Predictive value for thrombotic disease of plasminogen activator inhibitor-1 plasma levels

Summary Plasminogen activator inhibitor-1 plays a major role in the fibrinolytic system as the main physiological inhibitor of both tissue-type and urinary-type plasminogen activators. The inhibitor is present in plasma in small amounts and derives mainly from endothelial cells. Positive correlations have been reported between plasma levels and different parameters, such as serum triglycerides, insulin plasma levels and body mass index. Moreover, high plasma inhibitor concentrations have been observed in different disease states, but it must be stressed that plasminogen activator inhibitor-1 behaves as an acute-phase reactant and measurement of plasma levels is not significant in the acute phase of the disease. A possible predictive value of inhibitor levels for thrombotic events such as deep vein thrombosis and ischemic heart disease has been studied. On the basis of available studies, the predictive value is not clear for venous thrombosis, whereas plasminogen activator inhibitor-1 levels can predict some coronary events, at least in subgroups of young patients with a first myocardial infarction. It remains to be established if treatments able to reduce plasma inhibitor levels lead to a decrease in the risk of thromboembolic events.     

The plasma levels of plasminogen activator inhibitor-1 in subjects with white coat hypertension

High plasminogen activator inhibitor-1 (PAI-1) levels are potential risk factors for cardiovascular disease. The risk profile of white coat hypertension (WCHT) has not yet been completely clear. In this study, we aimed to determine the plasma levels of PAI-1, markers of fibrinolysis and increased cardiovascular disease risk, in a group with WCHT and to obtain clinical results by comparing WCHT group with hypertensive and healthy groups. Age and sex matched 30 patients with WCHT, 30 patients with sustained hypertension, and 30 healthy subjects were included in the study. The plasma levels of PAI-1 were significantly higher in sustained hypertension group than in WCHT group (p < 0.01). There were significantly higher levels in patients with WCHT than in control group (p < 0.01). Our data suggests one possible mechanism by which WCHT subjects may be at increased cardiovascular risk.     

Plasminogen activator inhibitor-1 predicts coronary in-stent restenosis of drug-eluting stents

Background : We tested the hypothesis that plasma levels of plasminogen activator inhibitor-1 (PAI-1) are influenced by percutaneous coronary intervention (PCI) with the implantation of drug eluting stents (DES) and are able to predict the occurrence of in-stent restenosis (ISR). Methods and results : PAI-1 active antigen plasma levels were determined in 75 patients before and 24 h after PCI with DES implantation. Patients with ISR after six to eight months (16%) showed significantly lower PAI-1 plasma levels before PCI (ISR, 11.7 ± 8.1 ng mL⁻¹; non-ISR, 22.8 ± 18.8 ng mL⁻¹; P  < 0.05). PAI-1 levels in the lowest tertile were associated with a 9.5-fold increased risk of ISR, independent of clinical risk factors, angiographic or procedural characteristics, compared to the highest tertile ( P  <   0.05). The induced change of PAI-1 active antigen 24 h after PCI was significantly higher in patients with ISR (ISR, +5.6 ± 8.0 ng mL⁻¹; non-ISR, −3.2 ± 12.1 ng mL⁻¹; P  <   0.05) with positive correlation to late lumen loss ( r  =   0.30; P  <   0.05). Conclusions : ISR after DES implantation is significantly related to plasma levels of PAI-1 active antigen before and after PCI. If confirmed by larger multicenter studies, the determination of PAI-1 plasma levels might be clinically helpful in the identification of patients at high risk of developing of ISR, even after DES implantation.     

Neointima formation and thrombosis after vascular injury in transgenic mice overexpressing plasminogen activator inhibitor-1 (PAI-1)

Summary.  The controversial role of plasminogen activator inhibitor-1 (PAI-1) in neointima formation and restenosis was studied with the use of a vascular injury model in transgenic mice overexpressing murine PAI-1 (PAI-1 Tg) and in wild-type (WT) controls. Despite the high circulating PAI-1 levels in the PAI-1 Tg mice (52 ± 9.8 ng mL⁻¹ vs. 0.76 ± 0.17 ng mL⁻¹ in WT mice), no significant fibrin deposition was observed in non-injured femoral arteries of 8- to 12-week-old mice. Two weeks after severe electric injury, extensive and comparable fibrin deposition was observed in both genotypes, despite a significantly reduced in situ fibrinolytic activity in arterial sections of the PAI-1 Tg mice. The neointimal and medial areas were similar in WT and PAI-1 Tg mice, resulting in comparable intima/media ratios (e.g. 0.94 ± 0.25 and 1.04 ± 0.17 at the center of the injury). Nuclear cell counts in cross-sectional areas of the neointima of the injured region were also comparable in arteries from WT and PAI-1 Tg mice (224 ± 63, 233 ± 20), and the distribution pattern of α-actin-positive smooth muscle cells was similar. These findings indicate that in a vascular injury model that induces extensive and persistent fibrin deposition in femoral arteries of mice, overexpression of PAI-1 does not affect neointima formation.     

