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。     

冠心病患者纤溶活性的研究

【目的】了解冠心病不同阶段纤溶活性的改变。【方法】选择 4 7例经冠脉造影证实为冠心病 (其中不稳定型心绞痛 2 5例 ,稳定型心绞痛 2 2例 ) ,2 0例急性心肌梗死及 30例正常人为研究对象 ,测定各对象的血浆组织型纤溶酶原激活剂活性 (t PA :a)及其抑制物活性 (PAI 1:a)。【结果】急性心肌梗死组、不稳定型心绞痛组分别与稳定型心绞痛组及正常组相比 ,血浆PAI 1:a及PAI/t PA比值均显著升高 (P <0 .0 1) ,而t PA :a显著降低 (P <0 .0 1) ,稳定型心绞痛与正常组相比 ,各指标无显著差异 ;在冠脉单支与多支病变组间 ,各项指标无差异。【结论】冠心病患者不同阶段纤溶活性不同 ,急性冠脉综合征患者纤溶活性降低。     

吡格列酮对老年高血压并胰岛素抵抗病人纤溶系统的影响

目的评价吡格列酮对老年高血压并胰岛素抵抗病人纤溶功能的影响。方法24例老年高血压并胰岛素抵抗病人口服吡格列酮15mg／d,共16周．服药前后分别测定血浆纤溶酶原激活物抑制物-1（PAO-1）、组织型纤溶酶原激活物、二聚体和纤维蛋白原含量,同时测定空腹胰岛素、空腹血糖和24h动态血压。结果吡格列酮治疗后血浆纤溶酶原激活物抑制物-1、二聚体抗原水平明显下降（P〈0．01）,组织型纤溶酶原激活物抗原水平明显增加（P〈0．01）,胰岛素敏感指数显著提高（P〈0、01）,空腹胰岛素和纤维蛋白原明显降低（P〈0．01）;24h平均收缩压和舒张压均降低（P〈0．05）。多因素分析结果表明治疗前空腹胰岛素水平对PAI-1的降低影响最大（P〈0．01）。结论吡格列酮能有效改善老年高血压并胰岛素抵抗病人纤溶系统功能,提高胰岛素敏感性,降低收缩压和舒张压;空腹胰岛素水平是影响病人纤溶功能的主要因素。     

糖耐量减低患者纤溶受抑的临床观察

目的探讨糖耐量减低(IGT)及IGT合并急性冠状动脉综合征(ACS)患者纤溶受抑状态。方法97例患者随机分成3组,IGT组33例,IGT+ACS组32例,ACS组32例;正常对照组20例。检测血浆中组织型纤溶酶原激活剂(t-PA),纤溶酶原激活物抑制剂-1(PAI-1)及D-二聚体的水平,并计算出PAI-1/D-二聚体的比值。结果IGT组、IGT+ACS组和ACS组血浆t-PA、PAI-1和D-二聚体浓度均显著高于正常对照组(P<0.05,P<0.01);IGT组和IGT+ACS组血浆D-二聚体水平增高幅度则显著低于ACS组(P<0.05,P<0.01);IGT组和IGT+ACS组的PAI-1/D-二聚体比值分别比正常对照组及ACS组明显增高(P<0.01)。结论IGT患者存在纤溶受抑状态,血浆D-二聚体的水平结合PAI-1/D-二聚体比值能反映患者纤溶受抑的状态及预后。     

Thrombogenic and Fibrinolytic Factors and Cardiovascular Risk in Non-insulin-dependent Diabetes Mellitus

