Relationships between fibrinolytic and inflammatory parameters in human adipose tissue: strong contribution of TNFalpha receptors to PAI-1 levels

Plasminogen activator inhibitor type 1 (PAI-1), a risk marker of atherosclerosis, is highly expressed in adipose tissue from obese subjects. PAI-1 is also considered as an acute phase protein. Recently, adipose tissue has been described as a source of inflammatory cytokines. Therefore, our aim was to study the relationships between PAI-1, and IL-6, TNF, TNF receptors (TNFRSF1s) and TGFbeta1, in plasma and adipose tissue from obese (n = 60) and lean (n = 28) subjects. Study has been extended to plasminogen activators (t-PA and u-PA). Compared to lean subjects, obese subjects exhibited higher plasma levels of all the studied parameters (except for TGFbeta1) whereas in adipose tissue only PAI-1, t-PA and TGFbeta antigen levels differed. In the obese population, plasma PAI-1 levels were weakly associated with circulating TNF, and this relationship disappeared after adjustment for plasma t-PA. Adipose tissue PAI-1 levels were positively associated with TNFRSF1s and TGFbeta, the strongest relationship being observed with TNFRSF1A, which explained 82% of PAI-1 variability. TNF and IL-6 were the main contributors to t-PA variability in plasma and in adipose tissue, respectively. Our results argue on the relevance of TNFRSF1s in the regulation of PAI-1 expression by adipose tissue. Association between t-PA, which is mainly produced by endothelial cells, and IL-6 or TNF suggest that inflammation might be involved in angiogenesis in adipose tissue.     

血纤溶活性变化对颈动脉粥样硬化和急性脑梗死患者的影响和分析

目的：研究血纤溶活性变化对颈动脉粥样硬化患者和急性脑梗死患者的影响。方法：67例急性脑梗死患者（ACI组）和62名健康体检老年人（对照组），均行彩色多普勒超声诊断仪超声观察颈动脉有无斑块；同时测定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）的活性。结果：对照组中有颈动脉斑块者与无颈动脉斑块者相比，血浆t-PA降低，PAI-1升高，P／t值升高（P〈0．05）；观察组颈动脉斑块发生率明显高于对照组（P〈0．05）；观察组患者急性期血浆t-PA、PAI-1升高，P／t值减少（P〈0．05）。结论：颈动脉硬化时，机体纤溶活性处于减低状态；急性脑梗死发生时，纤溶活性处于相对亢进状态。     

In vitro effects of detergent sclerosants on fibrinolytic enzymes and inhibitors

Objective

To investigate the effects of Sodium Tetradecyl Sulphate (STS) and Polidocanol (POL) on fibrinolytic mechanisms.

Materials and methods

Measurements were done with serial dilutions of sclerosants in whole blood (WB), platelet rich (PRP) and platelet poor plasma (PPP). Control experiments were done in 5% bovine serum albumin (BSA), spiked with the enzyme/inhibitor. Plasminogen was measured with a chromogenic assay. Alpha-2-antiplasmin (AP) activity, plasmin-alpha-2-antiplasmin (PAP) complexes, plasminogen activator inhibitor-1 (PAI-1) activity, tissue plasminogen activator (t-PA) total antigen, t-PA activity, t-PA/PAI-1 complexes, thrombin activatable fibrinolysis inhibitor (TAFI) antigen and activated TAFI (TAFIa) were measured by ELISA.

Results

At high concentrations (> 0.3%), STS destroyed plasminogen, PAI-1, t-PA/PAI-1 complexes and total t-PA antigen but increased t-PA activity. At low concentrations (< 0.3%), both agents reduced PAP complexes while increasing AP activity. Low concentration STS increased PAI-1 activity, t-PA/PAI-1 complexes, TAFI and TAFIa. Low concentration POL mildly increased the total t-PA antigen and TAFI.

