Tissue factor in acute coronary syndromes

Thrombosis at the site of atherosclerotic plaque disruption is the principal cause of acute coronary syndromes. The severity of the clinical consequences is determined by the extent and the progression of the thrombus that are caused by local and systemic factors. In atherosclerotic lesions mediators induce tissue factor (TF) in macrophages, smooth muscle cells, and endothelial cells. Procoagulant microparticles in the lipid core further enhance the thrombogenicity of the plaque. In addition, in acute coronary syndromes circulating monocytes and microparticles express TF and, thereby, contribute to systemic procoagulant activity. As a regulatory mechanism surface-bound, endogenous tissue factor pathway inhibitor-1 (TFPI) inhibits TF activity by translocation of the quaternary complex TF-FVIIa-FXa-TFPI into glycosphingolipid-rich microdomains more efficiently than exogenously added TFPI. This inhibition occurs not only in endothelial cells but also on circulating monocytes and presumably microparticles. Because therapeutic thrombolysis in acute myocardial infarction degrades TFPI, a prothrombotic state due to unopposed TF activity may occur. Several studies have demonstrated a contribution of local and bloodborne TF to thrombus formation; a direct relationship with the clinical outcome, however, awaits further studies. This article discusses the current understanding of the role of TF and its regulation by TFPI in acute coronary syndromes.     

Activated factor X and thrombin formation triggered by tissue factor on endothelial cell matrix in a flow model: effect of the tissue factor pathway inhibitor

The procoagulant subcellular matrix of stimulated endothelial cells that contains tissue factor (TF) was used to investigate the mechanism by which TF pathway inhibitor (TFPI) inhibits thrombin formation initiated by TF/factor VIIa (FVIIa) under flow conditions. Purified coagulation factors VII, X, and V and prothrombin were perfused at a wall shear rate of 100 s-1 through a flow chamber containing a coverslip covered with matrix of cultured human umbilical vein endothelial cells. This resulted in a TF- and FVII-dependent FXa and thrombin generation as measured in the effluent at the outlet of the system. Inhibition of this TF/FVIIa-triggered thrombin formation by TFPI purified from plasma was dependent on the amount of TF present on the endothelial cell matrix. The rate of prothrombinase assembly and steady-state levels of thrombin formation were decreased by TFPI. Because persistent albeit decreased steady-state levels of thrombin formation occurred in the presence of TFPI, we conclude that plasma- TFPI does not inhibit FXa present in the prothrombinase complex. The addition of FIX and FVIII to perfusates containing FVII and FX increased the FXa generation on endothelial matrices, and counteracted the inhibition of thrombin formation on endothelial cell matrices by TFPI. Our data provide further evidence for the hypothesis that the rapid inactivation of TF/FVIIa by TFPI in combination with the absence of either FVIII or FIX causes the bleeding tendency of patients with hemophilia A or B.     

急性心肌梗死患者直接介入治疗后无再流与血浆组织因子及其途径抑制物的关系

目的 通过测定急性心肌梗死(AMI)患者直接经皮冠状动脉介入治疗(PCI)前后血浆组织因子(TF)、组织因子途径抑制物(TFPI)水平的变化,探讨TF、TFPI与无再流的关系.方法 选择2006年5月至2007年5月于我院急诊行PCI的AMI患者53例,用ELISA法检测患者PCI术前、术后即刻、术后24 h外周静脉血 TF、TFPI水平.比较其中无再流者与再灌流者不同时点TF、TFPI水平的变化.结果 PCI术前、术后即刻、术后24 h无再流组血浆TF、TFPI水平均明显高于再灌流组[TF(275.3±46.2)ng/L比(236.8±44.3)ng/L、(332.7±41.3) ng/L 比(282.3±38.7) ng/L、(315.5±47.8) ng/L 比(248.1±46.9) ng/L;TFPI(165.2±38.4) μg/L 比(128.5±18.7) μg/L、(176.3±36.8)μg/L 比(135.6±20.3) μg/L、(149.8±31.7) μg/L 比(118.7±19.2) μg/L;均P＜0.01];PCI术后即刻,丽组TF水平均较术前明显升高(P＜0.01);PCI术后24 h,无再流组TF水平仍高于术前水平(P＜0.05),再灌流组与术前比较无差异(P＞0.05);PCI前后两组TFPI水平均无明显变化(P＞0.05).结论 AMI患者直接PCI后无再流的发生与血浆,TF水平呈正相关,TF可激活外源性凝血途径,形成微血栓而导致无再流,而TFPI可阻止血栓形成而防治无再流的发生.     

