冠心病活化血小板内TFPI的表达及低分子肝素对其抗凝机制的探讨
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摘要
目的:探讨冠心病患者活化血小板内组织因子途径抑制剂(TFPI,Tissue factor pathway inhibitor)的表达及其与低分子肝素(LMWH,Low molecular weigh heparin)抗凝机制的关系。
方法:采用病例对照研究的方法,收集福建省立医院经冠脉造影确诊的冠心病患者37例做为病例组,包括急性心肌梗死(AMI)、不稳定型心绞痛(UA)、稳定型心绞痛(SA)三组患者,同期我院体检正常者31例做为对照组;统计所有研究对象的年龄、性别、生化指标等临床资料;测定血浆白细胞计数(WBC)、中性粒细胞比例(N%)、血小板计数(PLT)、总蛋白(TP)、白蛋白(ALB)、球蛋白(GLB)、丙氨酸转氨酶(ALT)、天门冬氨酸转氨酶(AST)、甘油三酯(TG)、总胆固醇(TC)、高密度脂蛋白(HDL)、低密度脂蛋白(LDL)、空腹血糖(FPG)、尿素氮(BUN)、肌酐(Scr)、尿酸(UA)等生化指标;三组患者应用低分子肝素(LMWH)前后及对照组,采用酶联免疫吸附法(ELISA)检测血浆游离组织因子途径抑制剂(FTFPI)浓度;采用Trizol一步法提取血小板内总RNA(mRNA)、逆转录(RT)法合成cDNA、聚合酶链反应(PCR)扩增目的基因,PCR产物经紫外凝胶成像系统扫描成像并做半定量分析,了解目的基因表达情况;应用SPSS13.0软件分析数据。
结果:1.两组研究对象及三组患者之间年龄、性别、WBC、N%、PLT、TP、ALB、GLB、ALT、AST、TC、TG、HDL、LDL、FPG、BUN、CR、UA均无显著性差异(P>0.05)。
2. One-Way ANOVA检验结果显示:AMI组、UA组血小板内TFPI mRNA的表达升高,分别为1.07、0.92,与对照组0.64相比较,差异有统计学意义(P﹤0.05)。Independent-Samples T Test检验结果显示:病例组血小板内TFPI mRNA的表达为0.87,与对照组0.92相比较,差异有统计学意义(P﹤0.01)。
3. One-Way ANOVA检验结果显示:AMI组、UA组和SA组的血浆FTFPI水平分别为92.08、74.91、62.76ug/L,与对照组55.45ug/L相比,前两组水平明显升高(P﹤0.05)。Independent-Samples T Test检验结果显示:病例组血浆FTFPI水平为77.04ug/L,与对照组55.45ug/L相比明显升高(P﹤0.05)。
4.Pearson相关分析显示:血小板TFPI mRNA的表达与AMI组、UA组、SA组血浆FTFPI水平存在正相关关系,相关系数r=0.760;抗凝治疗后,血浆FTFPI水平与血小板内mRNA表达水平存在正相关关系,相关系数r=0.656。
5.Paired-Samples T Test检验显示:三组患者应用LMWH后,FTFPI水平分别为141.87、116.82、107.28ug/L,与治疗前92.08、74.91、62.76ug/L相比,差异有统计学意义(P<0.01)。Paired-Samples T Test检验显示:病例组抗凝治疗后,血浆FTFPI水平为121.85ug/L,与治疗前77.04ug/L相比有明显升高(P<0.01)。
结论:1. TFPI是重要的血小板内容物,TFPI的mRNA存在于血小板内,并普遍存在于正常人体内;2.冠心病有异常激活的高凝状态,导致基础血浆FTFPI水平增高;3.冠心病患者活化血小板内TFPI mRNA的表达升高,TFPI表达与冠心病严重程度相关或与血小板活化程度相关;4. TFPI与LMWH的抗凝机制有关,应用LMWH抗凝治疗后血浆FTFPI水平明显升高,LMWH具有独特的TFPI释放机制;5.通过对血小板内TFPI的表达研究及应用LMWH的影响,为进一步研究TFPI及冠心病的治疗提供了新的思路。
Objective: To investigate the expression of TFPI mRNA in activated platelet in patients with CHD and the anticoagulant mechanism of LMWH for them.