Conclusion

At low concentrations, both agents demonstrated a prothrombotic, antifibrinolytic (increase in PAI-1, total t-PA antigen, AP, TAFI and TAFIa) activity. At high concentrations, STS demonstrated non-prothrombotic (destruction of PAI-1, t-PA/PAI-1 complexes), antifibrinolytic (destruction of plasminogen, increase in AP) activity while POL had minimal effect.     

Influence of heparin and a low molecular weight heparinoid on specific endogenous and exogenous fibrinolytic factors during rest and exercise.

The effects of heparin (5,000 IU i.v.) and the low molecular weight heparinoid Org 10172 (Orgaran) (3,250 anti-Xa units i.v.) on components of the fibrinolytic system were studied in two double-blind, randomised, placebo-controlled, cross-over trials using healthy subjects. In study A (n = 6) the effects were studied during rest and standardized exercise and in study B (n = 6) during a low dose infusion of recombinant tissue-type plasminogen activator (rt-PA; 80 micrograms over 16 min). At rest, heparin and Org 10172 did not influence the plasma concentrations of endogenous t-PA antigen and activity, urokinase-type PA (u-PA) antigen, plasmin activatable pro-urokinase (scu-PA), active urokinase (tcu-PA) and plasminogen activator inhibitor-1 (PAI-1) antigen. Recombinant t-PA antigen and activity during rt-PA infusion were also not affected. During exercise, neither heparin nor Org 10172 influenced the area under the curve (AUC) of t-PA and u-PA antigen and t-PA activity when compared with placebo. Unexpectedly, after heparin the AUC of t-PA activity was 49% larger (range +19 to +245%) than after Org 10172 (p < 0.05). The last difference was considered spurious, scu-PA, tcu-PA and PAI-1 antigen levels at 2 min after termination of exercise were unaffected by both compounds (p > 0.05). Sulphated polysaccharides do not increase fibrinolytic activity of the plasma by changing the concentrations of the components of the fibrinolytic system.     

Fibrinolytic activity in peripheral atherosclerosis in the elderly

Increased concentrations of plasminogen activator inhibitor type 1 (PAI-1) and of D-dimer have jointly been found in subjects with cardiovascular disease. To understand this apparent paradox of increased inhibition of fibrinolysis (high PAI-1) combined with increased fibrinolytic activity (high D-dimer), we examined the relation between D-dimer, PAI-1 and the activator of fibrinolysis, tissue type plasminogen activator (t-PA) in subjects with varying severity of peripheral atherosclerosis. In 325 subjects selected from the Rotterdam Study, a cohort of 7983 men and women aged 55 years and over, the ankle to brachial systolic blood pressure ratio, t-PA antigen and activity, PAI-1 antigen and D-dimer were measured. T-PA antigen and t-PA activity were, independent from each other, increased with degree of atherosclerosis; t-PA antigen increased with 3.5 ng/ml (SE 1.7, p = 0.04) and t-PA activity with 0.46 IU/ml (0.20, p = 0.02) per unit decrease in ankle to brachial pressure ratio (i.e. increase in atherosclerosis). PAI-1 antigen was not related to atherosclerosis. More marked atherosclerosis was associated with increased D-dimer, mainly in subgroups with PAI-1 antigen below 50 ng/ml, t-PA antigen below 10 ng/ml, or t-PA activity above 1.5 IU/ml. In contrast to current beliefs, we found that only a fraction of the variation of t-PA antigen was due to the variation in circulating PAI-1 antigen. A slight positive association was observed between t-PA antigen and D-dimer. PAI-1 and t-PA activity were not associated with D-dimer concentration. In conclusion, in subjects with peripheral atherosclerosis PAI-1 antigen is not increased, but low PAI-1 levels (and possibly also low levels of t-PA antigen and high levels of t-PA activity) appear to be required to increase circulating D-dimer. This suggests that increased D-dimer levels in subjects with atherosclerosis do not reflect increased inhibition, but rather reflect increased fibrinolysis.     