Disturbances of the haemostatic system may favour the development of vascular damage and the final occlusion events in the progress of coronary heart disease (CHD). It has been shown recently in epidemiological studies, that increased concentration of several factors, mainly fibrinogen, factor VII, von Willebrand factor (vWF), and the fibrinolytic variables plasminogen activator inhibitor 1 (PAI-1) and tissue plasminogen activator (t-PA), can be considered as risk factors for CHD. As morbidity and mortality through coronary atherosclerosis are higher in type 2 diabetic patients than in non-diabetic subjects and as insulin resistance represents a situation which favours the development of atherothrombosis, evaluation of the haemostatic factors which are recognized as risk factors may be interesting to consider in these situations. In fact, it has been shown that the fibrinolytic parameters PAI-1 and t-PA antigen are strongly related to the metabolic disorder of insulin resistance, whereas the link with fibrinogen, factor VII, and vWF remains weak. Many cross-sectional studies conducted in different populations have shown that PAI-1 and t-PA antigen (which represents t-PA/PAI-1 complexes) are strongly correlated with insulin, triglyceride, high-density lipoprotein (HDL) cholesterol, body mass index, waist-to-hip ratio and blood pressure, and that the improvement of insulin resistance improves in parallel the metabolic abnormalities and the concentration of the fibrinolytic parameters. Attempts at explaining the elevated PAI-1 and t-PA antigen levels in the insulin resistance syndrome have involved many clinical and in vitro studies, in which the role of insulin, insulin propeptides, very-low-density lipoprotein (VLDL) triglyceride, insulin resistance per se, glucose, and adipose tissue have successively been analysed and the main results of these studies are presented in this review. Due to recent experimental data from animal models of thrombosis, a pathogenic role of decreased fibrinolytic activity or increased PAI-1 levels can be proposed and could play a role in the development of vascular disease in subjects with Type 2 diabetes or insulin resistance.     

Relationship between fibrinolytic and metabolic variables: a study in patients attending a lipid clinic

We investigated the relationship between plasma levels of metabolic and fibrinolytic variables in 163 fasted patients attending a lipid clinic. Of these patients, 118 had hypertriglyceridaemia (HTG) and 45 had normotriglyceridaemia (NTG). In HTG, basal fibrinolytic activity, ie tissue plasminogen activator (t-PA) activity, was impaired as a result of high plasminogen activator inhibitor type 1 (PAI-1) antigen and activity. Multiple stepwise regression analysis identified insulin and triglyceride levels as independent determinants of plasma PAI-1 levels (R² = 0.18; P = 0.0001). When the patients were stratified into tertiles according to their levels of triglyceride and insulin, PAI-1 antigen levels were found to increase with rising levels of triglyceride in each insulin tertile. In contrast, the increase of PAI-1 with rising insulin levels was evident in the highest triglyceride tertile. In addition, subjects in the lowest tertile of both triglyceride and insulin had the lowest PAI-1 antigen levels, and subjects in the highest tertile of both triglyceride and insulin had the highest levels of PAI-1. Both basal and stimulated levels of t-PA antigen were significantly higher in HTG than in NTG. Multiple stepwise regression analysis identified triglyceride level as the sole major determinant of t-PA antigen levels (R² = 0.13; P = 0.00003). The observation that both insulin and triglycerides correlate with PAI-1, whereas triglycerides were involved only in the increased secretion of t-PA, suggests that these two proteins are regulated by different mechanisms.     

急性冠状动脉综合征病人血清CRP与纤溶活性变化

目的探讨急性冠状动脉综合征（ACS）病人血清C-反应蛋白（CRP）与纤溶活性变化。方法检测并比较47例ACS病人、41例稳定型心绞痛（SA）病人和40例正常人（正常对照组）CRP、纤维蛋白原（FIB）、血脂、D-二聚体浓度，组织型纤溶酶原激活物（tPA）、纤溶酶原激活物抑制物-1（PAI-1）活性及自细胞（WBC）总数。结果与SA组及正常对照组比较，ACS组病人CRP、FIB、WBC、D-二聚体及PAI-1明显升高（F=6．027～2543．668，q=3．571～16．098，P〈0．05、0．01），tPA降低（F=4．138，q=3．043～3．913，P〈0．05）；CRP与D-二聚体及PAI-1活性呈正相关（r=0．326、0．393，P〈0．05、0．01），与tPA活性呈负相关（r=-0．387，P％0．05）。结论ACS病人炎症标志物水平增高及纤溶活性降低，CRP水平升高与纤溶活性降低密切相关。炎症反应及纤溶活性降低在ACS的发生发展中具有重要作用。     

急性脑血栓形成患者血浆及脑脊液纤溶指标的观察

目的：研究急性脑血栓形成患者血浆及脑脊液组织型纤溶酶原激活物(t-PA)及其抑制物(PAI-1)和D-二聚体含量的变化及其临床意义。方法：采用双抗体夹心固相酶联免疫吸附法(ELISA)检测35例急性脑血栓形成患者(血栓组)的血浆和其中3l例的脑脊液t—PA、PAI-l和D-二聚体的抗原含量，与35例无心脑、肝肾及血液疾病患者(对照组)血浆和其中20例脑脊液进行比较。结果：血栓组血浆及脑脊液中t-PA、PAI-1和D-二聚体含量均高于对照组；脑脊液中t-PA、PAI-l和D-二聚体的含量分别与血浆中含量呈正相关。结论：急性脑血栓形成患者纤溶活性明显下降,t-PA及PAI-l参与了脑血栓形成的病理过程。     

