Increased plasminogen activator inhibitor-1 activity in offspring of type 2 diabetic patients: lack of association with plasma insulin levels

OBJECTIVE: To determine whether a dysregulation of the fibrinolytic system exists in normal glucose tolerant offspring of type 2 diabetic patients. RESEARCH DESIGN AND METHODS: In this cross-sectional study, 32 offspring of type 2 diabetic patients and 26 subjects with no family history of diabetes were studied. With respect to the metabolic parameters, plasma fasting and 2-h postload (75 g glucose) glucose and insulin levels, total cholesterol, triglycerides, and HDL cholesterol concentrations were determined. To evaluate the status of hemostatic factors, fibrinogen, tissue plasminogen activator (tPA) antigen level, plasminogen activator inhibitor-1 (PAI-1) antigen level, and PAI-1 activity were assessed. The statistical analyses included the Mann-Whitney U test to check the significance of differences between variables in the two groups and Spearman's rank correlation tests to check the interrelationships between the hemostatic and metabolic parameters in the offspring group. RESULTS: All subjects had normal glucose tolerance according to the American Diabetes Association criteria. Plasma fasting and postload insulin concentrations were significantly higher in offspring compared with control group (P<0.00001 and P<0.01, respectively). Plasma fasting and postload glucose, fibrinogen, tPA antigen, total cholesterol, and BMI were comparable between the groups. The offspring had significantly higher waist-to-hip ratio (WHR) (P = 0.03), higher triglycerides (P = 0.01), and lower HDL cholesterol (P<0.01) compared with the control group. PAI-1 antigen level and PAI-1 activity were higher in the offspring (P = 0.05 and P = 0.04, respectively). In the offspring group, PAI-1 activity was correlated with plasma PAI-1 antigen level (r = 0.40, P = 0.02), fibrinogen (r = 0.45, P = 0.01), and HDL cholesterol (r = -0.36, P = 0.04). However, tPA antigen level, fasting and postload plasma glucose and insulin, total cholesterol, triglycerides, WHR, and BMI did not correlate with PAI-1 activity. CONCLUSIONS: These data suggest that normal glucose tolerant offspring of type 2 diabetic subjects have elevated PAI-1 activity indicating to hypofibrinolysis in this group. The elevated PAI-1 activity has no association with plasma insulin concentration.     

The regulation by fibrinogen and fibrin of tissue plasminogen activator kinetics and inhibition by plasminogen activator inhibitor 1

BACKGROUND: Tissue plasminogen activator (tPA) is unusual in the coagulation and fibrinolysis cascades in that it is produced as an active single-chain enzyme (sctPA) rather than a zymogen. Two chain tPA (tctPA) is produced by plasmin but there are conflicting reports in the literature on the behaviour of sc- and tctPA and little work on inhibition by the specific inhibitor plasminogen activator inhibitor-1 (PAI-1) under physiological conditions. OBJECTIVES: To perform a systematic study on the kinetics of sctPA and tctPA as plasminogen activators and targets for PAI-1. METHODS: Detailed kinetic studies were performed in solution and in the presence of template stimulators, fibrinogen and fibrin, including native fibrin and partially digested fibrin. Numerical simulation techniques were utilized to cope with the challenges of investigating kinetics of activation and inhibition in the presence of fibrin(ogen). RESULTS: Enzyme efficiency (k(cat)/K(m)) was higher for tctPA than sctPA in solution with chromogenic substrate (3-fold) and plasminogen (7-fold) but in the presence of templates, such as fibrinogen and native or cleaved fibrin, the difference disappeared. sctPA was more susceptible to PAI-1 in buffer solution and in the presence of fibrinogen; however, in the presence of fibrin, PAI-1 inhibited more slowly and there was no difference between sc and tctPA. CONCLUSIONS: Fibrinogen and fibrin modulate the activity of tPA differently in regard to their activation of plasminogen and inhibition by PAI-1. Fibrinogen and fibrin stimulate tPA activity against plasminogen but fibrin protects tPA from PAI-1 to promote fibrinolysis.     

