体外治疗性超声对大鼠纤溶系统的影响

目的　研究体外治疗性超声对大鼠血浆组织型纤溶酶原激活因子 (t-PA)、纤溶酶原激活物抑制因子 -1(PAI -1)的影响。方法　采用酶联免疫吸附法测定超声治疗前后大鼠血浆t-PA、PAI -1的改变。结果　超声治疗后ETUS组t-PA(0 .5 4± 0 .19)IU/ml,PAI -1(0 .44± 0 .18)AU/ml,对照组t -PA(0 .5 1± 0 .2 5 )IU/ml,PAI -1(0 .43± 0 .19)AU/ml,二者比较无明显差异 (P >0 .0 5 )。结论　治疗剂量超声对大鼠纤溶系统没有影响     

普伐他汀对不稳定性心绞痛患者血管内皮功能的影响

目的　探讨普伐他汀对不稳定性心绞痛 (UA)患者血管内皮依赖性舒张功能和纤溶系统的影响。方法　采用高分辨超声技术 ,将 42例 AU患者按随机编码分为普伐他汀组和对照组 ,观察降脂治疗前后血管内皮依赖性舒张功能和血浆纤溶酶原激活物 (t PA)及其抑制物 (PAI)活性。结果　普伐他汀组与对照组和治疗前比较 ,血流介导的肱动脉舒张百分率显著增加 ,(9.5± 3.2 ) %和 (5.0± 2 .2 ) %、(4.2± 2 .0 ) % (均 P<0 .0 1 )。血浆 t PA活性增强 ,(0 .48± 0 .1 7) IU/ml和 (0 .352± 2 .0 ) IU/ml、(0 .2 75± 0 .1 5) IU/ml(P<0 .0 1 ) ;血浆 PAI活性减弱 (0 .350± 0 .1 0 5) AU/ml和 (0 .450± 0 .1 2 ) AU/ml、(0 .52 5± 0 .2 5) AU/ml(均 P<0 .0 5)。线性相关分析显示 :血流介导的肱动脉舒张百分率及血浆纤溶活性改变与血脂的降低无关。结论　普伐他汀能改善 UA时受损的血管内皮依赖性舒张功能和血浆纤溶活性。     

急性心肌梗死时血管内皮功能的变化及福辛普利的干预作用

目的 :观察急性心肌梗死早期应用血管紧张素转换酶抑制剂治疗对血管内皮依赖性舒张功能和血浆纤溶平衡的影响。方法 :采用高分辨超声技术和发色底物显示法 ,检测 3 4例急性心肌梗死患者和 3 0例无冠心病患者 (对照组 )肱动脉内皮依赖性舒张功能和血浆组织型纤溶酶原激活物 (t PA)及其抑制物 (PAI)。应用随机编码将 3 4例急性心肌梗死患者分为福辛普利组和常规治疗组 ,治疗 8周后复测其肱动脉内皮依赖性舒张功能和血浆t PA和PAI活性。结果 :急性心肌梗死患者肱动脉内皮依赖性舒张功能 (3 8± 2 3 ) %较对照组 (9 5± 3 2 ) %明显降低 ,血浆t PA活性显著降低和PAI活性明显增加 ,有非常显著性差异 (P均 <0 0 1)。福辛普利治疗 8周后 ,肱动脉内皮依赖性舒张功能(9 45± 3 2 0 ) %与治疗前基础水平 [(3 5 2± 2 70 ) % ,P <0 0 1]、常规治疗后 [(4 60± 2 80 ) % ,P <0 0 5 ]相比有显著改善 ;血浆纤溶活性也有明显改善 (t PA :0 49± 0 2 0IU /mlvs 0 2 8± 0 15IU /ml,P <0 0 1和 0 3 2± 0 15IU/ml,P <0 0 5 ;PAI :0 3 6± 0 12AU /mlvs .0 5 3± 0 2 5AU/ml,P <0 0 1和 0 45± 0 0 9AU /ml,P <0 0 5 ) ,均有显著性差异。结论 :急性心肌梗死患者内皮依赖性舒张功能明显减退 ;血     