Vagus nerve stimulation inhibits activation of coagulation and fibrinolysis during endotoxemia in rats

BACKGROUND: Sepsis and endotoxemia are associated with concurrent activation of inflammation and the hemostatic mechanism, which both contribute to organ dysfunction and death. Electrical vagus nerve stimulation (VNS) has been found to inhibit tumor necrosis factor (TNF)-alpha release during endotoxemia in rodents. OBJECTIVE: To determine the effect of VNS on activation of coagulation and fibrinolysis. METHODS: Rats received a sublethal i.v. dose of lipopolysaccharide (LPS) after electrical VNS or sham stimulation. Activation of coagulation and fibrinolysis, as well as cytokine release, was measured before LPS injection and 2, 4 and 6 h thereafter. Results: LPS induced activation of the coagulation system (increases in the plasma concentrations of thrombin-antithrombin complexes and D-dimer, and a decrease in antithrombin) and biphasic changes in the fibrinolytic system [early rises of plasminogen activator activity and tissue-type plasminogen activator, followed by a delayed increase in plasminogen activator inhibitor type 1 (PAI-1)]. VNS strongly inhibited all LPS-induced procoagulant responses and more modestly attenuated the fibrinolytic response. In addition, VNS attenuated the LPS-induced increases in plasma and splenic concentrations of the proinflammatory cytokines TNF-alpha and interleukin-6 (IL-6), while not influencing the release of the anti-inflammatory cytokine IL-10. CONCLUSION: These data illustrate a thus far unrecognized effect of VNS and suggest that the cholinergic anti-inflammatory pathway not only impacts on inflammation but also on the coagulant-anticoagulant balance.     

心绞痛患者介入术后血小板活化及纤溶功能的变化

目的 研究冠心病不稳定心绞痛患者经皮冠状动脉腔内成形术（PTCA）和冠状动脉内支架术（stent)后外周循环中血小板活化及纤溶功能的变化。方法 由外周静脉采血，采用ELISA检测PTCA和stent术前后血浆血小板表面α-颗粒膜蛋白（GMP-140），血管性假血友病因子（VWF），组织纤溶酶原激活剂（t-PA)，纤溶酶原激活剂抑制物-1（PAI-1），D-二聚体（D-D）的含量。结果 31例不稳定型心绞痛患者PTCA术后10min血浆血小板膜表面GMP-140及D-二聚体明显增高。术后24h虽明显下降，但血小板膜表面GMP-140尚未降至正常，PAI-1术后24h亦明显增高。结论 冠心病不稳定型迟缓绞痛患者PTCA和stent术后确有血小板活化和纤溶活性受损。     

急性脑梗死患者血浆t-PA、PAI-1、TM及GMP-140的变化及意义

目的 :探讨血浆组织型纤溶酶原激活物 (t -PA)及其抑制物 (PAI -1)、血栓调节蛋白 (TM )和血小板α颗粒膜蛋白 -14 0 (GMP -14 0 )在急性脑梗死发病中的意义。方法 :对 5 7例急性脑梗死患者进行血浆t -PA、PAI -1、TM及GMP -14 0的检测 ,并与对照组进行比较。结果 :急性脑梗死患者较正常对照组t -PA水平明显降低 ,PAI -1、TM及GMP -14 0水平明显升高 (P <0 0 1)。结论 :急性期脑梗死患者内皮细胞损伤、血小板活化及纤溶活性的变化可能参与了疾病的发生发展过程 ,为脑梗死的治疗提供了理论依据     

Tissue plasminogen activator genetic polymorphisms do not influence tissue plasminogen activator release in patients with coronary heart disease