冠心病患者血浆组织因子和组织因子途径抑制物的变化

目的 :通过检测不同类型冠心病 (CHD)患者血浆组织因子 (TF)和组织因子途径抑制物 (TFPI)水平变化 ,探讨其在CHD发病过程中的作用。方法 :以酶联免疫吸附测定法测定CHD患者血浆中TF和TFPI抗原水平。结果 :不稳定型心绞痛 (UAP)和急性心肌梗死 (AMI)患者的血浆TF和TFPI水平与正常对照者和稳定型心绞痛 (SAP)患者相比均有显著性增高 (P <0 .0 5 ) ,以AMI患者尤为明显 (P <0 .0 1) ;UAP和AMI患者的TF PI/TF比值显著降低 (P <0 .0 5 ) ,而SAP患者的上述指标与正常对照者相比 ,其差异均无显著性意义 (P >0 .0 5 )。结论 :UAP和AMI患者TFPI/TF系统失衡 ,标志高凝状态的存在 ;TF和TFPI在这两种类型CHD的发病机制中可能起着重要的作用     

Changes of plasma tissue factor and tissue factor pathway inhibitor antigen levels and induction of tissue factor expression on the monocytes in coronary artery disease

BACKGROUND: Several studies have shown that thrombosis and inflammation play an important role in the pathogenesis of coronary artery disease (CAD). Tissue factor (TF) is responsible for the thrombogenicity of the atherosclerotic plaque and plays a key in triggering thrombin generation. The aim of this study was to assess the levels of TF and tissue factor pathway inhibitor (TFPI) in patients with angiographically documented CAD and also to evaluate TF induction on monocytes in vitro in the presence of these plasmas from patients with CAD. METHODS: Plasma antigen levels of soluble TF and TFPI were measured in 65 CAD patients and 22 healthy controls. Surface TF expression on monocytes from a healthy donor treated with plasma samples was evaluated by flow cytometry with a direct double-color immunofluorescence technique. RESULTS: Significantly elevated levels of both TF and TFPI were found in CAD patients compared with healthy controls (303.6 +/- 134.1 vs. 187.3 +/- 108.7 pg/ml, p < 0.05; 85.2 +/- 48.6 vs. 65.0 +/- 29.0 ng/ml, p < 0.05). By flow cytometry, monocytes from a healthy donor displayed higher TF antigen expression when incubated in the presence of CAD plasmas than in control plasmas (34.6 +/- 10.7 vs. 23.2 +/- 10.2%, p < 0.05). CONCLUSIONS: The high levels of circulating TF are present in CAD, which were not sufficiently inhibited by the elevated TFPI plasma levels. Although the source of circulating TF is unclear, TF induction of monocytes by plasma from CAD patients may contribute to the hypercoagulable state.     

Polymorphisms of the tissue factor pathway inhibitor (TFPI) gene in patients with acute coronary syndromes and in healthy subjects : impact of the V264M substitution on plasma levels of TFPI

-Mutations of the gene encoding tissue factor pathway inhibitor (TFPI), an inhibitor of TF-induced activation of the coagulation cascade, were screened for in 130 patients and 142 healthy controls to determine whether these variants contribute to acute coronary syndromes or modify plasma TFPI levels. The following 3 new polymorphisms were identified: 384T-->C in exon IV, which does not change the corresponding amino acid (tyrosine 57); -33C-->T in intron 7 (the T/T, C/T, and C/C genotypes were found in approximately 50%, 40%, and 10% of subjects in both groups); and 874G-->A in exon IX (GTG-->ATG), which predicts a valine to methionine change (V264M) in the carboxy-terminus tail of TFPI. The V264M polymorphism was found in 9.2% of the cases and 4.9% of the controls; the associated odds ratio (OR) for acute coronary syndromes was 2.0 (95% confidence interval [CI], 0.7 to 5.1). The OR increased to 3.6 (95% CI, 0.8 to 15.7) and 3.2 (95% CI, 0.9 to 11.8) in nonsmokers and patients without other risk factors, respectively. The possible link between the V264M polymorphism and coronary heart disease was checked in a large case-control study of myocardial infarction (Etude Cas-Témoins de l'Infarctus du Myocarde [the ECTIM Study]). The results showed no link between the V264M polymorphism and coronary syndromes. Interestingly, however, 5 patients heterozygous for the V264M polymorphism had significantly lower plasma TFPI levels than did 13 patients with the most common genotype. Although our present results do not support an association between TFPI polymorphisms and acute coronary syndromes, the possibility that 1 of them, especially the exon IX polymorphism, is associated with subtypes of myocardial infarction or to evolutive particularities that were not assessed in this study, cannot be excluded and is currently being evaluated.     

