急性冠脉综合征患者组织因子途径抑制物血浆水平及其基因V264M多态性的研究
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摘要
背景 冠状动脉粥样硬化斑块溃疡、破裂基础上的血栓形成是急性冠脉综合征(ACS)的重要发病机制。近年研究发现，组织因子(TF)是凝血瀑布的主要启动因素，在动脉血栓形成中起关键作用。组织因子途径抑制物(TFPI)通过阻断TF介导的凝血系统活化，发挥天然的抗凝作用。此外，TFPI可以减少炎症趋化因子水平及抑制血管壁细胞增殖。因此，TFPI在动脉粥样硬化形成和血栓性疾病发病中具有重要意义。冠心病是多因素疾病，对冠心病新的危险因素的探索有助于其病理机制的深入理解。ACS是冠心病一系列心肌缺血谱中危险性大、死亡率高的严重状态，研究ACS相关危险因素意义重大。
目的 本研究旨在检测ACS患者血浆总TFPI(T．TFPI)水平及TFPI基因9号外显子V264M多态性，分析血浆T．TFPI水平与ACS的相关性，对血浆T．TFPI水平在ACS危险分层和预后判断的价值进行评估，并对TFPI基因V264M多态性与血浆TFPI水平及ACS之间的相关性进行初步探讨。
材料和方法选：择2003年2月～8月郑州大学第一附属附院心内科53例ACS住院患者，按发病时ST段变化分为两组：ST段抬高的ACS (STEACS)组27例；非ST段抬高的ACS(NSTEACS)组26例。所有患者均经心电图和心肌酶学检测证实，其中19例冠脉造影进一步证实，STEACS组均为ST段抬高的心肌梗死(STEMI)病例。设门诊健康体检者53例为正常对照组。所有研究对象均为河南籍汉族人。ACS患者发病24h以内于肝素注射前、对照组于门
郑州大学2004届硕士学位论文
急性冠脉综合征患者组织因子途径抑制物血浆水平及其基因VZMM多态性的研究
诊SAM前空腹抽取肘正中静脉血4ml，3.8%构椽酸钠1:9(v/v)抗凝。应用酶
联免疫吸附试验(E LISA)法测定各组血浆T.TFPI水平，比较各组血浆T.TFPI水
平变化。根据血浆T.n子PI水平分别将53例ACS患者分为血浆T.吓PI水平)
137.47ng/ml组和血浆’r.TFpl水平<137.47ng/Inl组，观察两组住院及随访(6
个月)期间主要心血管事件(MACE)的发生率，包括再发缺血性心绞痛、非致
死性心肌梗死、心源性碎死。同时，采用聚合酶链式反应一限制性片段长度多态
性(P CR一RFLP)技术对53例ACS患者和53例正常对照组TFPI基因v264M多态
性进行检测。
结果(l) ACS患者血浆T.TFPI水平显著高于正常对照组(137.4升51.93
vs 78.1肚9.49，尸<0.001)。STEACS组血浆T.TFPI水平明显高于对照组
(177.95士33.02 vs 78.13士9.49，P<0.001);NSTEACS组血浆T.TFPI水平明显高
于对照组(95.44土29.4三;vs 78.18士9.49，P<0.001);STEACS组血浆T.TFPI水平
明显高于NSTEACS组(177.95士33.02 vs 95.科士29.45，P<0.05)。(2)血浆T.吓Pl
<137.47ng/ml组中NS;TEACS者占88.9%，STEACS者占11.1%;而T.TFpl)
137.47ng/ml组NSTEACS者占7.7%，STEACS者占 92.3%，两组间有显著差异
(尸<0.001)。T.TFPI〕137.47ng/ml组ACS患者住院及随访期间MAcE发生率
为50%，而血浆T.TFPI<1 37.47n岁ml组MACE发生率为n.1%，两组差异有统
计学意义(尸<0.01)。(3) Cox比例风险回归分析显示:校正年龄、性别、血压、
糖尿病、血脂、吸烟、家族史等临床因素影响后，白细胞计数和T.TFPI可以估
计ACS患者总体预后。白细胞计数相对危险度(RR)2一083(95%CI:1 .301一
3.334)，血浆T.TFPI水平RR 1.216(95%Cl:1.203一1.229)。(4)检测53例ACS
患者和53例对照组Tl了Pl基因9号外显子V264M多态性，中国河南地区汉族人
群未显示V264M多态性。
结论(l) TFPI作为TF凝血途径的抑制物，可间接反映内皮损伤及凝血系
统激活;(2) ACS患者发病24h以内血浆T.TFP一【水平有助于早期识别ACS高危
患者，并对ACS患者预后判断有一定价值;(3)中国河南籍汉族人群未显示TFPI
9号外显子V264M多态性。
Background: Thrombus formation on disrupted and ulcer atherosclerotic lesions plays a fundamental role in the onset of acute coronary syndrome(ACS). Recent studies have showed tissue factor(TF) plays a major role in arterial thrombosis. TF is the main initiator of the coagulation cascade. Tissue factor pathway inhibitor(TFPI), as a natural anticoagulant, is thought to inhibit TF-induced activation of the coagulation cascade. In addition, TFPI decreases plasma levels of inflammatory chemotaxin and inhibits the proliferation of vascular wall cells by inducing apoptosis. Therefore, TFPI plays an important role in the atherosclerosis and thrombosis. Coronary artery disease is caused by multifactor. To explore new risk factors of coronary artery disease will contribute to understand deeply its mechanism. ACS is thought to the severe state of a series of myocardial ischemia spectrum according to its high risk and mortality, so it is very significant to study the involved risk factors of ACS.