OBJECTIVES: To determine if polymorphisms of the tissue plasminogen activator (t-PA) gene influence acute endogenous t-PA release in patients with coronary heart disease (CHD). METHODS: Forearm blood flow and plasma t-PA concentrations were measured in response to intra-brachial infusion of substance P and sodium nitroprusside in 96 patients with stable CHD. Genotyping was performed using a Taqman polymerase chain reaction assay specifically designed to detect the polymorphisms of interest: (i) Alu-repeat insertion/deletion sequence; (ii) C-->T substitution in an upstream enhancer region (-7351 C/T); (iii) T-->C in exon 6 (20 099 T/C); and (iv) T-->A (27 445 T/A) in intron 10. RESULTS: Substance P and sodium nitroprusside caused dose-dependent increases in forearm blood flow in all patients (P < 0.001 for all) that were independent of the four genetic polymorphisms. Similarly, there were no differences in basal plasma t-PA antigen concentrations or net t-PA release between genotypes. Compared to non-smokers, smokers exhibited impaired substance P-induced vasodilatation (P < 0.001) and t-PA release (P = 0.05). CONCLUSIONS: Despite confirming our previous findings in cigarette smokers, we have found no effect of polymorphisms of the t-PA gene on two complementary aspects of endothelial function. We conclude that genetic variation of the t-PA locus is unlikely to have a major influence on acute t-PA release in subjects with established CHD.     

Relationship between CRP and hypofibrinolysis: Is this a possible mechanism to explain the association between CRP and outcome in critically ill patients?

BACKGROUND-: Endothelial cell dysfunction may be implicated in the development of multiple organ failure (MOF) by a number of mechanisms. Among these, altered fibrinolysis promotes fibrin deposition, which may create microvascular alterations during inflammation. Elevated concentrations of C-reactive protein (CRP), especially when these persist over time, are correlated with an increased risk of MOF and death. CRP may inhibit fibrinolysis by inducing plasminogen activator inhibitor-1 (PAI-1) release from human aortic endothelial cells. Moreover, the administration of recombinant CRP in volunteers may increase circulating PAI-1 levels.In this study, we tested the hypothesis that CRP is associated with hypofibrinolysis in intensive care patients with and without sepsis. METHODS-: We studied the association of inflammation and abnormal fibrinolysis in intensive care unit (ICU) patients with (n = 11) and without (n = 21) sepsis. The inflammatory response was assessed by serum concentration of C-reactive protein (CRP), a marker of the acute phase reaction, which increase rapidly in the inflammatory response, and the plasma fibrinolytic capacity was evaluated by the Euglobulin Clot Lysis Time (ECLT), determined by a new semi-automatic method. RESULTS-: ECLT was significantly higher in septic than non-septic patients (1104 +/- 439 vs 665 +/- 275 min; p = 0.002) and was significantly correlated with CRP concentration (R2 = 0.45; p < 0.001). In a multivariate analysis, CRP was the strongest predictor of ECLT (R2 = 0.51, F = 25.6, p < 0.001). In addition, the overall ICU length of stay was significantly correlated with CRP (R2 = 0.264, p = 0.003) and ECLT (R2 = 0.259, p = 0.003). CONCLUSION-: In critically ill patients a significant correlation thus exists between plasma fibrinolytic capacity and serum CRP levels. Our data were obtained in the first 24 hours of ICU admission or of sepsis, thus, the relation between CRP and hypofibrinolysis appeared very quickly. This finding is compatible with a link between inflammation and abnormal fibrinolysis, and may explain the negative prognostic value of CRP in critically ill patients.     

Fibrinolytic dysfunction in insulin-resistant women with previous gestational diabetes

BACKGROUND: Women with a history of gestational diabetes (p-GDM) are at increased risk of developing type 2 diabetes mellitus (DM2) later in life, and therefore at increased risk for future cardiovascular disease. MATERIALS AND METHODS: Three months after delivery we investigated the plasma levels of plasminogen activator inhibitor type 1 (PAI-1), tissue plasminogen activator (t-PA), fibrinogen and von Willebrand factor (vWF) in 74 women with p-GDM and 20 healthy females with normal glucose tolerance during and after pregnancy, as well as the relation of fibrinolytic parameters to insulin resistance and glycaemic control. All women underwent an oral (OGTT) as well as an intravenous glucose tolerance test (FSIGT). Mathematical model analysis disclosed that 50% (n=37 each) of the p-GDM subjects had normal (NIS) or impaired (IIS) insulin sensitivity. Parameters of interest were determined using commercially available test systems. RESULTS: Women with p-GDM and IIS had significantly increased body fat mass (BFM) (P相似文献   

Relationship between fibrinolytic and metabolic variables: a study in patients attending a lipid clinic