脑梗死急性期患者凝血与纤溶指标的改变及降纤酶的疗效

目的 :研究脑梗死急性期患者纤溶、凝血指标的变化及降纤酶的疗效。方法 :测定 38例脑梗死急性期 (<3天 )患者降纤酶治疗前、后的血浆纤维蛋白原 (Fbg)、α2 抗纤溶酶 (α2 - PI)、血浆组织型纤溶酶原激活物 (t- PA)及其抑制物 (PAI- 1)和 D-二聚体 (D- D)的变化。结果 :脑梗死急性期患者血浆 Fbg、α2 - PI、 PAI- 1、 D- D水平分别为 4.32± 1.7g/ L、 (15 4.39± 34 .86 ) %、 0 .2 6± 0 .1IU/ m l、 1.12± 0 .32 AU/ ml和 1.34± 1.18mg/ L,明显升高 ,较正常对照组有显著差异 P<0 .0 1) ,t- PA水平下降非常显著 (P<0 .0 0 1)。降纤酶治疗后 Fbg、α2 - PI、 PAI- 1、 D- D水平显著下降 (P<0 .0 5～ P<0 .0 0 1) ,t- PA水平升高非常显著 (P<0 .0 0 1)。结论 :降纤酶有良好降纤、溶纤作用 ,对脑梗死急性期患者有显著疗效。     

氯沙坦对高血压病患者尿白蛋白及纤溶活性的影响

目的　探讨尿白蛋白排泄率与纤溶活性的关系及氯沙坦对其影响。方法　选择 6 2例高血压病伴轻、中度肾功能损害 (肌酐清除率 <70mL/min ,但≥ 30mL/min)患者 ,经随机分为两组分别予氯沙坦 5 0～ 10 0mg/d或卡托普利75～ 15 0mg/d降压治疗 12周。同时选择 2 4例高血压病伴肾功能完全正常 (肌酐清除率≥ 80mL/min)患者作为对照组 ,降压治疗前后分别测定尿白蛋白排泄率 (UAE)、纤溶酶原激活剂活性 (tPA)、纤溶酶原激活抑制剂活性 (PAI)。结果　肾功能异常组UAE、PAI均升高 (P <0 0 1) ,tPA降低 (P <0 0 5 ) ;UAE与tPA ,PAI,PAI/tPA相关系数分别为 0 2 0 (P >0 1)、0 32 (P <0 0 5 )、0 34(P <0 0 1) ,UAE与纤溶活性降低正相关 ;降压治疗后两组均降低UAE、PAI(P <0 0 1) ,卡托普利组还升高tPA(P <0 0 5 )。结论　肾功能异常时纤溶活性降低 ,肾功能损害与纤溶降低有关 ,氯沙坦及卡托普利改善肾功能 ,也改善纤溶活性。     

血管紧张素Ⅱ和卡托普利、缬沙坦对人脐静脉内皮细胞PAI-1、tPA蛋白表达的影响

目的研究血管紧张素Ⅱ(Ang Ⅱ)和血管紧张素转换酶抑制剂(ACEI),卡托普利和Ang Ⅱ 1型受体(AT-1)拮抗剂缬沙坦对人脐静脉内皮细胞(HUVECs)1型纤溶酶原激活物抑制剂(PAI-1)、组织型纤溶酶原激活剂(tPA)蛋白的释放及活性的影响.方法将不同浓度的Ang Ⅱ(10-6～10-9 mol/L)与HUVECs共同孵育24 h,以及将10-6 mol/L的Ang Ⅱ与HUVECs作用不同时间(0、4、8、12、24 h)后,用细胞酶联免疫法和发色底物法分别检测细胞培养液中PAI-1、tPA的含量及活性,并观察卡托普利和缬沙坦干预后的影响.结果 10-6mol/L Ang Ⅱ作用HUVECs 24 h后,可使细胞分泌的PAI-1含量与对照组相比明显增高(280±15.60 vs 83.33±10.56) ng/mL,P<0.01),PAI-1活性明显增加(9.25±0.39 vs 7.53±0.33) IU/mL,P<0.01),Ang Ⅱ虽也可刺激tPA含量增加(101.67±3.78 vs 70±5.62) ng/mL,(P<0.01),但PAI-1的增量是tPA增量的6～7倍(Δ196.67±21.34 vs Δ31±6.50) ng/mL,(P<0.01),Ang Ⅱ对tPA活性无影响(0.97±0.05 vs 0.95±0.08) ng/mL,(P>0.05);缬沙坦可显著抑制Ang Ⅱ的促PAI-1分泌作用(212.67±5.38 vs 290±6.57) IU/mL,(P<0.01),而卡托普利对Ang Ⅱ的促PAI-1分泌作用无明显抑制作用(278.33±9.16 vs 290±6.57) IU/mL,(P>0.05).结论 Ang Ⅱ可促使HUVECs分泌PAI-1,并使其活性增加;Ang Ⅱ亦可刺激tPA分泌,但作用弱于PAI-1,对其活性无明显影响.缬沙坦可抑制Ang Ⅱ促HUVECs分泌PAI-1的作用;卡托普利的作用不显著.     