厄贝沙坦对心肌梗死后大鼠心肌组织因子和组织因子途径抑制物的影响

目的观察大鼠心肌梗死后心肌组织因子（TF）和组织因子途径抑制物（TFPI）的mRNA表达及厄贝沙坦对其的影响。方法通过结扎大鼠左冠状动脉前降支建立大鼠急性心肌梗死模型组,另设假手术组（20只）。模型组术后24h存活大鼠随机分为安慰剂组（20只）和厄贝沙坦组（50mg·kg^-1d^-1,20只）。用药4周后处死各组大鼠并分别称其心室重量,计算左心室重量指数及心肌梗死面积,应用反转录聚合酶链反应（RT—PCR）方法检测心肌TFmRNA和TFPImRNA。结果模型组左心室重量指数大于假手术组（F=7．83,P〈0．05）。模型组内药物组左心室重量指数明显低于安慰剂组（F=8．96,P〈0．05）,心肌梗死面积比较差异无统计学意义（F=0．96,P〉0．05）;模型组TFmRNA、TFPImRNA表达均高于假手术组（F：8．24,P〈0．05）,其中药物组＇IFmRNA较安慰剂组明显降低（F=8．57,P〈0．05）,药物组TFPI mRNA较安慰剂组增加（F=1．35,P〉0．05）。结论大鼠心肌梗死后心肌TF mRNA、TFPI mRNA表达均明显增高。厄贝沙坦可显著降低心肌梗死大鼠心肌TF mRNA的表达。     

组织因子及其抑制物在急性冠脉综合征中的作用研究

探讨急性冠脉综合征发生中血浆组织因子 (TF)及其抑制物 (TFPI)含量的动态变化及其血管紧张素转换酶抑制剂 (ACEI)captopril干预治疗的作用。用ELISA方法检测急性心肌梗塞 (AMI)不稳定心绞痛(UA)患者入院后即刻、第 1天、2天、3天、1周、2周、3周不同时间点血浆TF及TFPI的含量。 1 50例AMI患者中 ,AMI用ACEI干预治疗 (AMI +ACEI组 ) 2 5例 ,常规治疗组 (AMI组 ) 2 5例 ,UA组 2 8例 ,血浆TF、TFPI水平均明显高于正常对照组 (P <0 0 0 1)。AMI+ACEI组血浆TF水平发病后第 3天开始下降 ,于 2周时间点明显下降 ,同AMI组及UA组比较有显著的差异 (P <0 0 0 1)而较对照组比较差异无显著性 (P >0 0 5) ,AMI +ACEI组TFPI含量无明显下降 ,持续稳定在较高水平。 2 TF与TFPI呈正相关 (P <0 .0 1) (r=0 549)。组织因子及其抑制物在急性冠脉综合征中起重要作用。ACEI药物降低血浆TF水平对TFPI无影响 ,降低TF/TFPI比值     

Expression of exogenous tissue factor pathway inhibitor in vivo suppresses thrombus formation in injured rabbit carotid arteries

OBJECTIVES: The aim of the present study was to test the hypothesis that retrovirus-mediated in vivo tissue factor pathway inhibitor (TFPI) gene transfer to the arterial wall would efficiently inhibit thrombosis without causing significant changes in systemic hemostatic variables. BACKGROUND: Acute coronary syndromes (unstable angina and acute myocardial infarction) are usually caused by atherosclerotic plaque rupture, with consequent activation of the coagulation cascade and circulating platelets. Tissue factor (TF) exposure represents an early event in this pathophysiologic sequence, leading to activation of the extrinsic coagulation pathway and thrombin formation. Tissue factor pathway inhibitor is a naturally occurring inhibitor of the extrinsic pathway. METHODS: In the present study, the gene coding for rabbit TFPI was inserted in a retroviral vector under control of a tetracycline-inducible promoter. Replication-defective, infectious, recombinant retroviruses were used to transfect rabbit carotid arteries with either TFPI or a reporter gene--green fluorescent protein (GFP). RESULTS: Retroviral-mediated arterial gene transfer of TFPI resulted in potent inhibition of intravascular thrombus formation in stenotic and injured rabbit carotid arteries, whereas transfection of the contralateral carotid artery with GFP had no effect on thrombosis. No significant changes in systemic hemostatic variables (prothrombin time and partial thromboplastin time) were observed when thrombosis was inhibited. CONCLUSIONS: These data suggest that retroviral-mediated transfection of the arterial wall with TFPI might represent an attractive approach for the treatment of thrombotic disorders.     