缺血性脑卒中患者血纤溶活性变化规律的研究

目的 研究脑梗死组和非脑梗死组患者急性期,亚急性期和恢复期组织型纤溶酶原激活物（tPA）,纤溶酶原激活物抑制物-1（PAI-1）的变化规律.方法 135例脑梗死组患者于发病96h内,病后14d、3月、6月、9月分别采血,77例非脑梗死组患者先采血一次,然后分别在第一次采血后14d、3月、6月、9月采血.结果 脑梗死急性期tPA含量明显升高,PAI-1的含量明显升高.恢复期脑梗死即发病后3月,6月,9月tPA的含量比急性期明显降低,且脑梗死后时间越长tPA含量越低,恢复期脑梗死PAI-1的含量比急性期明显降低.结论 在缺血性卒中的患者,高tPA含量提示纤溶活性的降低.高PAI-1代表纤溶抑制增强.     

阻塞性睡眠呼吸暂停低通气综合征患者血管内皮细胞及纤溶系统功能变化

目的：探讨阻塞性睡眠呼吸暂停低通气综合征(OSAHS)患者血管内皮细胞及纤溶系统功能变化。方法：根据多导睡眠呼吸监测仪监测结果，选择年龄、性别、体重指数(BMI)无明显差异的OSAHS患者52例和健康者48例。以Clauss法测定纤维蛋白原(Fg)，以发色底物法测定组织纤溶酶原激活物活性(tPA：A)、纤溶酶原激活物抑制物-1活性(PAI-1：A)，以酶联免疫法测von Willebrand因子含量(vWF)、组织纤溶酶原激活物含量(tPA：Ag)、纤溶酶原含量(PLg：Ag)和纤溶酶原激活物抑制物-1含量(PAI-1：Ag)。结果：与对照组比较，(3SAHS组vWF、Fg、PAI-1：A、PAI-1：Ag水平明显升高，PLg：Ag、tPA：Ag含量明显降低，tPA：A无明显变化。结论：OSAHS患者血管内皮细胞功能受损，纤溶系统功能降低。     

Vitamin C affects thrombosis/ fibrinolysis system and reactive hyperemia in patients with type 2 diabetes and coronary artery disease

OBJECTIVE: To examine the effect of vitamin C on forearm vasodilatory response to reactive hyperemia and on plasma level of plasminogen activator inhibitor 1 (PAI-1), von Willebrand factor (vWF), tissue plasminogen activator (tPA), antithrombin III (ATIII), proteins C and S, and factors V (fV) and VII (fVII) in patients with both type 2 diabetes and CAD. RESEARCH DESIGN AND METHODS: A total of 39 patients with type 2 diabetes and CAD were divided into two groups and received vitamin C (2 g/day) or no antioxidant for 4 weeks. Forearm blood flow was determined using venous occlusion gauge-strain plethysmography at baseline and after treatment. Forearm vasodilatory response to reactive hyperemia (RH%) or nitrate (NTG%) was defined as the percent change of flow from baseline to the maximum flow during reactive hyperemia or after administration of nitrate, respectively. Biochemical markers were determined by enzyme-linked immunosorbent assay (ELISA) or other standard methods. RESULTS: RH% was significantly increased after treatment with vitamin C (from 62.4 +/- 7.2 to 83.1 +/- 9.3%, P = 0.024) but remained unaffected in the control group. Vitamin C decreased plasma levels of fV (from 143 +/- 5.4 to 123 +/- 6.03%, P = 0.038), vWF (from 133.5 +/- 14.5 to 109.5 +/- 11.4%, P = 0.016), and tPA (from 12.3 +/- 0.99 to 8.40 +/- 0.60 ng/ml, P = 0.001), whereas these levels remained unaffected in the control group. The changes in RH%, vWF, and tPA were significantly greater (P = 0.028, 0.036, and 0.007, respectively) in the vitamin C-treated group than in the control group. Levels of ATIII, proteins S and C, fVII, and PAI-1 remained unchanged in all groups. CONCLUSIONS: Short-term treatment with high doses of vitamin C improved RH% and decreased plasma levels of tPA and vWF in patients with type 2 diabetes and CAD.     