高脂蛋白a血症对冠状动脉支架术后再狭窄的影响

目的 探讨高血清脂蛋白(a)[LP(a)]血症与冠状动脉支架植入术后支架内再狭窄的关系.方法 对152例成功在我院行经皮冠状动脉成形术(PTCA)+支架植入术并于术后行冠状动脉造影随访的患者进行回顾性分析.分为再狭窄组(29例)和无再狭窄组(123例),检测患者血LP(a)水平,对其一般临床资料也进行调查分析.统计学采用Logistic多因素逐步回归分析.结果 2组患者在高LP(a)血症、吸烟、糖尿病比例方面差异均有统计学意义(P均<0.05).Logistic多因素逐步回归分析显示:LP(a)水平是支架术后支架内再狭窄发生的独立危险因素,RR为2.648,95%CI为1.066～6.575,P<0.05.其他因素如吸烟(P=0.023)、糖尿病(P=0.036)、支架类型(P=0.011)也与支架内再狭窄发生有关(P均<0.05).结论 高LP(a)血症是发生冠状动脉支架术后再狭窄的独立危险预测因素.     

纤溶酶原激活剂抑制物-1检测及其对脑血栓的诊断价值

目的 检测血浆纤溶酶原激活剂抑制物-1(PAI-1),了解脑血栓患者PAI-1在治疗前后的变化.方法 采用酶联免疫吸附双抗体夹心法检测35例脑血栓伴高血压患者(混合组)、33例单纯脑血栓患者(血栓组)、30例高血压患者(高血压组)和30例对照者(对照组)治疗前后以及30例健康人(健康组)血浆PAI-1水平.结果 PAI-1治疗前后分别为:混合组(185.6±31.6) ng/mL和(87.2±26.7)ng/mL,脑血栓组(163.5±30.8)ng/mL和(80.4±23.6)ng/mL,高血压组(96.2±26.3)ng/mL 和(54.8±22.5)ng/mL,对照组(45.5±15.4)ng/mL 和(40.2±12.8)ng/mL,健康组(25.2±8.3)ng/mL.前二组治疗前后血浆PAI-1差异有统计学意义(P<0.01),前三组与健康组比较,差异有统计学意义(P<0.01).结论血浆PAI-1水平反映患者的凝血纤溶改变情况,与内皮细胞损伤密切相关,是观察脑血栓患者病情和疗效的有效实验指标.     

Bispecific targeting of thrombin activatable fibrinolysis inhibitor and plasminogen activator inhibitor‐1 by a heterodimer diabody

Summary. Background and objectives: Thrombin activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor‐1 (PAI‐1) play important roles in fibrinolysis. Both reduce plasmin generation, but they exert their antifibrinolytic effects via different mechanisms. This study reports the cloning and characterization of a heterodimer diabody that inhibits TAFI and PAI‐1 simultaneously. Methods and results: The diabody was derived from two inhibiting monoclonal antibodies, i.e. MA‐33H1F7, an anti‐PAI‐1 antibody that induces non‐inhibitory substrate behavior of PAI‐1, and MA‐T12D11, an anti‐TAFI antibody that inhibits activation of TAFI by the thrombin–thrombomodulin complex. A single‐chain variable fragment (scFv) was derived from MA‐T12D11 that displayed slightly reduced binding and inhibitory properties as compared to MA‐T12D11. Characterization of the diabody revealed a similar affinity for TAFI and PAI‐1 as that of the parental antibodies. Furthermore, the inhibitory properties of MA‐33H1F7 and MA‐T12D11 were fully preserved in the diabody format. In platelet‐free plasma (PFP) clots, addition of the diabody had a stronger effect in shortening lysis times than either MA‐T12D11 or MA‐33H1F7. A similar reduction in clot lysis time was observed in platelet‐rich plasma (PRP) clots. The same effect on clot lysis times in PFP and PRP was also achieved by the combined addition of MA‐T12D11 and MA‐33H1F7. The lysis rate of human model thrombi, made from whole blood, was approximately doubled after addition of the diabody. Moreover, this effect was significantly better than after the combined addition of the individual antibodies. Conclusions: These observations demonstrate that simultaneous inhibition of TAFI and PAI‐1 results in faster lysis of the formed thrombus.     