冠心病患者血浆组织因子、组织因子途径抑制物、白介素18、白介素10水平的变化及其关系

目的观察冠心病患者血浆组织因子(TF)、组织因子途径抑制物(TFPI)、白介素18(IL-18)、白介素10(IL-10)的变化,探讨其在冠心病(CHD)中的意义及其相互关系。方法 121例患者分为对照组(33例)与CHD组(96例),CHD组又分为急性心肌梗死(AMI)(33例),不稳定性心绞痛(UAP)(33例)和稳定性心绞痛(SAP)(30例)三个小组。采用酶联免疫吸附法分别测定血浆TF、TFPI、IL-18、IL-10的含量。结果 CHD组患者血浆TF、TFPI、TF/TFPI高于对照组,AMI小组患者血浆TF、TFPI、TF/TFP显著高于UAP及SAP小组患者,UAP小组患者高于SAP小组患者;CHD组患者血浆IL-18、IL-10、IL-18/IL-10高于对照组,AMI小组患者血浆IL-18、IL-18/IL-10显著高于UAP及SAP小组患者,UAP小组患者高于SAP小组患者;AMI和UAP小组患者血浆IL-10水平低于SAP小组患者;CHD组患者血浆TF与IL-18呈显著正相关(r=0.753,P=0.03),TF/TFPI与IL-18/IL-10呈正相关(r=0.496,P=0.01)。结论 CHD患者促凝因素和促炎症因子均显著升高,且与病情平行。促凝因子和促炎因子呈正相关,提示凝血因子和炎症因子在CHD发病中起重要作用,并可作为病情严重程度评价的参考指标。     

Reconstituted high-density lipoprotein inhibits thrombin-induced endothelial tissue factor expression through inhibition of RhoA and stimulation of phosphatidylinositol 3-kinase but not Akt/endothelial nitric oxide synthase

Endothelial cells express negligible amounts of tissue factor (TF) that can be induced by thrombin, which is important for acute coronary syndromes. Recent research suggests that endothelial TF expression is positively regulated by RhoA and p38mapk, but negatively by Akt/endothelial nitric oxide synthase (eNOS) pathway. High-density lipoprotein (HDL) is atheroprotective and exerts antiatherothrombotic effect. This study investigated the effect of a reconstituted HDL (rHDL) on endothelial TF expression induced by thrombin and the underlying mechanisms. In cultured human umbilical vein and aortic endothelial cells, thrombin (4 U/mL, 4 hours) increased TF protein level, which was reduced by rHDL (0.1 mg/mL, 43% inhibition, n=3 to 7, P<0.01). Activation of RhoA but not p38mapk by thrombin was prevented by rHDL. rHDL stimulated Akt/eNOS pathway. The phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin or LY294002 abolished the activation of Akt/eNOS and reversed the inhibitory effect of rHDL on TF expression. Adenoviral expression of the active PI3K mutant (p110) reduced TF expression stimulated by thrombin without inhibiting RhoA activation, whereas expression of the active Akt mutant (m/p) further facilitated TF upregulation by thrombin. Moreover, a dominant-negative Akt mutant (KA) reduced thrombin's effect and did not reverse the rHDL's inhibitory effect on TF expression. Inhibition of eNOS by N(omega)-nitro-L-arginine methyl ester (100 micromol/L) did not affect the rHDL's effect. In conclusion, rHDL inhibits thrombin-induced human endothelial TF expression through inhibition of RhoA and activation of PI3K but not Akt/eNOS. These findings implicate a novel mechanism of antiatherothrombotic effects of HDL.     

Angiotensin-converting enzyme inhibition reduces monocyte chemoattractant protein-1 and tissue factor levels in patients with myocardial infarction.