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.     

tPA和PAI-1活性与自然流产的相关性

【目的】探讨组织型纤溶酶原激活剂（tPA）和纤溶酶原激活剂抑制剂-1（PAI-1）活性与自然流产的相关性。【方法】选择2003年10月至2004年3月中南大学湘雅二医院门诊有自然流产史患者71例（非孕50例．孕妇21侧）和对照组41例（非孕20侧,孕妇21例）进行研究,运用发色底物法测定血浆tPA和PAI-1活性。【结果】非孕有自然流产史的研究组tPA活性比对照组低（t=2．226,P=0．029〈0．05）,早孕研究组tPA活性比对照组低（t=2．166,P=0．036〈0．05）,差别均有统计学意义;研究组中,tPA活性早孕高于非孕（t=-2．937,P=0．005）,PAI-1活性早孕低于非孕（t=2．428,P=0．018）;在对照组中,tPA活性早孕也高于非孕（t=2．597,P=0．013）,PAI-1活性早孕也低于非孕者（t=2．653,P=0．012）。差别均有统计学意义。【结论】妊娠后tPA活性增高和PAI-1活性下降。有自然流产史者在非孕状态时tPA活性明显下降,且妊娠后呈低增长水平。tPA活性下降与引起自然流产的发病机制有关。     

Effect of Low Dose Aspirin on Augmented Piasminogen Activator Inhibitor Type 1 Activity in Patients with Permanent Pacemakers

To clarify the activity states of coagulation and fibrinolysis in patients with a permanent pacemaker, we studied 29 patients more than 4 months after operation. They were divided into a single pacemaker lead group (S, n = 14) and a double lead group (D, n = 15). Prothrombin time, activated partial thromboplastin time, fibrinogen, antithrombin III, tissue-type plasminogen activator (tPA) activity, plasminogen activator inhibitor type-1 (PAI-1) activity, and platelet aggregation were measured and compared to those in an age-matched control group (C, n - 7). The effects of low dose aspirin (81 mg/day) in the patients (n = 21) were also studied 2 weeks after administration. PAI-1 activity in groups S and D was significantly higher than that in the group C (53.5 ± 36.5, 86.8 ± 59.2 ng/ mL vs 19.4 ± 7.2 ng/mL; P < 0.01 and P < 0.005). Platelet aggregation induced by collagen was slightly higher in groups S and D than group C. Other parameters were not significantly different. In the patients, low dose aspirin significantly suppressed collagen induced platelet aggregation (71.8 ± 20.3% vs 41.7 ± 28.3%; P < 0.005), but not PAI-1 activity. tPA activity was increased significantly by the low dose aspirin administration (3.94 ± 1.85 ng/mL vs 2.48 ± 1.19 ng/mL; P < 0.005). Thus, PAI-1 activity in patients with a permanent pacemaker is elevated, and the activity is not suppressed by low dose aspirin unlike the platelet aggregation.     

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。     

Synergy between a plasminogen cascade and MMP-9 in autoimmune disease

Extracellular proteolysis by the plasminogen/plasmin (Plg/plasmin) system and MMPs is required for tissue injury in autoimmune and inflammatory diseases. We demonstrate that a Plg cascade synergizes with MMP-9/gelatinase B in vivo during dermal-epidermal separation in an experimental model of bullous pemphigoid (BP), an autoimmune disease. BP was induced in mice by antibodies to the hemidesmosomal antigen BP180. Mice deficient in MMP-9 were resistant to experimental BP, while mice deficient in Plg and both tissue Plg activator (tPA) and urokinase Plg activator (uPA) showed delayed and less intense blister formation induced by antibodies to BP180. Plg-deficient mice reconstituted locally with Plg or the active form of MMP-9 (actMMP-9), but not the proenzyme form of MMP-9 (proMMP-9), developed BP. In contrast, proMMP-9 or actMMP-9, but not Plg, reconstituted susceptibility of MMP-9-deficient mice to the skin disease. In addition, MMP-3-deficient mice injected with pathogenic IgG developed the same degree of BP and expressed levels of actMMP-9 in the skin similar to those of WT controls. Thus, the Plg/plasmin system is epistatic to MMP-9 activation and subsequent dermal-epidermal separation in BP.     

