危险因素。

目的缺陷性PC（蛋白C）通路使患者易患静脉血栓栓塞症（VTE），主要但并非唯一地归因于遗传性PC或PS（蛋白S）缺陷以及由因子V莱顿突变引起的活化的PC抗性。方法和结果：在患有急性肠系膜静脉血栓形成和VTE阳性家族史并伴有凝血酶生成测试确定的PC通路功能受损的患者中，我们鉴定了一种新型的杂合性凝血酶原突变p.Arg541Trp。在另外373名无亲缘关系的患者队列中，又发现了两名VTE家族史阳性且携带相同突变的患者，总体患病率为0.8％。家庭调查显示，这3个家系中有11个个体携带杂合的凝血酶原p.Arg541Trp突变，其中8位（72％）曾经历过VTE发作。功能研究表明，该突变会适度降低凝血酶原的促凝血活性，并通过其抑制剂抗凝血酶对凝血酶的失活产生轻微影响。然而，在不存在和存在可溶性血栓调节蛋白的情况下，氨基酸残基取代均显着损害了凝血酶对PC的激活，从而使凝血酶原功能偏向促凝剂。结论综上所述，凝血酶原p.Arg541Trp突变通过损害PC通路功能和使凝血酶的促凝血活性超过抗凝功能而构成VTE的新的遗传危险因素。功能研究表明，该突变会适度降低凝血酶原的促凝血活性，并通过其抑制剂抗凝血酶对凝血酶的失活产生轻微影响。然而，在不存在和存在可溶性血栓调节蛋白的情况下，氨基酸残基取代均显着损害了凝血酶对PC的激活，从而使凝血酶原功能偏向促凝剂。结论综上所述，凝血酶原p.Arg541Trp突变通过损害PC通路功能和使凝血酶的促凝血活性超过抗凝功能而构成VTE的新的遗传危险因素。功能研究表明，该突变会适度降低凝血酶原的促凝血活性，并通过其抑制剂抗凝血酶对凝血酶的失活产生轻微影响。然而，在不存在和存在可溶性血栓调节蛋白的情况下，氨基酸残基取代均显着损害了凝血酶对PC的激活，从而使凝血酶原功能偏向促凝剂。结论综上所述，凝血酶原p.Arg541Trp突变通过损害PC通路功能和使凝血酶的促凝血活性超过抗凝功能而构成VTE的新的遗传危险因素。