Objectives: The aim of this study was designed to examine the plasma level of total TFPI(T.TFPI) in patients with ACS and the V264M polymorphism of the TFPI gene exon IX. The relationship between the plasma level of T.TFPI and ACS was analysed. We also sought to evaluate the predicting value of plasma level of T.TFPI for risk stratification and prognosis in patients with ACS. Meanwhile, the
relationships between the V264M polymorphism of the TFPI gene exon DC in Han nationality of Chinese in Henan area and plasma level of T.TFPI and ACS were analyzed.
Methods: We selected fifty-three in-patients with ACS in the cardiovascular department of the first affiliated hospital of zhengzhou university from February 2003 to August 2003. They were divided into two groups: twenty-seven ST-segment elevated ACS (STEACS) patients and twenty-six non-ST-segment elevated ACS (NSTEACS) patients, according to the ST-segment changes on the onset of ACS. All patients with ACS were diagnosed by electrocardiogram and cardiac enzyme, of which, 19 documented also by coronary angiography. In addition, there were fifty-three healthy subjects for physical examination served as a control group. All of the studied subjects were Han nationality of Chinese in Henan area. 4ml venous blood of the patients with ACS in hospital was taken from the antecubital vein within 24h and before intravenous heparin; while that of the control subjects in out-patient before 8AM on an empty stomach. Those blood was collected into 3.8% trisodium citrate anticoagulant solution in the proportion of 9 volumes of blood to 1 volume of anticoagulant solution. Plasma level of T.TFPI was determined by enzyme linked immunosorbent assay (ELISA) and compared in each group. Meanwhile, fifty-three patients with ACS were divided into >137.47ng/ml group and <137.47ng/ml group according to the plasma level of T.TFPI. The incidences of major adverse cardiovascular events (MACE), including recurrent ischemic angina, nonfatal myocardial infarction and cardiac sudden death, were observed in each group during in-hospital and follow-up period (six months). The V264M polymorphism of the TFPI was also examined by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) technology in 53 patients with ACS and 53 control subjects.