OBJECTIVES: We investigated the effects of enalapril therapy on plasma tissue factor (TF), tissue factor pathway inhibitor (TFPI) and monocyte chemoattractant protein-1 (MCP-1) levels in patients with acute myocardial infarction. BACKGROUND: Macrophages express TF in human coronary atherosclerotic plaques. Both TF and TFPI are major regulators of coagulation and thrombosis. Monocyte chemoattractant protein-1 is a monocyte and macrophage chemotactic and activating factor. METHODS: In a randomized, double-blind, placebo-controlled study beginning about two weeks after myocardial infarction, 16 patients received four weeks of placebo (placebo group) and another 16 patients received four weeks of enalapril 5 mg daily therapy (enalapril group). We performed blood sampling after administration of the doses. RESULTS: There were no significant differences in the serum angiotensin-converting enzyme (ACE) activity, plasma TF, free TFPI or MCP-1 levels before administration between the enalapril and placebo groups. In the enalapril group, ACE activity (IU/liter) (14.0 before, 5.2 on day 3, 5.8 on day 7, 6.3 on day 28), TF levels (pg/ml) (223, 203, 182, 178) and MCP-1 levels (pg/ml) (919, 789, 790, 803) significantly decreased by day 28. However, the free TFPI levels (ng/ml) (28.2, 26.5, 26.8, 28.4) did not change. These four variables were unchanged during the study period in the placebo group. CONCLUSIONS: This study demonstrated that administration of enalapril reduces the increased procoagulant activity in patients with myocardial infarction associated with inhibition of the activation and accumulation of macrophages and monocytes.     

Tissue factor/tissue factor pathway inhibitor system and long-term prognosis after acute myocardial infarction

The tissue factor and tissue factor pathway inhibitor (TFPI) system has been studied in the acute phase of coronary disease but its prognostic importance has been less well assessed. We evaluated its association with recurrent coronary events during long-term follow-up after a myocardial infarction. Methods: We studied 55 consecutive patients with the following criteria for inclusion: (1) first myocardial infarct; (2) aged < 70 years; (3) non-complicated infarct; (4) low risk effort-test. Blood samples were taken 60-80 days after infarction. Tissue factor, total and free-TFPI were measured. A 4-year follow-up was carried out. Death, unstable angina and new myocardial infarction were considered as poor prognosis. Results: There were no statistical differences in tissue factor/TFPI levels between patients and controls. Total-TFPI showed statistical correlation with total cholesterol (r = 0.59), triglycerides (r = 0.34), LDL-cholesterol (r = 40) and Lipoprotein(a) (r = 0.48). Patients with high levels of cholesterol, LDL-cholesterol and triglycerides showed elevated levels of total-TFPI with no differences in free-TFPI. During follow-up, 8 patients showed poor prognosis. There were no statistical associations between tissue factor/TFPI levels and prognosis. Conclusions: After acute myocardial infarction, we did not find any differences in the tissue factor/TFPI system between controls and patients. The tissue factor/TFPI system showed little value as a prognostic factor.     

组织因子与急性冠脉综合征研究进展

组织因子作为FⅦ/FⅦa的细胞膜表面受体,是外源性凝血系统的关键因子,组织因子通过介导凝血激活形成血栓。动脉粥样硬化斑块破裂处血栓形成是急性冠脉综合征的主要原因,其临床后果的严重性决定于血栓的范围和进展。急性冠脉综合征时循环单核细胞和微颗粒表达组织因子,促进全身的促凝活性。动脉粥样硬化斑块中巨噬细胞、平滑肌细胞、血管内皮细胞表达组织因子,不稳定性斑块中组织因子表达和活性较稳定性斑块更高。组织因子通路抑制物是内源性组织因子抑制物,对调剂血栓形成有重要作用。现就目前组织因子与急性冠脉综合征研究进展作一综述。     