血管紧张素Ⅱ和卡托普利、缬沙坦对人脐静脉内皮细胞PAI-1、tPA蛋白表达的影响

目的研究血管紧张素Ⅱ(AngⅡ)和血管紧张素转换酶抑制剂(ACEI),卡托普利和AngⅡ1型受体(AT-1)拮抗剂缬沙坦对人脐静脉内皮细胞(HUVECs)1型纤溶酶原激活物抑制剂(PAI-1)、组织型纤溶酶原激活剂(tPA)蛋白的释放及活性的影响。方法将不同浓度的AngⅡ(10-6~10-9mol/L)与HUVECs共同孵育24h,以及将10-6mol/L的AngⅡ与HUVECs作用不同时间(0、4、8、12、24h)后,用细胞酶联免疫法和发色底物法分别检测细胞培养液中PAI-1、tPA的含量及活性,并观察卡托普利和缬沙坦干预后的影响。结果10-6mol/LAngⅡ作用HUVECs24h后,可使细胞分泌的PAI-1含量与对照组相比明显增高(280±15.60vs83.33±10.56)ng/mL,P<0.01),PAI-1活性明显增加(9.25±0.39vs7.53±0.33)IU/mL,P<0.01),AngⅡ虽也可刺激tPA含量增加(101.67±3.78vs70±5.62)ng/mL,(P<0.01),但PAI-1的增量是tPA增量的6~7倍(Δ196.67±21.34vsΔ31±6.50)ng/mL,(P<0.01),AngⅡ对tPA活性无影响(0.97±0.05vs0.95±0.08)ng/mL,(P>0.05);缬沙坦可显著抑制AngⅡ的促PAI-1分泌作用(212.67±5.38vs290±6.57)IU/mL,(P<0.01),而卡托普利对AngⅡ的促PAI-1分泌作用无明显抑制作用(278.33±9.16vs290±6.57)IU/mL,(P>0.05)。结论AngⅡ可促使HUVECs分泌PAI-1,并使其活性增加;AngⅡ亦可刺激tPA分泌,但作用弱于PAI-1,对其活性无明显影响。缬沙坦可抑制AngⅡ促HUVECs分泌PAI-1的作用;卡托普利的作用不显著。     

纤溶活性及D-二聚体变化与老年高血压肾损害关系的研究

目的　了解纤溶活性和血、尿 D-二聚体 ( D-d)水平变化在老年高血压肾小动脉硬化症( HANS)中的作用。　方法　采用 ELISA法测定血、尿 D-d,用发色底物法测定纤溶酶 ( P∶ A)、组织型纤溶酶原激活剂 ( t PA∶ A)及纤溶酶原抑制剂 ( PAI∶A)活性 ,并同时用放免法测定尿微量白蛋白和光电比色法测定尿 N-乙酰 -β-葡萄糖苷酶 ( NAG)。　结果　原发性高血压 ( PH)组及 HANS组较健康对照组 P∶ A( 2 8.3 %± 1 3 .8%及 2 6.1 %± 1 3 .2 %较 4 8.8%± 1 3 .6%)和 t PA∶ A〔( 0 .3 5± 0 .1 1 )IU/ ml及 ( 0 .3 2± 0 .1 3 ) IU/ ml较 ( 0 .54± 0 .1 8) IU/ ml〕明显降低 ,PAI∶ A〔( 0 .55± 0 .1 8) IU/ ml及( 0 .78± 0 .2 1 ) IU/ ml较 ( 0 .3 6± 0 .1 1 ) IU/ ml〕和血、尿 D-d〔血 :( 0 .3 1± 0 .1 3 ) mg/ L及 ( 0 .3 8± 0 .1 4 )mg/ L较 ( 0 .1 6± 0 .1 0 ) mg/ L;尿 :( 0 .2 9± 0 .1 4 ) mg/ L及 ( 0 .52± 0 .1 3 ) mg/ L较 ( 0 .1 7± 0 .1 1 ) mg/ L〕水平显著升高 ;HANS组与 PH组比较 ,血浆 PAI∶ A、尿 D-d、尿白蛋白〔( 3 89.7± 1 1 3 .4 ) mg/ 2 4 h较( 48.4± 1 5.8) mg/ 2 4 h〕和 NAG〔( 1 6.59± 4 .87) U/ mmol Cr较 ( 1 .0 5± 0 .3 5) U/ mmol Cr〕排泄水平均明显升高 ;另外 ,P     