Methods: In order to undertake a case-control study,37 coronary heart disease (CHD)hospitalized patients diagnosed by coronary angiography(case group) and 31 subjects without CHD (control group)in Fujian provincial hospital were studied.Case group was divided into three groups,AMI,UA and SA group.Basic clinical data such as age,gender,vital sign were collected.Biochemical parameters such as white blood-cell count(WBC),neutroplil%(N%),Platelet count(PLT),Total Protein(TP),Albumin(ALB),Globulin (GLB),Alanine aminotransferase(ALT),Aspartate aminotransferase(AST),Triglyceride(TG),Total cholesterol(TC),High density lipoprotein(HDL),Low density lipoprotein(LDL),Fasting Plasma Glucose(FPG),Blood urea nitrogen(BUN),Serun creatinine(Scr) and Uric acid(UA)were measured. By means of ELISA technique, the levels of free-TFPI were measured in the both groups in the study,before and after LMWH treatment.By means of Trizol astracted the mRNA of platelet,RT-PCR appropriated the aim fragement,Gel Imaging System scanned and semi-quantitative analyzed,the activated pletelet mRNA levels were measured.SPSS 13.0 was used to analyze all the data.
Results: 1.The level of age,gender,WBC,N%,PLT,TP,ALB,GLB,ALT,AST,TC,TG,HDL,LDL,FPG,BUN,CR and UA had no significant differences between case group and control group(P>0.05). 2.One-way ANOVA showed that the mRNA expression level of TFPI in platelet in patients with AMI and UA were significant higher than that of control group(P﹤0.05). [1.07,0.92vs 0.64]. Independent-Samples T Test showed that the mRNA expression level of TFPI in platelet with case group were significant higher than that of control group(P﹤0.01). [0.92 vs 0.64] 3.One-way ANOVA showed that level of free-TFPI in patients with AMI ,UA and SA were 92.08、74.91 and 62.76ug/L.The front two groups were significantly higher than the control group whose level was 55.45ug/L.Independent-Samples T Test showed that the average level of FTFPI with case group were significant higher than that of control group(P﹤0.05).[ 77.04ug/L vs55.45ug/L] 4.There were positive correlation between the mRNA expression of TFPI in platelet and the change of plasma free-TFPI in patients with AMI,UA and SA before and after LMWH treatment. Correlation coefficient R were 0.760 and 0.656.5.Paired-Samples T Test showed that after the treatment by LMWH,free-TFPI increased significantly among the AMI,UA and SA group(P<0.01).The average level of FTFPI of those three groups exposured to LMWH were141.87、116.82 and 107.28ug/L,compared with 92.08、74.91、62.76ug/L before treatment. Paired-Samples T Test showed that the average level of free-TFPI after treatment by LMWH were significant higher than that without treatment(P<0.01). [121.85ug/L vs 77.04ug/L].
Conclusions:1.The mRNA of TFPI which was one of the major contents in platelet was expressed in platelet of human being.2.CHD had unusually activated hypercoagulative state,which caused the basic plasma FTFPI level elevation.3.The expression of TFPI were enhanced in CHD patient with platelet activation and had correlation to the severity of CHD or activation level of platelet.4.TFPI had relevant to the unique anticoagulant mechanism of LMWH.The plasma FTFPI level further rises obviously after applying LMWH anti-freezing in CHD.5.According to the research of TFPI expression in platelet and anticoagulant mechanism of LMWH,we might provide a new and unique way to study the TFPI and the treatment of CHD.