Alpha-黑素细胞刺激素及其新型类似物对小鼠脑微血管内皮细胞产生组织因子的抑制作用

目的研究Alpha-黑素细胞刺激素(α-MSH)及其新型类似物(STY39)对原代小鼠脑微血管内皮细胞(MBMEC)在脂多糖(LPS)刺激下产生组织因子(TF)和组织因子途径抑制物(TFPI)的影响。方法选用雌性BALB/c小鼠,纯化并原代培养MBMEC,培养至5~7d,采用免疫荧光法检测Ⅷ因子相关抗原,鉴定MBMEC模型。将MBMEC分为PBS对照组,LPS刺激组,LPS刺激后1、2、3 h加入10-7mol/L的α-MSH或STY39组(LPS+α-MSH,LPS+STY39),共8组,每组4孔。分别在LPS刺激后6h和8h收集细胞培养上清液和细胞,应用酶联免疫吸附法检测细胞上清液的TF和TFPI浓度,RT-PCR检测细胞TF mRNA表达水平。结果 (1)LPS可诱导MBMEC产生TF和TFPI蛋白,细胞培养上清液中TF水平于6 h达到高峰,TFPI水平于8 h达到高峰。(2)LPS刺激MBMEC后1、2、3 h给予10-7mol/L的α-MSH或STY39,均可显著降低细胞上清液中TF蛋白含量(P0.01),尤其在LPS刺激后1 h给予α-MSH或STY39的效果最显著(P0.05),STY39降低TF含量的作用较α-MSH明显(P0.05);但α-MSH和STY39对LPS诱导MBMEC产生TFPI均没有显著的上调作用。(3)在LPS刺激后不同时间点给予10-7mol/L的α-MSH或STY39,均可显著下调MBMEC TF mRNA的表达水平(P0.01),其中1 h时间点作用最显著(P0.05),但α-MSH与STY39的作用差异无统计学意义。结论α-MSH和STY39均能抑制LPS诱导原代MBMEC产生TF蛋白和表达TF mRNA,且LPS刺激1 h后给药效果较好;STY39对MBMEC产生TF蛋白的抑制作用优于α-MSH。     

Anticoagulant versus amidolytic activity of tissue factor pathway inhibitor in coronary artery disease.

In view of raised levels of endothelial markers in coronary artery disease (CAD), the aim of the present study was to investigate the status of tissue factor pathway inhibitor (TFPI), another endothelium-associated glycoprotein and coagulation protease inhibitor, in CAD. The intravascular pool of TFPI is heterogeneous with respect to assay-dependent activity. While the standard amidolytic assay works well with both full-length and truncated (lipoprotein-associated) TFPI, the anticoagulant assay works better with the former. The anticoagulant activity of TFPI can be estimated using dilute tissue factor (TF) to trigger clotting of plasma. In the present study, recombinant TF diluted 2,000-fold was used to initiate coagulation. A dose-dependent shortening of clotting time of normal plasma pools with polyclonal antibody against the C-terminal but not the N-terminal peptide of TFPI demonstrated the importance of the C-terminal region, and hence that of full-length TFPI, in conferring its anticoagulant activity, corroborating current opinion. As a further confirmation, the C-terminal peptide itself prolonged dilute TF clotting time of normal pooled plasma in a concentration-dependent manner. The amidolytic and anticoagulant activities of TFPI were determined in 20 patients with clinically and angiographically assessed CAD and in 68 asymptomatic controls. The mean +/- SD ages of patients and controls were 54.9 +/- 10.3 and 48.8 +/- 11.6 years, respectively, the difference being statistically significant (P = 0.04). The mean TFPI activity measured by amidolytic assay was comparable for patients and controls (1.2 +/- 0.3 and 1.3 +/- 0.5 U/ml, respectively). However, the dilute TF clotting time was 115 +/- 26 s in patients, against 99 +/- 10 s in controls (P < 0.0001, irrespective of age adjustment). Since none of the patients had received heparin or had coagulation factor deficiency that may interfere with the assay, prolongation of clotting time may be attributed to the presence of TFPI, particularly the full-length form. To verify this inference, 33 extra aliquots left over from 88 samples (62.5%), 21 from controls and 12 from patients, were incubated with 1:10 diluted antibody against the C-terminal peptide of TFPI prior to dilute TF assay. The mean clotting time of both patients and controls decreased, and the between-group difference leveled (90 +/- 10 versus 88 +/- 20 s for controls and patients, respectively; P = 0.841). The mean drop in clotting time was 9% for the controls and 24% for the patients. This illustrates the specificity of dilute TF assay for full-length TFPI and supports the conclusion that relative to lipoprotein-associated TFPI, the proportion of the full-length form was possibly greater in patients with CAD. Contribution of lipoprotein-associated TFPI to the overall anticoagulant activity by its activated factor X-dependent inhibition of activated factor VII-TF complex seems less important considering the similar between-group mean amidolytic activities.     