绝经后女性冠心病与非冠心病患者雌激素水平与凝血及纤溶功能分析

背景绝经后女性冠心病发病率及死亡率升高多认为与雌激素降低有关,但确切机制不明.目的探讨绝经后女性冠心病与非冠心病患者血中内源性雌激素水平与凝血及纤溶功能的变化.设计以诊断为依据,非随机对照试验.地点、对象和方法选择2001-09/2002-05,以因胸闷痛收住本院的正常绝经≥1年的妇女为研究对象.纳入标准均为绝经后妇女;2周内未用抗凝剂;未服用免疫抑制剂、雌激素.排除标准肝、肾、内分泌、神经及生殖系统疾病.根据冠状动脉造影结果,将62例绝经后的妇女分为冠心病(32例)与非冠心病(30例)两组.清晨空腹取静脉血,抽提血浆和血清后测定雌二醇、孕酮、促卵泡刺激素和促黄体生成素,凝血系统的纤维蛋白原、血管性血友病因子抗原(von Wille-brand factor antigen,vWFAg)及纤溶系统的组织纤溶酶原激活剂(tissue plasminogen activator,tPA)、纤溶酶原激活剂抑制物-1(plasminogen activator inhibitor-1,PAI-1)和D-二聚体等.主要观察指标两组患者凝血及纤溶系统指标比较及雌激素水平.结果冠心病组血中雌二醇[(39.97±9.73)ng/L],孕酮[(6.42±1.14)nmol/L]明显低于非冠心病组[(64.92±9.77)]ng/L,(7.01±0.85)nmol/L(t=10.6860,2.3960,P＜0.01,0.05);冠心病组患者凝血系统的纤维蛋白原,vWFAg,PAI-I,D-二聚体明显高于非冠心病组(t=2.3377～4.3560,P＜0.05);冠心病组患者纤溶系统的tPA水平明显低于非冠心病组(t=2.4307,P＜0.05).结论绝经后女性冠心病较非冠心病组血中雌二醇水平明显降低,凝血功能亢进及纤溶功能低下.     

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。     

Pleiotropic functions of plasminogen activator inhibitor-1

Plasminogen activator inhibitor-1 (PAI-1), a 45-kDa serine proteinase inhibitor with reactive site peptide bond Arg345-Met346, is the main physiological plasminogen activator inhibitor. It occurs in human plasma at an antigen concentration of about 20 ng mL(-1). Besides the active inhibitory form of PAI-1 that spontaneously converts to a latent form, also a substrate form exists that is cleaved at the P1-P1' site by its target enzymes, but does not form stable complexes. Besides its role in regulating hemostasis, PAI-1 plays a role in several biological processes dependent on plasminogen activator or plasmin activity. Studies with transgenic mice have revealed a functional role for PAI-1 in wound healing, atherosclerosis, metabolic disturbances such as obesity and insulin resistance, tumor angiogenesis, chronic stress, bone remodeling, asthma, rheumatoid arthritis, fibrosis, glomerulonephritis and sepsis. It is not always clear if these functions depend on the antiproteolytic activity of PAI-1, on its binding to vitronectin or on its intereference with cellular migration or matrix binding.     

Prion protein stimulates tissue-type plasminogen activator-mediated plasmin generation via a lysine-binding site on kringle 2.

Recombinant human prion-protein (PrP23-231) stimulates plasminogen activation by tissue-type plasminogen activator (t-PA). The stimulatory activity is conserved in the N-terminal fragment (PrP23-110). It has further been shown by others that PrP(c) binds to kringle-domains of plasminogen. We compared the stimulatory activity of recombinant PrP23-231 and PrP23-110 on plasminogen activation catalyzed by t-PA, urokinase (u-PA), streptokinase and Desmodus salivary plasminogen activator (DSPAalpha1). As these plasminogen activators are distinct, with respect to their kringle domains we studied their binding to immobilized PrP23-110. Plasminogen activation was measured in a chromogenic assay in vitro and binding studies were carried out using surface plasmon resonance technology. We found that recombinant full-length prion protein, PrP23-231, and PrP23-110 specifically stimulate t-PA mediated plasminogen activation. Two hundred nanomoles per liter of PrP23-110 stimulated 1.8 nmol L(-1) t-PA 48-fold, 180 nmol L(-1) DSPA(alpha1) 2.5-fold, 1.8 nmol L(-1) u-PA 1.1-fold, and 1.8 nmol L(-1) streptokinase 1.8-fold. Our data show no specific binding for streptokinase. In contrast all plasminogen activators carrying a kringle domain bound to PrP23-110. We further studied the effect of lysine on binding to PrP23-110 and on plasminogen activation by DSPA(alpha1) or t-PA. Lysine decreased both the binding of t-PA to PrP23-110 and the stimulation of plasmin generation by t-PA. Both binding and plasminogen activation of DSPA(alpha1) were not influenced by the presence of lysine. All plasminogen activators tested bearing kringle domains bind to PrP23-110. Binding to PrP23-110 is not sufficient for stimulation of plasmin generation. Thus the lysine-binding site of kringle 2 that is unique to t-PA appears to mediate the specific stimulation of plasminogen activation by the cellular prion protein.     