心房颤动的低纤溶状态

目的 :研究心房颤动 (房颤 )的纤溶系统改变及其临床意义。方法 :采用发色底物法测定 30例房颤患者(其中冠心病 14例 ,风湿性心脏病 16例 )和 2 5例正常人血浆组织型纤溶酶原激活剂活性 ( t- PA∶ a)和纤溶酶原激活剂抑制物活性 ( PAI∶ a) ;并测定血浆纤维蛋白原 ( Fg)浓度、凝血酶原时间 ( PT)和部分凝血活酶时间( APTT)。结果 :房颤患者与正常人相比 ,血浆 t- PA∶ a降低〔( 340 .0± 70 .0 )对 ( 480 .0± 5 0 .0 ) IU /L ,P <0 .0 1)〕;PAI∶ a升高〔( 90 0 .0± 80 .0 )对 ( 6 90 .0± 5 0 .0 ) AU/L,P <0 .0 1〕;PAI∶ a/t- PA∶ a比值增高〔( 2 .87±0 .89)对 ( 1.49± 0 .2 9) ,P <0 .0 1〕,而 Fg、PT、APTT无显著性差异 ( P >0 .0 5 )。风湿性心脏病房颤与冠心病房颤之间血浆 t- PA∶ a,PAI∶ a,PAI∶ a/t- PA∶ a比值及 PT、APTT均无显著性差异 ( P>0 .0 5 ) ,但前组血浆 Fg浓度较后组低〔( 2 .5 9± 0 .6 9)对 ( 3.35± 1.0 4) g/L,P <0 .0 5〕。结论 :房颤患者血浆存在低纤溶状态 ,表现为 PAI活性增加 ,t- PA活性降低。房颤的低纤溶状态可能与其高发血栓栓塞并发症有关     

运动负荷对不稳定性心绞痛患者纤溶活性影响的研究

对20例健康受试者和25例不稳定性心绞痛患者进行运动负荷前、后组织型纤溶酶原激活剂(t-PA)、纤溶酶原激活剂抑制剂(PAI-1)活性的测定.结果发现运动前静息时,两组t-PA活性无显著差异,而PAI-1活性不稳定性心绞痛组明显高于对照组;运动后,不稳定性心绞痛组t-PA活性显著低于对照组(0.96±0.45IU/ml对1.89±0.68IU/ml,P<0.01),PAI-1活性下降幅度小于对照组(12.0%对31.9%),使其PAI-1活性仍显著高于对照组(8.20±2.28AU/ml对4.21±0.68AU/ml,P<0.01).提示不稳定性心绞痛患者不论是静息,还是在运动负荷激发后,均存在着纤溶活性的下降.     

Association between physical activity and endogenous fibrinolysis in peripheral arterial disease: a cross-sectional study

The purpose of this study was to determine whether daily physical activity was independently related to endogenous fibrinolysis in subjects with peripheral arterial disease (PAD). One hundred and six subjects with peripheral arterial disease (PAD) and intermittent claudication were characterized on the activity level of tissue plasminogen activator (tPA, the activator of fibrinolysis), the activity level of plasminogen activator inhibitor (PAI-1, the inhibitor of fibrinolysis), daily physical activity, ambulatory function, and demographic information. Subjects were separated into low (n = 36), moderate (n = 34), and high (n = 36) physical activity tertiles based on a 48-hour monitoring period with use of an accelerometer. The tPA activity of the low physical activity group (1.30 +/- 0.16 IU/mL) was 21% and 19% lower (p<0.05) than that of the moderate (1.65 +/- 0.18 IU/mL) and the high (1.61 +/- 0.15 IU/mL) physical activity groups, respectively. The PAI-1 activity of the low physical activity group (21.41 +/- 1.14 AU/mL) was 15% and 23% higher than that of the moderate (18.61 +/- 1.34 AU/mL) and the high (17.47 +/- 1.14 AU/mL) physical activity groups, respectively. Group differences in tPA activity and PAI-1 activity persisted after our controlling for group differences in measured and self-reported ambulatory measures. Daily physical activity is related to a more favorable endogenous fibrinolytic profile in PAD subjects with intermittent claudication. Subjects who expend fewer than 175 kcal/day in physical activities (approximately 35 minutes) are particularly susceptible to having a prothrombotic state. Subjects should be encouraged to participate in at least 35 minutes of physical activity each day to enhance fibrinolysis.     