方法:采用病例对照研究的方法,收集福建省立医院经冠脉造影确诊的冠心病患者37例做为病例组,包括急性心肌梗死(AMI)、不稳定型心绞痛(UA)、稳定型心绞痛(SA)三组患者,同期我院体检正常者31例做为对照组;统计所有研究对象的年龄、性别、生化指标等临床资料;测定血浆白细胞计数(WBC)、中性粒细胞比例(N%)、血小板计数(PLT)、总蛋白(TP)、白蛋白(ALB)、球蛋白(GLB)、丙氨酸转氨酶(ALT)、天门冬氨酸转氨酶(AST)、甘油三酯(TG)、总胆固醇(TC)、高密度脂蛋白(HDL)、低密度脂蛋白(LDL)、空腹血糖(FPG)、尿素氮(BUN)、肌酐(Scr)、尿酸(UA)等生化指标;三组患者应用低分子肝素(LMWH)前后及对照组,采用酶联免疫吸附法(ELISA)检测血浆游离组织因子途径抑制剂(FTFPI)浓度;采用Trizol一步法提取血小板内总RNA(mRNA)、逆转录(RT)法合成cDNA、聚合酶链反应(PCR)扩增目的基因,PCR产物经紫外凝胶成像系统扫描成像并做半定量分析,了解目的基因表达情况;应用SPSS13.0软件分析数据。
结果:1.两组研究对象及三组患者之间年龄、性别、WBC、N%、PLT、TP、ALB、GLB、ALT、AST、TC、TG、HDL、LDL、FPG、BUN、CR、UA均无显著性差异(P>0.05)。
2. One-Way ANOVA检验结果显示:AMI组、UA组血小板内TFPI mRNA的表达升高,分别为1.07、0.92,与对照组0.64相比较,差异有统计学意义(P﹤0.05)。Independent-Samples T Test检验结果显示:病例组血小板内TFPI mRNA的表达为0.87,与对照组0.92相比较,差异有统计学意义(P﹤0.01)。
3. One-Way ANOVA检验结果显示:AMI组、UA组和SA组的血浆FTFPI水平分别为92.08、74.91、62.76ug/L,与对照组55.45ug/L相比,前两组水平明显升高(P﹤0.05)。Independent-Samples T Test检验结果显示:病例组血浆FTFPI水平为77.04ug/L,与对照组55.45ug/L相比明显升高(P﹤0.05)。
4.Pearson相关分析显示:血小板TFPI mRNA的表达与AMI组、UA组、SA组血浆FTFPI水平存在正相关关系,相关系数r=0.760;抗凝治疗后,血浆FTFPI水平与血小板内mRNA表达水平存在正相关关系,相关系数r=0.656。
5.Paired-Samples T Test检验显示:三组患者应用LMWH后,FTFPI水平分别为141.87、116.82、107.28ug/L,与治疗前92.08、74.91、62.76ug/L相比,差异有统计学意义(P<0.01)。Paired-Samples T Test检验显示:病例组抗凝治疗后,血浆FTFPI水平为121.85ug/L,与治疗前77.04ug/L相比有明显升高(P<0.01)。
结论:1. TFPI是重要的血小板内容物,TFPI的mRNA存在于血小板内,并普遍存在于正常人体内;2.冠心病有异常激活的高凝状态,导致基础血浆FTFPI水平增高;3.冠心病患者活化血小板内TFPI mRNA的表达升高,TFPI表达与冠心病严重程度相关或与血小板活化程度相关;4. TFPI与LMWH的抗凝机制有关,应用LMWH抗凝治疗后血浆FTFPI水平明显升高,LMWH具有独特的TFPI释放机制;5.通过对血小板内TFPI的表达研究及应用LMWH的影响,为进一步研究TFPI及冠心病的治疗提供了新的思路。
Objective: To investigate the expression of TFPI mRNA in activated platelet in patients with CHD and the anticoagulant mechanism of LMWH for them.
Methods: In order to undertake a case-control study,37 coronary heart disease (CHD)hospitalized patients diagnosed by coronary angiography(case group) and 31 subjects without CHD (control group)in Fujian provincial hospital were studied.Case group was divided into three groups,AMI,UA and SA group.Basic clinical data such as age,gender,vital sign were collected.Biochemical parameters such as white blood-cell count(WBC),neutroplil%(N%),Platelet count(PLT),Total Protein(TP),Albumin(ALB),Globulin (GLB),Alanine aminotransferase(ALT),Aspartate aminotransferase(AST),Triglyceride(TG),Total cholesterol(TC),High density lipoprotein(HDL),Low density lipoprotein(LDL),Fasting Plasma Glucose(FPG),Blood urea nitrogen(BUN),Serun creatinine(Scr) and Uric acid(UA)were measured. By means of ELISA technique, the levels of free-TFPI were measured in the both groups in the study,before and after LMWH treatment.By means of Trizol astracted the mRNA of platelet,RT-PCR appropriated the aim fragement,Gel Imaging System scanned and semi-quantitative analyzed,the activated pletelet mRNA levels were measured.SPSS 13.0 was used to analyze all the data.