Plasma homocysteine and its relationships with atherothrombotic markers in psoriatic patients

BACKGROUND: Hyperhomocysteinemia may constitute an independent risk factor for cardiovascular disease and may promote atherothrombosis. Psoriasis is one of the diseases associated with increased atherothrombosis. The aim of the present study was to examine serum total homocysteine (tHcy) level and its relationships with atherothrombotic markers. METHODS: The study group included 30 patients with psoriasis (17 females and 13 males) with a mean age of 34.2 (age range: 27-40) and 30 sex and age matched healthy volunteers (15 females and 15 males) with a mean age of 36.7 (age range: 26-48). The concentrations of lipids, lipoproteins, acute phase reactants, tHcy and atherothrombotic markers [fibronectin, soluble vascular adhesion molecules-1 (sVCAM-1), soluble intercellular adhesion molecules-1 (sICAM-1), tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), autoantibodies against oxidized LDL (AuAb-oxLDL)] were determined. RESULTS: The mean levels of serum tHcy, fibrinogen, fibronectin, sICAM, PAI-1 and AuAb-oxLDL were increased in patients whereas tPA, vitamin B(12) and folate levels were decreased significantly. Increased levels of sVCAM were not statistically significant. tHcy levels were negatively correlated with vitamin B(12) (r=-0.40, P=0.027) and positively correlated with PAI-1 and AuAb-oxLDL levels (r=0.46, P=0.011; r=0.39, P=0.035, respectively). CONCLUSIONS: It was concluded that the increased homocysteine concentration and altered endothelial cell-mediated proteins associated with increased lipids and LDL oxidation may play an important role for the development of atherothrombotic complications with psoriasis.     

Measurement of different forms of tissue plasminogen activator in plasma

BACKGROUND: We evaluated assays to measure both total tissue plasminogen activator (tPA) and the three principle forms of tPA in plasma: active tPA, tPA complexed with plasminogen activator inhibitor type 1 (PAI-1), and tPA complexed with C1-inhibitor. METHODS: Active tPA was measured by use of an indirect amidolytic assay and immunofunctional assays. tPA/PAI-1, tPA/C1-inhibitor, and total tPA antigen were measured by use of microtiter plates coated with anti-tPA antibodies and, respectively, anti-PAI-1, anti-C1-inhibitor, and anti-tPA antibodies conjugated to peroxidase. RESULTS: The immunofunctional tPA assay detected 1 U/L (0.001 U/mL) tPA and recovered 108% +/- 12% of active tPA added to samples containing high (mean, 60 000 IU/L) PAI-1 activities vs a detection limit of 10 U/L (0.01 U/mL) and 13% +/- 25% recovery for the indirect amidolytic tPA activity assay. For measurement of tPA/PAI-1 complex, polyclonal anti-PAI-1 conjugates recovered 112% +/- 20% of the expected tPA/PAI-1 vs recovery of only 38% +/- 16% when monoclonal anti-PAI-1 conjugates were used. Of three methods tested, two total tPA antigen assays correlated well (r(2) = 0.85) and showed recoveries near 100%, whereas the third method showed lower correlations, higher intercepts, and falsely high recovery. A single anti-tPA capture antibody that performed the best in the individual assay evaluations was used to measure the different forms of tPA in 22 samples with a range of tPA and PAI-1 values. The sum of the molar concentrations of active tPA, tPA/PAI-1, and tPA/C1-inhibitor using the optimized methods was equal to 94% +/- 7% of measured total tPA. CONCLUSION: Optimized assays based on a single anti-tPA capture antibody can be used to accurately measure the major forms of tPA in plasma.     