西拉普利对心房颤动犬内皮细胞功能及纤溶系统的影响

目的研究血管紧张素转换酶抑制剂西拉普利对心房颤动(房颤)犬内皮功能和纤溶系统的影响。方法应用埋藏式高频心脏起搏器快速起搏心房建立房颤犬动物模型。实验分为未起搏组、单纯起搏组和起搏 西拉普利组。采用ISO-NOP3005一氧化氮(NO)敏感电极测定心内膜NO含量;酶联免疫吸附双抗体夹心法测定血浆血管性血友病因子水平;Westernblot定量分析心房心肌纤溶酶原激活剂抑制物-1(PAI-1)和组织型纤溶酶原激活剂(tPA)蛋白表达;同时免疫组化检测蛋白表达位置。血浆PAI-1和tPA含量采用酶联免疫吸附双抗体夹心法测定。结果西拉普利能显增加房颤犬心内膜NO合成,降低血浆血管性血友病因子水平,同时显减少心房肌PAI-1蛋白表达和血浆PAI-1含量,增加心房肌tPA蛋白表达和血浆含量。结论西拉普利能明显改善房颤犬内皮细胞功能,恢复纤溶系统平衡,可能对房颤的血栓前状态有益。     

Increased PAI-1 and tPA antigen levels are reduced with metformin therapy in HIV-infected patients with fat redistribution and insulin resistance

Cardiovascular disease (CVD) risk associated with fat redistribution seen among HIV-infected individuals remains unknown, but may be increased due to hyperlipidemia, hyperinsulinemia, increased visceral adiposity, and a prothrombotic state associated with these metabolic abnormalities. In this study we characterized plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (tPA) antigen levels, markers of fibrinolysis and increased CVD risk, in HIV lipodystrophic patients compared to controls. Furthermore, we investigated the effect of treatment with metformin on PAI-1 and tPA antigen levels in patients with HIV-associated fat redistribution. Eighty-six patients (age 43 +/- 1 yr, BMI 26.1 +/- 0.5 kg/m(2)) with HIV and fat redistribution were compared to 258 age- and BMI-matched subjects from the Framingham Offspring study. In addition, 25 HIV-infected patients with fat redistribution and fasting insulin >15 microU/mL [104 pmol/L] or impaired glucose tolerance, but without diabetes mellitus were enrolled in a placebo-controlled treatment study of metformin 500 mg twice daily. PAI-1 and tPA antigen levels were significantly increased in patients with HIV related fat redistribution compared to Framingham control subjects (46.1 +/- 4 vs 18.9 +/- 0.9 microg/L PAI-1, 16.6 +/- 0.8 vs. 8.0 +/- 0.3 microg/L tPA, P = 0.0001). Among patients with HIV infection, a multivariate regression analysis including age, sex, waist-to-hip ratio, BMI, smoking status, protease inhibitor use and insulin area under the curve (AUC), found gender and insulin AUC were significant predictors of tPA antigen. Twelve weeks of metformin treatment resulted in decreased tPA antigen levels (-1.9 +/- 1.4 vs +1.4 +/- 1.0 microg/L in the placebo-treated group P = 0.02). Similarly, metformin resulted in improvement in PAI-1 levels (-8.7 +/- 2.3 vs +1.7 +/- 2.9 microg/L, P = 0.03). Change in insulin AUC correlated significantly with change in tPA antigen (r = 0.43, P = 0.03). PAI-1 and tPA antigen, markers of impaired fibrinolysis and increased CVD risk, are increased in association with hyperinsulinemia in patients with HIV and fat redistribution. Metformin reduces PAI-1 and tPA antigen concentrations in these patients and may ultimately improve associated CVD risk.     

Platelet function and fibrinolytic activity in patients with bronchial asthma.