We investigated the relationship between plasma levels of metabolic and fibrinolytic variables in 163 fasted patients attending a lipid clinic. Of these patients, 118 had hypertriglyceridaemia (HTG) and 45 had normotriglyceridaemia (NTG). In HTG, basal fibrinolytic activity, ie tissue plasminogen activator (t-PA) activity, was impaired as a result of high plasminogen activator inhibitor type 1 (PAI-1) antigen and activity. Multiple stepwise regression analysis identified insulin and triglyceride levels as independent determinants of plasma PAI-1 levels (R2 = 0.18; P = 0.0001). When the patients were stratified into tertiles according to their levels of triglyceride and insulin, PAI-1 antigen levels were found to increase with rising levels of triglyceride in each insulin tertile. In contrast, the increase of PAI-1 with rising insulin levels was evident in the highest triglyceride tertile. In addition, subjects in the lowest tertile of both triglyceride and insulin had the lowest PAI-1 antigen levels, and subjects in the highest tertile of both triglyceride and insulin had the highest levels of PAI-1. Both basal and stimulated levels of t-PA antigen were significantly higher in HTG than in NTG. Multiple stepwise regression analysis identified triglyceride level as the sole major determinant of t-PA antigen levels (R2 = 0.13; P = 0.00003). The observation that both insulin and triglycerides correlate with PAI-1, whereas triglycerides were involved only in the increased secretion of t-PA, suggests that these two proteins are regulated by different mechanisms.     

Predictive value of plasma plasminogen activator inhibitor-1 for coronary restenosis: dependence on stent implantation and antithrombotic medication.

BACKGROUND: The plasmin activation system is involved in the development of restenosis after percutaneous coronary interventions (PCI). Conflicting data exist concerning the role of plasminogen activator inhibitor-1 (PAI-1) and its predictive value for restenosis. OBJECTIVES: To evaluate the fibrinolytic response to injury after PCI with or without stent implantation on different antithrombotic medications and its relation to late restenosis. PATIENTS AND METHODS: Eighty consecutive patients with successful PCI without (balloon only; n = 37) or with stent implantation (stent; n = 43) on different antithrombotic regimes (balloon only, aspirin; stent, aspirin/coumadin/dipyridamole vs. aspirin/ticlopidine). Blood samples were taken at baseline and up to 7 days after PCI and PAI-1 active antigen and tissue plasminogen activator (t-PA) antigen were determined. Restenosis was angiographically determined after 6 months. RESULTS: PCI increased both t-PA and PAI-1 levels (P < 0.001), with a significant prolonged and pronounced increase in stent vs. balloon-only patients (P < 0.05). Restenosis (stent 26%; balloon 38%) was significantly correlated to an attenuated PAI-1 increase after 24 h in the ticlopidine group (P = 0.007; restenosis, relative Delta PAI-1 + 50 +/- 28%; non-restenosis, + 139 +/- 50%), but not in the coumadin group. In the balloon-only group late restenosis (ISR) was associated with a trend for an augmented PAI-1 increase after 24 h. CONCLUSIONS: Coronary stent implantation significantly increases t-PA and PAI-1 plasma levels up to 1 week compared with balloon angioplasty alone. ISR in ticlopidine-treated patients was associated with an attenuated early PAI-1 active antigen increase. A less than 50% increase 24 h after stent implantation under ticlopidine treatment may identify patients at risk for the development of ISR.     

Does off‐pump coronary artery bypass surgery reduce secretion of plasminogen activator inhibitor‐1?

Prior studies showed that postoperative increase in plasminogen activator inhibitor-1 (PAI-1) levels is associated with an increased risk of graft occlusion after coronary artery bypass surgery (CABG). This prospective study aimed to compare the changes of PAI-1 antigen levels after off-pump and on-pump CABG. Forty-four patients admitted for elective CABG were randomised to on-pump (n=22) or off-pump (n=22) surgery. Serum samples were collected for estimation of PAI-1 and tissue plasminogen activator (t-PA) antigen levels preoperatively and 2 h after the operation. The groups were similar in terms of age, weight, gender ratio and extent of coronary disease, left ventricular function and number of grafts per patient. Fibrinogen and t-PA levels increased postoperatively in both the groups when compared with baseline values. After operation, statistical analysis revealed that increase of PAI-1 values was higher in off-pump group (44.1+/-9.1 vs. 25.3+/-6.9) than on-pump group (37.2+/-5.5 vs. 27.3+/-7.8, p=0.002). This study shows that increase in PAI-1 antigen values in patients who undergo off-pump (beating heart) CABG is significantly higher than in those who undergo conventional CABG with cardiopulmonary bypass.     