Results: (1) The plasma level of T.TFPI was significantly higher in the ACS group than in the control group (137.47+51.93ng/ml vs 78.18+9.49ng/ml, P<0.001), and was substantially higher in the STEACS group and in the NSTEACS group than in the control group(177.95+33.02 vs 78.18+9.49 and 95.44+29.45 vs 78.18+9.49, P
< 0.001, respectively). The plasma level of T.TFPI increased in the STEACS group more than in the NSTEACS group(177.95+33.02 vs 95.44+29.45, P<0.05). (2) The patients with NSTEACS and STEACS respectively accounted for 88.9% and 11.1% in T.TFPK137.47ng/ml group. In contrary, the patients with NSTEACS and STEACS accounted for 7.7% and 92.3% in T.TFPI> 137.47ng/ml group respectively. There was a significant difference between high-level grou
目的 本研究旨在检测ACS患者血浆总TFPI(T．TFPI)水平及TFPI基因9号外显子V264M多态性，分析血浆T．TFPI水平与ACS的相关性，对血浆T．TFPI水平在ACS危险分层和预后判断的价值进行评估，并对TFPI基因V264M多态性与血浆TFPI水平及ACS之间的相关性进行初步探讨。
材料和方法选：择2003年2月～8月郑州大学第一附属附院心内科53例ACS住院患者，按发病时ST段变化分为两组：ST段抬高的ACS (STEACS)组27例；非ST段抬高的ACS(NSTEACS)组26例。所有患者均经心电图和心肌酶学检测证实，其中19例冠脉造影进一步证实，STEACS组均为ST段抬高的心肌梗死(STEMI)病例。设门诊健康体检者53例为正常对照组。所有研究对象均为河南籍汉族人。ACS患者发病24h以内于肝素注射前、对照组于门
郑州大学2004届硕士学位论文
急性冠脉综合征患者组织因子途径抑制物血浆水平及其基因VZMM多态性的研究
诊SAM前空腹抽取肘正中静脉血4ml，3.8%构椽酸钠1:9(v/v)抗凝。应用酶
联免疫吸附试验(E LISA)法测定各组血浆T.TFPI水平，比较各组血浆T.TFPI水
平变化。根据血浆T.n子PI水平分别将53例ACS患者分为血浆T.吓PI水平)
137.47ng/ml组和血浆’r.TFpl水平<137.47ng/Inl组，观察两组住院及随访(6
个月)期间主要心血管事件(MACE)的发生率，包括再发缺血性心绞痛、非致
死性心肌梗死、心源性碎死。同时，采用聚合酶链式反应一限制性片段长度多态
性(P CR一RFLP)技术对53例ACS患者和53例正常对照组TFPI基因v264M多态
性进行检测。
结果(l) ACS患者血浆T.TFPI水平显著高于正常对照组(137.4升51.93
vs 78.1肚9.49，尸<0.001)。STEACS组血浆T.TFPI水平明显高于对照组
(177.95士33.02 vs 78.13士9.49，P<0.001);NSTEACS组血浆T.TFPI水平明显高
于对照组(95.44土29.4三;vs 78.18士9.49，P<0.001);STEACS组血浆T.TFPI水平
明显高于NSTEACS组(177.95士33.02 vs 95.科士29.45，P<0.05)。(2)血浆T.吓Pl
<137.47ng/ml组中NS;TEACS者占88.9%，STEACS者占11.1%;而T.TFpl)
137.47ng/ml组NSTEACS者占7.7%，STEACS者占 92.3%，两组间有显著差异
(尸<0.001)。T.TFPI〕137.47ng/ml组ACS患者住院及随访期间MAcE发生率
为50%，而血浆T.TFPI<1 37.47n岁ml组MACE发生率为n.1%，两组差异有统
计学意义(尸<0.01)。(3) Cox比例风险回归分析显示:校正年龄、性别、血压、
糖尿病、血脂、吸烟、家族史等临床因素影响后，白细胞计数和T.TFPI可以估
计ACS患者总体预后。白细胞计数相对危险度(RR)2一083(95%CI:1 .301一
3.334)，血浆T.TFPI水平RR 1.216(95%Cl:1.203一1.229)。(4)检测53例ACS
患者和53例对照组Tl了Pl基因9号外显子V264M多态性，中国河南地区汉族人
群未显示V264M多态性。
结论(l) TFPI作为TF凝血途径的抑制物，可间接反映内皮损伤及凝血系
统激活;(2) ACS患者发病24h以内血浆T.TFP一【水平有助于早期识别ACS高危
患者，并对ACS患者预后判断有一定价值;(3)中国河南籍汉族人群未显示TFPI
9号外显子V264M多态性。
Background: Thrombus formation on disrupted and ulcer atherosclerotic lesions plays a fundamental role in the onset of acute coronary syndrome(ACS). Recent studies have showed tissue factor(TF) plays a major role in arterial thrombosis. TF is the main initiator of the coagulation cascade. Tissue factor pathway inhibitor(TFPI), as a natural anticoagulant, is thought to inhibit TF-induced activation of the coagulation cascade. In addition, TFPI decreases plasma levels of inflammatory chemotaxin and inhibits the proliferation of vascular wall cells by inducing apoptosis. Therefore, TFPI plays an important role in the atherosclerosis and thrombosis. Coronary artery disease is caused by multifactor. To explore new risk factors of coronary artery disease will contribute to understand deeply its mechanism. ACS is thought to the severe state of a series of myocardial ischemia spectrum according to its high risk and mortality, so it is very significant to study the involved risk factors of ACS.