Results: 1.The level of age,gender,WBC,N%,PLT,TP,ALB,GLB,ALT,AST,TC,TG,HDL,LDL,FPG,BUN,CR and UA had no significant differences between case group and control group(P>0.05). 2.One-way ANOVA showed that the mRNA expression level of TFPI in platelet in patients with AMI and UA were significant higher than that of control group(P﹤0.05). [1.07,0.92vs 0.64]. Independent-Samples T Test showed that the mRNA expression level of TFPI in platelet with case group were significant higher than that of control group(P﹤0.01). [0.92 vs 0.64] 3.One-way ANOVA showed that level of free-TFPI in patients with AMI ,UA and SA were 92.08、74.91 and 62.76ug/L.The front two groups were significantly higher than the control group whose level was 55.45ug/L.Independent-Samples T Test showed that the average level of FTFPI with case group were significant higher than that of control group(P﹤0.05).[ 77.04ug/L vs55.45ug/L] 4.There were positive correlation between the mRNA expression of TFPI in platelet and the change of plasma free-TFPI in patients with AMI,UA and SA before and after LMWH treatment. Correlation coefficient R were 0.760 and 0.656.5.Paired-Samples T Test showed that after the treatment by LMWH,free-TFPI increased significantly among the AMI,UA and SA group(P<0.01).The average level of FTFPI of those three groups exposured to LMWH were141.87、116.82 and 107.28ug/L,compared with 92.08、74.91、62.76ug/L before treatment. Paired-Samples T Test showed that the average level of free-TFPI after treatment by LMWH were significant higher than that without treatment(P<0.01). [121.85ug/L vs 77.04ug/L].
Conclusions:1.The mRNA of TFPI which was one of the major contents in platelet was expressed in platelet of human being.2.CHD had unusually activated hypercoagulative state,which caused the basic plasma FTFPI level elevation.3.The expression of TFPI were enhanced in CHD patient with platelet activation and had correlation to the severity of CHD or activation level of platelet.4.TFPI had relevant to the unique anticoagulant mechanism of LMWH.The plasma FTFPI level further rises obviously after applying LMWH anti-freezing in CHD.5.According to the research of TFPI expression in platelet and anticoagulant mechanism of LMWH,we might provide a new and unique way to study the TFPI and the treatment of CHD.
引文
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[43].Kaiser B, Glusa E, Hoppensteadt DA, et al. A supersulfated low-molecular-weight heparin (IK-SSH) increases plasma levels of free and total tissue factor pathway inhibitor after intravenous and subcutaneous administration in humans[J].Blood Coagul Fibrinolysis,1998,9(6):517-523.
[1].Harrison P.Plate function analysis.Blood Rev,2005,19(2):111-123.
[2].Nassar T,Sachais BS,Akkawi S,et a1.Platelet factor 4 enhances the binding of oxidized low density lipoprotein to vascular wall cells.J Biol Chem,2003,278 (8):6187-6193.
[3].Andrews RK, Gardiner EE, Shen Y,et al.Platelet interactions in thrombosis[J].IUBMB Life,2004,56(1):13-8.
[4].Holinstat M,Voss B,Bilodeau ML,et al.PAR4,but not PAR1,signals human platelet aggregation via Ca2+ mobilization and synergistic P2Y12 receptor activation.J Biol Chem,2006,281(36):26665-26674.
[5].Kasuda S,Sakurai Y,Shima M,et al. Inhibition of PAR4 signaling mediates ethanol-induced attenuation of platelet function in vitro.Alcohol Clin Exp Res,2006,30(9):1608-1614.
[6].Chen YJ, Wang JS, Chow SE,et al. Resveratrol protects vascular endothelial cell from ox-LDL-induced reduction in antithrombogenicactivity.Chin J Physiol,2007,50(1):22-28.
[7].Saini HK,Takeda N,Goyal RK,et al.Therapeutic potentials of sarpogrelate in cardiovascular disease.Cardiovasc Drug Rev,2004 ,22(1):27-54.
[8].Vasdev S, Gill V, Parai S,et al. Low ethanol intake prevents salt-induced hypertension in WKY rats.Mol Cell Biochem,2006,287(1-2):53-60.
[9].Panchenko EP,Shalaev SV,et al.Free cytoplasmic calcium and thrombocyte aggregation in patients with ischemic heart disease:The effect of ADP,thrombocyte activation factor and serotonin.Biull Vsesoiuznogo Kardiol Nauchn Tsentra AMN SSSR,1986,9(2):90-96.
[10].Stenberg PE,McEver RP,Shuman MA,et a1.A platelet alpha granule membrane protein(GMP-140)is expressed on the plasma membrane after activation.J Cell Biol,1985,101(3):880-886.
[11].Sedlmayr P,Grobhaupt B,Mumtean W,et a1.Flow cytometric detecti of intracellular platelet antigens.Cytometry,1996,23(4):284.