Platelets have the capacity to release mediators with potent inflammatory or anaphylactic properties. Platelet factor-4 (PF4) and beta-thromboglobulin (BTG) are two of these mediators. On the other hand, plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (tPA) are two important mediators of fibrinolysis. Both mediators are secreted mainly by vascular endothelium. Plasma levels of PF4, BTG, PAI-1, and tPA may show changes in chronic inflammatory diseases such as asthma. This study examined the role of thrombocytes and the function of the endothelium in asthmatic patients during an attack and during a stable phase. Eighteen patients with known allergic asthma who came to our emergency department with an asthma attack and 14 control subjects were included in the study. Blood samples were taken after starting therapy with salbutamol inhalation. Lung function tests were performed after receiving the first emergency therapy for asthma. Plasma levels of PF4, BTG, PAI-1, tPA were determined before starting steroid therapy and after receiving 1 week of steroid therapy. Plasma levels of PF4 among patients with an asthma attack were significantly higher than those of controls (150.5+/-8.92 IU/mL vs. 92.5+/-7.63 IU/mL, p<0.001). A further increase in plasma PF4 levels was detected after steroid therapy (163.5+/-9.16 IU/mL). Plasma BTG levels of patients on admission were not statistically different from those in the control group (140.4+/-6.34 IU/mL vs. 152.2+/-8.71 IU/mL). An increase was detected after therapy (171.6+/-7.27 IU/mL) and post-treatment plasma levels were statistically meaningful versus the controls. Plasma levels of tPA and PAI were statistically higher than those in controls in asthmatic patients on admission (6.01+/-2.72 vs. 5.4+/-2.3 ng/mL for tPA and 75.2+/-27.2 ng/mL vs. 32.7+/-14.3 ng/mL for PAI-1). Further increases were detected in two parameters after 1 week of therapy with steroids (tPA levels were 6.85+/-2.96 ng/mL and PAI-1 levels were 83.5+/-29.6 ng/mL). There seems to be an increased activity of platelets during an asthma attack. Elevated PAI-1 and tPA levels may also indicate the activated endothelium in asthma. Increases of plasma levels of PAI-1 and tPA after steroid therapy need further investigation because elevated PAI-1 levels enhance airway remodeling.     

Adenoviral-mediated transfer of tissue plasminogen activator gene into brain capillary endothelial cells in vitro

Tissue plasminogen activator (tPA) has a critical role in fibrinolysis, converting plasminogen into active protease plasmin. Because intravenous tPA has only limited effectiveness as acute stroke therapy, enhancement of endogenous tPA represents a potential alternative to stroke treatment. Adenoviral-mediated gene transfer was used to enhance production of tPA in bovine brain capillary endothelial cells (BEC). Antigen and activity levels of tPA and plasminogen activator inhibitor-1 (PAI-1) in media from BEC infected with AdCMVtPA were analyzed. Conditioned media were analyzed for thrombomodulin, the integral membrane antithrombotic molecule that co-activates protein C. BEC infected with AdCMVtPA demonstrated enhanced expression of tPA antigen (40.2 +/- 0.4 ng/mL vs 1.1 +/- 1.5 ng/mL [p<0.001] and 0.3 +/- 0.5 ng/mL [p<0.0001], respectively) and increased tPA enzymatic activity (27.4 +/- 5.7 IU/mL vs 8.3 +/- 1.7 IU/mL [p<0.05] and 13.3 +/- 3.2 IU/mL [p<0.05], respectively) compared to BEC infected with the control adenovirus (Adl327) or uninfected BEC. There was a moderate increase in PAI-1 protein 4 days after transfection with AdCMVtPA, and the integral membrane protein thrombomodulin was released into media by transfected BEC. These results demonstrate that adenoviral-mediated delivery in vitro of the human tPA gene resulted in high levels of expression of tPA in BEC. Transient overexpression of tPA by gene transfer might be a useful strategy to protect against thrombotic occlusion during the period of risk of acute stroke.     