Activation of the fibrinolytic system and utilization of the coagulation inhibitors in sepsis: comparison with severe sepsis and septic shock

OBJECTIVES: To determine whether the fibrinolytic system is activated and coagulation inhibitors are utilized in sepsis, to compare the findings detected in sepsis with those found in severe sepsis and septic shock, and to compare the role played by different infectious pathogens on fibrinolysis and coagulation inhibitors. DESIGN AND SETTING: Prospective study comparing patients with sepsis, severe sepsis, and septic shock and healthy volunteers in the general intensive care unit of a tertiary university hospital. PATIENTS: Eighty-two consecutive septic patients (47 with sepsis, 18 with severe sepsis, and 17 with septic shock), and 14 healthy volunteers (controls). MEASUREMENTS AND RESULTS: After blood sampling we measured activation markers of fibrinolysis [plasmin/alpha(2)-antiplasmin complexes (PAP), complexes of tissue plasminogen activator/plasminogen activator inhibitor (tPA/PAI), fibrin(ogen) degradation products (FDPs), D-dimmers fibrin degradation products (D-d)], the utilization marker of antithrombin III (ATIII) thrombin/antithrombin complexes (TAT), several factors of fibrinolysis [plasminogen, tissue plasminogen activator (tPA), plasminogen activator inhibitor 1 (PAI-1), alpha(2)-antiplasmin], and the natural coagulation inhibitors [ATIII, protein C (PrC), protein S (PrS)]. In sepsis, PAP, FDPs, D-d, and TAT were increased to 439.8+/-32.35 microg/l, 57% positive, 49% positive, and 3.46+/-0.27 microg/l, respectively, compared with control subjects (205.57+/-28.58 microg/l, 0% positive, 7% positive, and 1.61+/-0.1 microg/l, respectively). These markers further increased in severe sepsis and septic shock. With the exception of a decrease in ATIII and an increase in tPA and PAI-1, coagulation inhibitors and factors of fibrinolysis were not changed in sepsis. In severe sepsis and mainly in septic shock, coagulation inhibitors (ATIII, PrC) and plasminogen were markedly decreased, whereas tPA and PAI-1 were further increased. All changes were independent of the causative infectious pathogen. CONCLUSIONS: Fibrinolysis is strongly activated and ATIII is utilized in sepsis. These findings are further enhanced in severe sepsis and septic shock. In sepsis only ATIII is decreased. In contrast, in severe sepsis and mainly in septic shock plasminogen and the main coagulation inhibitors (i.e., ATIII, PrC) are depleted, indicating exhaustion of fibrinolysis and coagulation inhibitors. Finally, Gram-positive, Gram-negative and other micro-organisms produce identical impairment.     

Cardiac fibrinolytic capacity is markedly increased after brief periods of local myocardial ischemia, but declines following successive periods in anesthetized pigs

BACKGROUND: Fibrinolysis in blood is mainly reflected by the activities of tissue plasminogen activator (tPA) and of plasminogen activator inhibitor-1 (PAI-1). The effect of myocardial ischemia on their activities in the coronary circulation is, however, not established. OBJECTIVES: With an improved experimental model, we therefore examined the effect of a brief period of myocardial ischemia on their activities. Furthermore, the consequences of repeated periods of ischemia, mimicking the situations in patients with unstable angina, were investigated. METHODS: In six anesthetized pigs, we occluded the distal left anterior descending coronary artery (LAD) four times for 10 min with 40 min intervals and determined the activities of tPA and PAI-1 in arterial and coronary venous blood. By simultaneously recording LAD flow, we could estimate cardiac release of these factors at baseline conditions and during reperfusion. RESULTS: Neither net cardiac release of PAI-1 nor alterations in plasma PAI-1 levels were demonstrated during the experiment. However, a significant net release of tPA activity of 10.4 +/- 3.2 IU mL(-1) (P < 0.005) was recorded during baseline conditions. During reperfusion following the first period of ischemia, the cardiac release of tPA activity increased to a peak of 103 +/- 30-fold baseline release, but declined progressively after repeated periods of ischemia. After the fourth period, tPA release did not exceed an estimated baseline accumulation during ischemia and early reperfusion. CONCLUSIONS: In this porcine model, a substantial local increase in fibrinolytic capacity was observed after brief periods of ischemia, but declined subsequently by repeated periods of ischemia.