急性早幼粒细胞白血病止凝血变化的研究

目的　探讨急性早幼粒细胞白血病（APL）患者用全反维甲酸（ATRA）和砷剂（AS2O3）治疗期间细胞组织因子（TF）表达及血浆止凝血分子标志物含量变化。方法　用ELISA法检测血浆TF、组织因子途径抑制物（TFPI）、凝血酶-抗凝血酶复合物（TAT）、纤溶酶-抗纤溶酶复合物（PAP）、尿激酶型纤溶酶原激活物（u-PA）、尿激酶型纤溶酶原激活物受体（u-PAR）和细胞裂解液TF含量;RT-PCR法检测细胞TFmRNA转录水平。结果　治疗前,患者血浆TF［(98.3±19.8)ng/L、(89.6±15.2)ng/L］、TFPI［(94.4±37.0)mg/L、(93.5±36.4)mg/L］、TAT［(21.9±9.6)μg/L、(18.2±9.7)μg/L］、PAP［(0.73±0.26)mg/L、(0.63±0.33)mg/L］、u-PA［(0.63±0.23)μg/L、(0.57±0.01)μg/L］、u-PAR［(0.41±0.14)μg/L、(0.47±0.16)μg/L］水平与正常对照组相比为高,差异有显著性或极显著意义（P＜0.05～0.01）。骨髓分离的单个核细胞TFmRNA转录、裂解液TF水平［（680.24±456.61)pg/10     

Paclitaxel enhances thrombin-induced endothelial tissue factor expression via c-Jun terminal NH2 kinase activation

Paclitaxel is used on drug-eluting stents because it inhibits proliferation of vascular cells. Stent thrombosis remains a concern with this compound, particularly with higher dosages. This study investigates the effect of paclitaxel on tissue factor (TF) expression in human endothelial cells. Paclitaxel enhanced thrombin-induced endothelial TF protein expression in a concentration- and time-dependent manner. A concentration of 10(-5) mol/L elicited a 2.1-fold increase in TF protein and a 1.6-fold increase in TF surface activity. The effect was similar after a 1 hour as compared with a 25-hour pretreatment period. Real-time polymerase chain reaction revealed that paclitaxel increased thrombin-induced TF mRNA expression. Paclitaxel potently activated c-Jun terminal NH2 kinase (JNK) as compared with thrombin alone, whereas the thrombin-mediated phosphorylation of p38 and extracellular signal-regulated kinase remained unaffected. Similar to paclitaxel, docetaxel enhanced both TF expression and JNK activation as compared with thrombin alone. The JNK inhibitor SP600125 reduced thrombin-induced TF expression by 35%. Moreover, SP600125 blunted the effect of paclitaxel and docetaxel on thrombin-induced TF expression. Paclitaxel increases endothelial TF expression via its stabilizing effect on microtubules and selective activation of JNK. This observation provides novel insights into the pathogenesis of thrombus formation after paclitaxel-eluting stent deployment and may have an impact on drug-eluting stent design.     

Combined effects of irbesartan and carvedilol on expression of tissue factor and tissue factor pathway inhibitor in rats after myocardial infarction

The objective of this study was to investigate the effects of irbesartan, carvedilol, and irbesartan plus carvedilol on the expression of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) mRNA and protein in rat myocardium after myocardial infarction (MI). MI was induced in male Wistar rats by ligation of the anterior descending branch of the left coronary artery. Irbesartan at 50 mg/kg/day, carvedilol at 1 mg/kg/day, irbesartan plus carvedilol, or placebo was administered intragastrically; expression of TF and TFPI mRNA and protein was determined by RT-PCR and Western blot analysis. The relative left ventricle weights were lower in all three treatment groups than in the placebo group, with the lowest relative weight in the irbesartan plus carvedilol group (P < 0.001). The size of the infarcted area was lower in the carvedilol and the combined groups than in the placebo group (P < 0.001). The levels of expression of TF and TFPI mRNA and protein were lower in the combined group than in the placebo group or the carvedilol group (P < 0.001). Treatment with irbesartan plus carvedilol reduced the expression of TF and TFPI mRNA and protein after MI in rats, and combined treatment with both agents had greater effects than the single agents alone. These findings suggest that the beneficial effects of these drugs may include anticoagulation and that combined therapy with both agents is an option that should be evaluated further.