Vascular release of plasminogen activator inhibitor-1 impairs fibrinolysis during acute arterial thrombosis in mice

The role of plasminogen activator inhibitor-1 (PAI-1) in the plasma, blood platelets, and vessel wall during acute arterial thrombus formation was investigated in gene-deficient mice. Photochemically induced thrombosis in the carotid artery was analyzed via transillumination. In comparison to thrombosis in C57BL/6J wild-type (wt) mice (113 +/- 19 x 10(6) arbitrary light units [AU] n = 15, mean +/- SEM), thrombosis in PAI-1(-/-) mice (40 +/- 10 x 10(6) AU, n = 13) was inhibited (P <.01), indicating that PAI-1 controls fibrinolysis during thrombus formation. Systemic administration of murine PAI-1 into PAI-1(-/-) mice led to a full recovery of thrombotic response. Occurrence of fibrinolytic activity was confirmed in alpha(2)-antiplasmin (alpha(2)-AP)-deficient mice. The sizes of thrombi developing in wt mice, in alpha(2)-AP(+/-) and alpha(2)-AP(-/-) mice were 102 +/- 35, 65 +/- 8.1, and 13 +/- 6.1 x 10(6) AU, respectively (n = 6 each) (P <.05), compatible with functional plasmin inhibition by alpha(2)-AP. In contrast, thrombi in wt mice, t-PA(-/-) and u-PA(-/-) mice were comparable, substantiating efficient inhibition of fibrinolysis by the combined PAI-1/alpha(2)-AP action. Platelet depletion and reconstitution confirmed a normal thrombotic response in wt mice, reconstituted with PAI-1(-/-) platelets, but weak thrombosis in PAI-1(-/-) mice reconstituted with wt platelets. Accordingly, murine (wt) PAI-1 levels in platelet lysates and releasates were 0.43 +/- 0.09 ng/10(9) platelets and plasma concentrations equaled 0.73 +/- 0.13 ng/mL. After photochemical injury, plasma PAI-1 rose to 2.9 +/- 0.7 ng/mL (n = 9, P <.01). The plasma rise was prevented by ligating the carotid artery. Hence, during acute thrombosis, fibrinolysis is efficiently prevented by plasma alpha(2)-AP, but also by vascular PAI-1, locally released into the circulation after endothelial injury.     

Influence of prolonged dalteparin treatment on coagulation, fibrinolysis and inflammation in unstable coronary artery disease

BACKGROUND. Unstable coronary artery disease (CAD) is a multi-factorial disease involving thrombotic and inflammatory processes. Short-term low molecular weight (LMW) heparin treatment reduces coagulation activity and clinical events. We investigated the influence of prolonged treatment on coagulation, fibrinolysis and inflammation. METHODS AND RESULTS. Serial blood samples were obtained from 555 of 2,267 unstable CAD patients in the FRISC II study. Patients were treated with the LMW heparin dalteparin 120 IU kg(-1) s.c. twice daily for 5-7 days and randomized to placebo (n=285) or gender and weight-adjusted doses of dalteparin (5,000 or 7,500 IU) twice daily (n=270) for 3 months. Dalteparin persistently depressed coagulation activity with, when compared with placebo, lower median levels of factor VIIa (63 IU mL(-1) vs. 84 IU mL(-1)), prothrombin fragment 1 + 2 (0.86 nmol L(-1) vs. 1.09 nmol L(-1)) and D-dimer (21 microg L(-1) vs. 43 microug L(-1)) after 3 months, all P<0.01. Reactivation of coagulation activity was observed after cessation of both short-term and prolonged dalteparin treatment. Higher levels of tPA/PAI-1 complex (11.7 microg L(-1) vs. 6.5 microg L(-1), P<0.001) and von Willebrand factor (162% vs. 136%, P<0.001) were found during prolonged dalteparin treatment. Interleukin-6, C-reactive protein and fibrinogen levels were unaffected by dalteparin treatment. CONCLUSIONS. Three months dalteparin treatment resulted in a sustained and pronounced reduction of coagulation activity, which corresponds to the observed reduction in death and myocardial infarction during the initial 6 weeks in the FRISC II study. The persistently elevated levels of tPA/PAI-1 complex and von Willebrand factor might reflect effects on platelets and endothelial cells and thus contribute to the gradually decreased efficacy by prolonged dalteparin treatment in unstable CAD.     