[12].Merten M, Thiagarajan P. P-selectin in arterial thrombosis.Z Kardiol,2004,93(11):855-863.
[13].Kappelmayer J, Nagy B Jr, Miszti-Blasius K,et al. The emerging value of P-selectin as a disease marker.Clin Chem Lab Med,2004,42(5):475-86.
[14].Furman MI,Benoit SE,Bamard MR,et a1.Increased platelet reactivity and circulating monocyte platelet aggregates in patients with stable coronary artery disease.J Am Coll Cardiol,1998,31(2):352.
[15].Ikuta T,Naruko T,Ikura Y,et al. Immunolocalization of platelet glycoprotein IIb/IIIa and P-selectin, and neutrophil-platelet interaction in human coronary unstable plaques.Int J Mol Med,2005,15(4):573-577.
[16].邱红,王静,江淑芳,等.冠心病患者血小板膜连蛋白V及P选择素的检测及临床意义.医学研究生学报,2007,2O(4):445-446.
[17].吴瑞霞,张群林,王玮,等.活化血小板检测在冠心病中的观察.实用老年医学,2003,17(1):29-30.
[18].Schneider DJ,Keating F,Sobel BE.Greater inhibitory effects of bivalirudin compared with unfractionated heparin plus eptifibitide on thrombin-induced platelet activation[J].Coron Artery Dis,2006,17(5):471-476.
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[20].Byzova TV,RabbaniR,Dsouza S,et a1.Role of integrin alpha(v) beta3 in vascular biology.Thromb Haemost,1998,80(5):726-734.
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[35].Haskel EJ,Torr SR,Day KC,et al.Prevention of arterial reocclusion after thrombolysis with recombinant lipoprotein-associated coagulation inhibitor.Circulation,1991,84(2):821-827.
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[1].Harrison P.Plate function analysis.Blood Rev,2005,19(2):111-123.
[2].Nassar T,Sachais BS,Akkawi S,et a1.Platelet factor 4 enhances the binding of oxidized low density lipoprotein to vascular wall cells.J Biol Chem,2003,278 (8):6187-6193.
[3].Andrews RK, Gardiner EE, Shen Y,et al.Platelet interactions in thrombosis[J].IUBMB Life,2004,56(1):13-8.
[4].Holinstat M,Voss B,Bilodeau ML,et al.PAR4,but not PAR1,signals human platelet aggregation via Ca2+ mobilization and synergistic P2Y12 receptor activation.J Biol Chem,2006,281(36):26665-26674.
[5].Kasuda S,Sakurai Y,Shima M,et al. Inhibition of PAR4 signaling mediates ethanol-induced attenuation of platelet function in vitro.Alcohol Clin Exp Res,2006,30(9):1608-1614.
[6].Chen YJ, Wang JS, Chow SE,et al. Resveratrol protects vascular endothelial cell from ox-LDL-induced reduction in antithrombogenicactivity.Chin J Physiol,2007,50(1):22-28.
[7].Saini HK,Takeda N,Goyal RK,et al.Therapeutic potentials of sarpogrelate in cardiovascular disease.Cardiovasc Drug Rev,2004 ,22(1):27-54.
[8].Vasdev S, Gill V, Parai S,et al. Low ethanol intake prevents salt-induced hypertension in WKY rats.Mol Cell Biochem,2006,287(1-2):53-60.
[9].Panchenko EP,Shalaev SV,et al.Free cytoplasmic calcium and thrombocyte aggregation in patients with ischemic heart disease:The effect of ADP,thrombocyte activation factor and serotonin.Biull Vsesoiuznogo Kardiol Nauchn Tsentra AMN SSSR,1986,9(2):90-96.
[10].Stenberg PE,McEver RP,Shuman MA,et a1.A platelet alpha granule membrane protein(GMP-140)is expressed on the plasma membrane after activation.J Cell Biol,1985,101(3):880-886.
[11].Sedlmayr P,Grobhaupt B,Mumtean W,et a1.Flow cytometric detecti of intracellular platelet antigens.Cytometry,1996,23(4):284.
[12].Merten M, Thiagarajan P. P-selectin in arterial thrombosis.Z Kardiol,2004,93(11):855-863.
[13].Kappelmayer J, Nagy B Jr, Miszti-Blasius K,et al. The emerging value of P-selectin as a disease marker.Clin Chem Lab Med,2004,42(5):475-86.