The hyperfibrinolytic state of liver cirrhosis: possible pathogenetic role of ascites

We evaluated coagulation and fibrinolytic parameters in both plasma and ascitic fluid of 39 patients with ascites secondary to liver cirrhosis and in 14 cirrhotic patients without ascites, in order to verify if the peritoneal compartment could be involved in the pathogenesis of the hyperfibrinolytic state of the disease. An activation of fibrinolysis, as suggested by increased levels of FDP, D-dimer and tissue plasminogen activator (t-PA) was demonstrated in both ascitic fluid and to a lesser extent in plasma. A positive correlation was also observed between plasma and ascitic fluid plasminogen, antiplasmin and fibrinogen, while a negative correlation was found between plasma and ascitic fluid plasminogen activator inhibitor-1 (PAI-1). Moreover, plasma PAI-1 was significantly lower in patients with ascites than in those without ascites and among ascitic patients in those who had bleeding into soft tissues when compared to those who did not present haemorrhagic events. Finally, a significant association was also shown between positivity for plasma D-dimer (> 200 ng/ml) and the presence of ascites. Taken together, our data suggest an exchange of some coagulation and fibrinolytic proteins between plasma and ascitic fluid and point out the key role of PAI-1 in regulating plasma fibrinolytic potential and in bleeding complications in cirrhotic patients.     

早期应用大剂量普伐他汀对不稳定型心绞痛患者C-反应蛋白及纤溶活性的影响

目的 探讨普伐他汀对不稳定型心绞痛(UAP)患者血清C-反应蛋白(CRP)水平及纤溶活性的影响。方法 52例UAP患者随机分为常规治疗组(25例)和普伐他汀治疗组(27例) 30例健康人为对照组 普伐他汀组于常规治疗基础上加用晋伐他汀40 mg／d,疗程为12周 各组分别于治疗前及结束时测定血清CRP、总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白-胆固醇(HDL-C)、低密度脂蛋白-胆固醇(LDL-C)浓度、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)活性。结果 普伐他汀组治疗12周后,CRP、TC、TG、LDL-C、PAI-1水平下降明显(P<0.05-P<0.01).t-PA明显升高(P<0.05)。常规组治疗前后则无显著性差异(P>0.05)。治疗前的UAP患者CRP与PAI-1活性呈正相关(P<0.01),与t-PA呈负相关(P<0.01) 普代他汀组治疗后CRP、PAI-1、t-PA与TC、LDL-C水平变化无相关关系 结论在UAP早期予以大剂量普代他汀治疗,可能有利于抑制炎症反应、改善内皮功能、提高纤溶活性、稳定斑块。     

Interaction between plasminogen activator inhibitor type 1 (PAI-1) bound to fibrin and either tissue-type plasminogen activator (t-PA) or urokinase-type plasminogen activator (u-PA). Binding of t-PA/PAI-1 complexes to fibrin mediated by both the finger and the kringle-2 domain of t-PA.

Plasminogen activation is catalyzed both by tissue-type-(t-PA) and by urokinase-type plasminogen activator (u-PA). This reaction is controlled by plasminogen activator inhibitor type 1 (PAI-1) that is either present in plasma or bound to fibrin, present in a thrombus. We studied the mechanism of in vitro inhibition of both t-PA and u-PA activity by PAI-1 bound to fibrin. It is shown that activation of latent PAI-1 unmasks a specific fibrin-binding site that is distinct from its reactive site. This reactive site of activated PAI-1 bound to fibrin is fully exposed to form complexes with t-PA and u-PA, that are unable to activate plasminogen. Upon complex formation with either one of the plasminogen activators, PAI-1 apparently undergoes a conformational change and loses its affinity for fibrin. Consequently, complexes of u-PA and PAI-1 dissociate from the fibrin matrix and are encountered in the fluid phase. In contrast, t-PA/PAI-1 complexes remain bound to fibrin. By employing recombinant t-PA deletion-mutant proteins, that precisely lack domains involved in fibrin binding, we demonstrate that binding of t-PA/PAI-1 complexes is mediated by both the "finger" (F) and the "kringle-2" (K2) domain of t-PA. A model is proposed that explains inhibition of the fibrinolytic process, at the level of plasminogen activation by t-PA, directed by PAI-1 bound to fibrin. An implication of the proposed model is that t-PA/PAI-1 complexes and free t-PA compete for the same binding sites on fibrin.