Acute hyperglycemia and acute hyperinsulinemia decrease plasma fibrinolytic activity and increase plasminogen activator inhibitor type 1 in the rat

Decreased plasma fibrinolysis may contribute to accelerated atherothrombosis in diabetes. To observe whether hyperglycemia and hyperinsulinemia, common findings in type 2 diabetes, acutely affect plasma fibrinolysis in vivo, we evaluated plasma fibrinolysis (lysis of fibrin plates, free PAI-1 activity and t-PA activity) in the rat after a hyperglycemic euinsulinemic clamp (n=8), an euglycemic hyperinsulinemic clamp (n=7) or a saline infusion (n=15). Plasma fibrinolytic activity was sharply reduced after both the hyperglycemic and hyperinsulinemic clamps as compared to the respective controls (mean lysis areas on the fibrin plate, 139+/-21 vs. 323+/-30 mm2, p<0.001; 78+/-27 vs. 312+/-27 mm2 p<0.001, respectively). Plasma PAI-1 activity was greater after both hyperglycemic and hyperinsulinemic clamps as compared to saline infusion (6.6+/-2.6 vs. 1.6+/-0.6 IU/ml, p<0.001; 26+/-4 vs. 1.3+/-0.7 IU/ml, p<0.0001, respectively). Plasma t-PA activity was significantly reduced both after the hyperglycemic (0.36+/-0.15 vs. 2.17+/-0.18 IU/ml in controls, p<0.001) and the hyperinsulinemic (0.3+/-0.1 vs. 2.3+/-0.3 IU/ml in control, p<0.001) clamps. These data show that in vivo both acute hyperglycemia and acute hyperinsulinemia can decrease plasma fibrinolytic potential and that this is due to increased plasma PAI-1 and decreased free t-PA activities.     

Altered interaction between plasminogen activator inhibitor type 1 activity and sympathetic nerve activity with aging

BACKGROUND: It has been reported that sympathetic nerve activity (SNA) is associated with fibrinolysis, but the interaction between SNA and the fibrinolytic system with aging has not been elucidated in humans. The purpose of this study was to examine the effect of age-related SNA on the activity of plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator (tPA) using muscle SNA (MSNA). METHODS AND RESULTS: This study included 16 young subjects (mean age 26.1 years) and 10 aged subjects (mean age 56.9 years). Lower body negative pressure (LBNP) was performed at -40 mmHg for 30 min. LBNP significantly increased both tPA and PAI-1 activity (from 5.2+/-0.5 to 7.3+/-1.2 IU/ml and from 2.85+/-0.68 to 4.06+/-0.73 U/ml, p<0.01, respectively) in the aged group. In the young group, tPA activity tended to increase, whereas PAI-1 activity was unchanged. There was a correlation between MSNA and PAI-1 activity in the aged group (r=0.47, p<0.01). CONCLUSIONS: SNA in an aging subject leads to an increase in the activity of PAI-1, which indicates that an altered interaction between SNA and PAI-1 activity contributes to increased cardiovascular events in the elderly population.     

Interleukin-2 induces activation of coagulation and fibrinolysis: resemblance to the changes seen during experimental endotoxaemia

The administration of Interleukin-2 (IL-2) causes the release or generation of other cytokines such as tumour necrosis factor (TNF) which, by disturbing the anticoagulant properties of the endothelium, may induce a procoagulant state in patients receiving this drug. We therefore evaluated the effects of IL-2 on coagulation and fibrinolysis in 14 patients receiving 12 or 18 x 10(6) IU/m2/d of IL-2 given as a 15 min infusion for 5 d. Blood samples were drawn at short intervals after the first IL-2 infusion. The parameters were analysed by way of analysis for repeated measures (F tests rather than t tests). During the first day, thrombin-antithrombin (TAT) complexes started to increase 2 h after the IL-2 infusion, reaching peak levels at 4 h (n = 14; 11.2 +/- 6.4 micrograms/l v 49.8 +/- 49.2 micrograms/l, P < 0.01). Plasma alpha 2 antiplasmin (PAP) complexes showed a similar pattern rising from a mean baseline value of 17.5 +/- 7.6 nmol/l to 66.8 +/- 47.7 nmol at 4 h (P < 0.01). In four patients the peak of PAP preceeded that of TAT. Tissue plasminogen activator (tPA) rose from a mean baseline value of 4.9 +/- 3.7 micrograms/l to 26.3 +/- 13.5 micrograms/l at 4 h (P < 0.01). Plasminogen-activator-inhibitor-1 (PAI-1) levels increased from 59 +/- 35 micrograms/l to 113 +/- 39 micrograms/l at 6 h (P < 0.01). tPA PAI-1 complexes increased from 0.15 +/- 0.07 to 0.69 +/- 0.21 nmol/l at 6 h (P < 0.01). Our study indicates that IL-2 activates the coagulation and fibrinolytic systems in vivo. The changes resemble the perturbations observed after endotoxin/TNF administration. These abnormalities may play a role in the side-effects induced by IL-2 therapy.