[14].Furman MI,Benoit SE,Bamard MR,et a1.Increased platelet reactivity and circulating monocyte platelet aggregates in patients with stable coronary artery disease.J Am Coll Cardiol,1998,31(2):352.
[15].Ikuta T,Naruko T,Ikura Y,et al. Immunolocalization of platelet glycoprotein IIb/IIIa and P-selectin, and neutrophil-platelet interaction in human coronary unstable plaques.Int J Mol Med,2005,15(4):573-577.
[16].邱红,王静,江淑芳,等.冠心病患者血小板膜连蛋白V及P选择素的检测及临床意义.医学研究生学报,2007,2O(4):445-446.
[17].吴瑞霞,张群林,王玮,等.活化血小板检测在冠心病中的观察.实用老年医学,2003,17(1):29-30.
[18].Schneider DJ,Keating F,Sobel BE.Greater inhibitory effects of bivalirudin compared with unfractionated heparin plus eptifibitide on thrombin-induced platelet activation[J].Coron Artery Dis,2006,17(5):471-476.
[19].Linden MD,Furman MI,Fox ML,et al. Indices of platelet activation and the stability of coronary artery disease.J Thromb Haemost,2007, 5(4):761-765.
[20].Byzova TV,RabbaniR,Dsouza S,et a1.Role of integrin alpha(v) beta3 in vascular biology.Thromb Haemost,1998,80(5):726-734.
[21].Coller BS.Blockade of platelet GPⅡb/Ⅲa receptors as an antithrombotic strategy.Circulation,1995,92(9):2373-2380.
[22]. Paolo P,Pier G M. The human platelet membrane glycoprotein IIb/IIIacomplex:a multi functional adhesion receptor.Haematologiea,1992,77(2):162-168.
[23].Andrews RK,Fox jE.Platelet receptors in hemostasis. Current opinion in cell biology,1990,2(5):894-901.
[24].Linden MD,Furman MI. Indices of platelet activation and the stability of coronary artery disease.J Thromb Haemost,2007,5(4):761-765.
[25].The PURSUIT trial Investigators.Inhibition of the platelet glycoprotein GP IIb/Ⅲa Receptor with epitifibatide in patients with acute coronary syndromes.N Engl J Med,1998,339(7):436-443.
[26].Chandler AB, Earhart AD, Speich HE,et al. Regulation of CD40L (CD154) and CD62P (p-selectin) Surface Expression upon GPIIb-IIIa Blockade of Platelets from Stable Coronary Artery Disease Patients.Thromb Res,2010,125(1):44-52.
[27].Ji Q,Ghaly M,Hjemdahl P,et al.Contrast medium attenutes platlet activation and platelet-leukocyte cross-talk.Thromb Haemost,2005,93(5):922 -926.
[28].Hanson PM.Textbook of immunopharmacology.Blackwell:Scientific ,1984,187.
[29].Yokoyama S,Ikeda H,Haramaki N,et al.Platelet P selectin plays an important role in arterial thrombogenesis by forming large stable platelet-leukocyte aggregates.J Am Coll Cardial,2005,45(8):1280-1286.
[30].Auchampath JA,Pieper GM,Caverol,et al.Effect of PAF antagonist RP59227 on myocardical ischemia reperfusion injury and neutrophil function.Basic Res Cardiol,1998,93(5):361-371.
[31].Serebruany VL,Gurbel PA,Murugesan SR,et al.Depressed plasma platelet activating factor acetylhydrolase in patients with acute myocardial infarction.Cardiology,1998,90(2):127-130.
[32].Soejima H,Ogawa H,Yasue H,et al.Heightened tissue factor associated with tissue factor pathway inhibitor and prognosis in patients with unstable angina1.Circulation,1999,99(22):2908 -2913.
[33].Ott I,Andrassy M,Zieglgansberger D,et al.Regulation of monocyte procoagulant activity in acute myocardial infarction: role of tissue factor and tissue factor pathway inhibitor-1.Blood,2001,97(12):3721 -3726.
[34].Ameri A,Kuppuswamy MN,Basu S.Expression of tissue factor pathway inhibition by cultured endothelial cells in response to inflammatory mediators.Blood,1992,79(12):3219-3226.
[35].Haskel EJ,Torr SR,Day KC,et al.Prevention of arterial reocclusion after thrombolysis with recombinant lipoprotein-associated coagulation inhibitor.Circulation,1991,84(2):821-827.