Reversible defects on myocardial perfusion imaging early after coronary stent implantation: a predictor of late restenosis

Purpose If coronary artery was treated with optimal stent implantation, myocardial perfusion in the territory supplied by a dilated coronary artery should be not reversible. However, several studies have demonstrated reversible perfusion in the territory supplied by a coronary artery with an optimally implanted stent. The main objective of this study was to evaluate the incidence of reversible defects detected by M-SPECT early after optimal PTCA with stent implantation. Its second objective was to determine the predictive value of detecting reversible defects after stent implantation for late restenosis. Methods About 66 patients that underwent M-SPECT within 24 h of successful PTCA with stent implantation were included. All patients were followed up clinically and angiographically. The incidence of reversible perfusion defects on M-SPECT and the rate of late restenosis in target coronary arteries were evaluated retrospectively. Results Reversible perfusion defects on M-SPECT were observed in 26% of the patients and in 36% of lesions following successful PTCA with stent implantation. The incidence of late restenosis was significantly higher in patients and lesions with reversible perfusion defects (47% vs. 18%). According to binary logistic regression analysis, the presence of a reversible perfusion defects was the only independent predictor of late restenosis.     

Gender-specific correlations of plasminogen activator inhibitor-1 and tissue plasminogen activator levels with cardiovascular disease-related traits

Summary.  Background:  The purpose of this study was to examine the correlations between plasma levels of plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (t-PA) and cardiovascular disease-related traits in a general population and whether these correlations differed between females and males. Methods:  Plasma PAI-1 and t-PA antigen levels and C-reactive protein (CRP), HDL-cholesterol, triglycerides, total cholesterol, systolic blood pressure, diastolic blood pressure, urinary albumin excretion, and glucose were measured in the population-based PREVEND study in Groningen, the Netherlands ( n  = 2527). Results:  Except for CRP and total cholesterol levels, all traits were significantly different between gender ( P  < 0.001). PAI-1 levels were correlated with all measured cardiovascular disease-related traits ( P  < 0.01) in both females and males. Except for urinary albumin excretion, similar results, albeit less significant, were found for t-PA levels. Age-adjusted correlations between PAI-1 and CRP, triglycerides, total cholesterol, systolic blood pressure, and diastolic blood pressure differed significantly between females and males ( P  < 0.01). Many of the gender differences were predominantly present between premenopausal females and males. Conclusion:  PAI-1 and t-PA levels were correlated with cardiovascular disease-related traits in subjects obtained from the general population and several of these correlations differed across gender. The correlations found in the present study suggest the presence of coordinated patterns of cardiovascular risk factors and indicate which traits might influence PAI-1 and t-PA levels and thereby provide a framework and potential tool for therapeutic intervention to reduce thromboembolic events in the general population.     

慢性心力衰竭患者血浆组织型纤溶酶原激活物和纤溶酶原激活物抑制物-1含量变化及其临床意义

目的　研究慢性心力衰竭 (CHF)患者血浆组织型纤溶酶原激活物 (t PA)和纤溶酶原激活物抑制物 1(PAI 1)含量的变化及其临床意义。方法　用酶联免疫吸附法 (ELISA)检测 6 0例CHF患者 (CHF组 )和 2 0例健康体检者 (正常对照组 )血浆t PA及PAI 1抗原含量。结果　CHF组血浆t PA和PAI 1平均含量都明显高于对照组 (P<0 .0 1)。CHF患者血浆PAI 1含量增高随心功能恶化而愈加明显。结论　CHF患者纤溶功能明显下降 ,可用血浆t PA、PAI 1含量作为判断病情的参考指标之一。     

Effect of pharmacologic plasminogen activator inhibitor-1 inhibition on cell motility and tumor angiogenesis

BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1) is integrally involved in tumorigenesis by impacting on both proteolytic activity and cell migration during angiogenesis. OBJECTIVES: We hypothesized that an orally active small molecule inhibitor of PAI-1 (PAI-039; tiplaxtinin) could affect smooth muscle cell (SMC) attachment and migration in vitro on a vitronectin matrix, and exhibit antiangiogenic activity in vivo. METHODS: In vitro assays were used to assess the mechanism of inhibition of PAI-1 by PAI-039 using wild-type PAI-1 in the presence or absence of vitronectin and wild-type PAI-1 and specific PAI-1 mutants in SMC adhesion and migration assays. An in vivo tumor angiogenesis model was used to assess the effect of PAI-039 administration on neovascularization in a Matrigel implant. RESULTS: PAI-039 dose-dependently inhibited soluble, but not vitronectin-bound, PAI-1. Cell adhesion assays using PAI-1 mutants unable to bind vitronectin (PAI-1K) or inactivate proteases (PAI-1R) further suggested that PAI-039 inactivated PAI-1 by binding near its vitronectin domain. In a tumor angiogenesis model, PAI-039 treatment of wild-type mice dose-dependently decreased hemoglobin concentration and endothelial cell staining within the Matrigel implant, indicating reduced angiogenesis, but exhibited no in vivo efficacy in PAI-1 null mice. CONCLUSIONS: Administration of an orally active PAI-1 inhibitor prevented angiogenesis in a Matrigel implant. The lack of activity of PAI-039 against wild-type PAI-1 bound to vitronectin and PAI-1K suggests PAI-039 binding near the vitronectin-binding site. Our studies further substantiate a role for PAI-1 in cellular motility and tumor angiogenesis, and suggest for the first time that these effects can be modulated pharmacologically.     

探讨糖尿病前期患者血浆IL-18、PAI-1水平变化与胰岛素抵抗的相关性

目的探讨血浆白细胞介素-18(IL-18)、纤溶酶原激活物抑制物-1(PAI-1)水平变化与Ⅱ型糖尿病发病危险因素的关系.方法 设立健康人对照(NGT)组、糖耐量减低( IGT )组、空腹血糖受损合并糖耐量减低(IFG/IGT)组,每组各100例.测定各受试者血浆 IL-18、PAI-1、血清空腹胰岛素、空腹血糖、餐后2 h血糖,应用稳态模型评估法评价胰岛素抵抗(HOMA-IR).结果 IGT组、IFG/IGT组血浆 IL-18、PAI-1 水平均高于NGT组(P<0.01).IFG/IGT组血浆 IL-18、PAI-1 水平均高于IGT组(P<0.05).相关分析显示IL-18、PAI-1 水平与空腹血糖、餐后2 h血糖、HOMA-IR呈正相关(P<0.01).结论血浆 IL-18、PAI-1 水平升高可能是加重糖尿病前期患者胰岛素抵抗的危险因素;在糖尿病前期,IL-18、PAI-1可能参与了Ⅱ型糖尿病的发生、发展.     

血栓调节蛋白和组织纤溶酶原激活物-纤溶酶原激活物抑制剂-1复合物在热射病中的诊断价值

目的 探讨热射病时血栓调节蛋白(TM)和组织纤溶酶原激活物-纤溶酶原激活物抑制剂-1复合物(t-PAIC)的临床价值。方法 回顾性分析解放军联勤保障部队第九〇八医院重症医学科2016年6月至2022年9月收治的45例中暑患者，根据中暑严重程度分为热衰竭组(n=23)和热射病组(n=22)。收集患者入科2 h内的常规凝血项目和血栓弹力图(TEG)指标以及血栓标志物TM、凝血酶-抗凝血酶复合物(TAT)、纤溶酶-α₂纤溶酶抑制剂复合物(PIC)、t-PAIC,并进行统计学分析。结果 与热衰竭组患者TM[7.3(5.4,9.3)TU/mL]、TAT[2.6(1.5,7.2)ng/mL]、PIC[0.7(0.4,1.0)μg/mL]、t-PAIC[3.8(2.1,7.0)ng/mL]相比，热射病组患者TM[17.1(9.2,24.7)TU/mL]、TAT[23.4(10.4,44.3)ng/mL]、PIC[2.0(0.9,5.2)μg/mL]和t-PAIC[17.0(8.3,44.1)ng/mL]均升高(P<0.05)。单因素联合多因素Logistic回归分析显示，...     