Objectives: The aim of this study was designed to examine the plasma level of total TFPI(T.TFPI) in patients with ACS and the V264M polymorphism of the TFPI gene exon IX. The relationship between the plasma level of T.TFPI and ACS was analysed. We also sought to evaluate the predicting value of plasma level of T.TFPI for risk stratification and prognosis in patients with ACS. Meanwhile, the
relationships between the V264M polymorphism of the TFPI gene exon DC in Han nationality of Chinese in Henan area and plasma level of T.TFPI and ACS were analyzed.
Methods: We selected fifty-three in-patients with ACS in the cardiovascular department of the first affiliated hospital of zhengzhou university from February 2003 to August 2003. They were divided into two groups: twenty-seven ST-segment elevated ACS (STEACS) patients and twenty-six non-ST-segment elevated ACS (NSTEACS) patients, according to the ST-segment changes on the onset of ACS. All patients with ACS were diagnosed by electrocardiogram and cardiac enzyme, of which, 19 documented also by coronary angiography. In addition, there were fifty-three healthy subjects for physical examination served as a control group. All of the studied subjects were Han nationality of Chinese in Henan area. 4ml venous blood of the patients with ACS in hospital was taken from the antecubital vein within 24h and before intravenous heparin; while that of the control subjects in out-patient before 8AM on an empty stomach. Those blood was collected into 3.8% trisodium citrate anticoagulant solution in the proportion of 9 volumes of blood to 1 volume of anticoagulant solution. Plasma level of T.TFPI was determined by enzyme linked immunosorbent assay (ELISA) and compared in each group. Meanwhile, fifty-three patients with ACS were divided into >137.47ng/ml group and <137.47ng/ml group according to the plasma level of T.TFPI. The incidences of major adverse cardiovascular events (MACE), including recurrent ischemic angina, nonfatal myocardial infarction and cardiac sudden death, were observed in each group during in-hospital and follow-up period (six months). The V264M polymorphism of the TFPI was also examined by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) technology in 53 patients with ACS and 53 control subjects.
Results: (1) The plasma level of T.TFPI was significantly higher in the ACS group than in the control group (137.47+51.93ng/ml vs 78.18+9.49ng/ml, P<0.001), and was substantially higher in the STEACS group and in the NSTEACS group than in the control group(177.95+33.02 vs 78.18+9.49 and 95.44+29.45 vs 78.18+9.49, P
< 0.001, respectively). The plasma level of T.TFPI increased in the STEACS group more than in the NSTEACS group(177.95+33.02 vs 95.44+29.45, P<0.05). (2) The patients with NSTEACS and STEACS respectively accounted for 88.9% and 11.1% in T.TFPK137.47ng/ml group. In contrary, the patients with NSTEACS and STEACS accounted for 7.7% and 92.3% in T.TFPI> 137.47ng/ml group respectively. There was a significant difference between high-level grou
引文
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42. Moatti D, Haidar B, Fumeron F, et al. A new T-287C polymorphism in the 5'regiontory region of the tissue factor pathway inhibitor gene. Association study of the T-287C and C-399T polymorphisms with coronary artery disease and plasma TFPI levels. Thromb haemost.2000;84(2):244-9.
43. Ameziane N, Seguin C, Borgel D, et al. The-33T→C polymorphism in intron 7 of the TFPI gene influnences the risk of venous thromboembolisis, independently of the factor V Leiden and prothrombin mutations. Thromb Haemost. 2002;88(2):195-9.
44. Gabriele M, Ravindra S. Allele frequencies of tissue factor pathway inhibitor polymorphisms in african-american, hispanic and caucasian populations. Thromb Haemost. 2002;88:875-7. Letter.