螺内酯对醛固酮刺激下大鼠肾小球系膜细胞PAI-1表达的影响

目的探讨醛固酮对体外培养大鼠肾小球系膜细胞纤溶酶原激活物抑制物－1（PAl-1）表达的影响及螺内酯的干预作用。方法体外培养大鼠肾小球系膜细胞,设正常对照组、醛固酮（10-7mol·L-1）组、不同浓度螺内酯（10-7,10-8,10-9mol·L-1）干预组,48h后收集细胞及上清液,以RT-PCR检测PM-1、醛固酮受体（MR）和保护其配体特异性的11p羟类固醇脱氢酶2（11β-HSD2）的mRNA表达,采用ELISA检测培养细胞上清中PAI-1蛋白的浓度。结果RT-PCR结果,肾小球系膜细胞表达MR和118．HSD2mRNA,醛固酮可显著上调肾小球系膜细胞PM-1mRNA表达,螺内酯可抑制醛固酮诱导的PA／-1mRNA表达,且呈剂量依赖性;ELISA结果示醛固酮组上清液中PAI-1水平明显增加,螺内酯干预组PAI-1水平明显降低并与浓度有关。结论螺内酯与醛固酮竞争结合MR,抑制醛固酮刺激的大鼠。肾小球系膜细胞中PAI-1mRNA的表达和蛋白合成。     

不稳定型心绞痛及其危险度分层对介入治疗预后和支架再狭窄的预测

目的 探讨不稳定型心绞痛及其危害度分层对介入治疗的近、中期预后及血管再狭窄的影响。方法 选择成功施行冠状动脉支架植入术并进行临床和血管造影随访的78例冠心病患者。分为稳定型心绞痛组和不稳定型心绞痛组，并对不稳定型心绞痛进行Braunwald危险度分层。分析不同分组和分层对预后的预测价值。结果 不稳定型心绞痛组的再狭窄率和心脏事件的发生率显著性高于稳定型心绞痛组（P＜0．05）。Braunwald分级Ⅱ、Ⅲ级的支架再狭窄率显著高于SA患者（P＜0．05）。而Braunwald分级I级的再狭窄率与SA患者无差异。Logistic多因素分析不稳定型心绞痛是再狭窄的独立危险因子（P＜0．05，OR：2．9）。结论 不稳定型心绞痛及其危险度分层对介入治疗预后和支架再狭窄具有重要预测价值。     

纤溶酶原激活物及其抑制剂-1的血浆含量测定在急性肺血栓栓塞症中的意义

目的探讨在急性肺血栓栓塞症(APE)发病中的组织型纤溶酶原激活物(tPA)及其抑制剂-1(PAI-1)的血浆含量、作用及其该病诊断中的意义。方法,对44例APE患者和56例健康正常对照者应用酶联免疫吸附双抗体夹心法(ELISA法)定量测定血浆tPA和PAI-1抗原水平。结果与正常对照组(tPA含量为11．05ng／ml和PAI-1含量为61．31ng／m1)相比,APE组的IPA含量(33．88ng／ml)和PAI-1含量(111．50ng／ml)较高,两组间差异有显著性。在急性肺血栓栓塞症的疾病诊断中,tPA和PAI-1的血浆含量合理诊断截断点分别为21．7ng／ml和79．4ng／ml.结论急性肺血栓栓塞症的发病是由于PAI-1抗原产生和释放增多,而非tPA抗原释放或产生不足所致．tPA和PAI-1抗原血浆含量测定在APE的疾病诊断中具有要意义。     

阿托伐他汀调脂治疗对急性冠脉综合征患者血管内皮功能及纤溶活性的影响

目的 :探讨急性冠脉综合征患者应用阿托伐他汀调脂治疗后对血管内皮舒张功能、血浆纤溶酶原激活物抑制物1及血管内皮素 1的影响。方法 :12 0例急性冠脉综合征患者随机分成阿托伐他汀治疗组 60例及常规治疗组 60例 ,比较治疗 8周前后应用超声检测肱动脉流量介导性扩张的血管内皮舒张功能及血浆内皮素 1及PAI 1水平的变化。结果 :( 1)治疗前两组比较 ,内皮依赖性血管舒张功能差异无显著性 ( 4 94%± 0 86%与 4 96%± 0 87%,P >0 0 5 ) ,治疗 8周后 ,常规组内皮依赖性血管舒张功能较治疗前差异无显著性 ( 4 94%± 0 86%与 5 17%± 0 79%)而阿托伐他汀组治疗后差异有十分显著性 ( 4 94%± 0 81%与 7 96%± 0 95 %,P <0 0 1)。 ( 2 )阿托伐他汀组治疗 8周后血浆纤溶酶原激活物抑制物 1、血管内皮素 1较治疗前 ( 5 82± 2 62ng/L、12 2 8± 3 16Au/ml)均有显著降低 ( 3 42± 1 95ng/L ,8 2 2± 2 5 6Au/ml,P <0 0 1)。结论 :急性冠脉综合征患者应用阿托伐他汀降脂治疗 8周后可改善内皮依赖性血管舒张功能 ,同时改善纤溶活性