Impaired fibrinolysis and postoperative thromboembolism in orthopedic patients.

The incidence of deep vein thrombosis (DVT) and pulmonary embolism was studied prospectively in patients undergoing elective total hip replacement. 96 patients were randomly allocated to receive either low molecular weight heparin (LMWH) or unfractionated heparin (UFH). All patients had bilateral phlebography and pulmonary perfusion/ventilation scintigraphy 10-12 days after surgery. The following fibrinolytic variables were analysed in plasma and related to thromboembolism: tissue plasminogen activator (t-PA) activity, t-PA antigen (t-PA Ag), plasminogen activator inhibitor (PAI-1) activity and PAI-1 antigen (PAI-1 Ag). No significant difference was found, regarding the fibrinolytic response to surgery, between patients treated with LMWH and UFH. The level of PAI-1 activity was significantly increased before operation in patients developing DVT as compared to non-DVT patients (p less than 0.03). Immediately after surgery and in the morning the first postoperative day the levels of PAI-1 activity, PAI-1 Ag and t-PA Ag were positively correlated to thromboembolism. PAI-1 activity was the only preoperative fibrinolytic variable correlated to thromboembolism.     

Regional fibrinolysis following total hip replacement

The local effect of operative trauma on the fibrinolytic system was studied in ten patients undergoing total hip replacement. Catheters were inserted in the femoral veins on both sides and blood was sampled from these catheters perioperatively. The following fibrinolytic variables were analysed in plasma and related to the different steps of surgery: tissue plasminogen activator (t-PA) activity, t-PA antigen and plasminogen activator inhibitor (PAI-1) activity. During surgery PAI-1 activity and t-PA antigen in the operated limb were significantly increased compared with preoperative values. There was a significant difference in PAI-1 activity and t-PA antigen between the operated and the non-operated limbs during surgery and within one hour postoperatively. During fixation of the femoral implant there was a significant difference between the operated and the non-operated limbs in t-PA activity. Thus the regional fibrinolytic response to trauma was dissociated from the response in the non-operated limb. The clinical relevance of the observed alterations in regional fibrinolysis, as related to thrombogenic mechanisms after hip surgery, remains to be elucidated.     

Systematic elucidation of effects of tranexamic acid on fibrinolysis and bleeding during and after cardiopulmonary bypass surgery.

The aim of this study was to systematically elucidate the effects of tranexamic acid on fibrinolysis and bleeding during and after cardiopulmonary bypass (CPB) surgery. Twenty-two patients undergoing CPB surgery were randomized to receive 100 mg/kg tranexamic acid or an equal volume of saline after anesthesia induction and prior to skin incision. Plasma levels of tissue plasminogen activator (t-PA) antigen and activity, crosslinked fibrin degradation products (D-dimer), alpha2-antiplasmin-plasmin complex, and plasminogen activator inhibitor-1 (PAI-1) antigen were measured. Blood samples were obtained after induction of anesthesia, before, during, and after CPB, at the end of surgery, and the next morning after surgery. Intraoperative and postoperative blood loss during 24 h after surgery was recorded. Patients' demographics were similar between the two groups. No patients suffered from thrombotic complications after surgery. In the tranexamic acid group, fibrinolytic activity and secondary fibrinolysis as measured by t-PA activity and D-dimer were markedly suppressed during CPB surgery (P=.042 and P=.015, respectively). Decreased fibrinolytic activity and fibrinolysis were accompanied by reduction of perioperative bleeding in the tranexamic acid group. We could also find a good positive correlation between the peak levels of t-PA activity and D-dimer (r(2)=.4203, P=.0011). No differences in the t-PA antigen, PAI-1 antigen release, and plasmin inhibition by alpha2-antiplasmin were apparent between the two groups. In a randomized, prospective trial of patients undergoing CPB surgery, we demonstrated that the synthetic antifibrinolytic drug tranexamic acid effectively suppresses fibrinolysis by inhibiting t-PA and plasmin activity with clear reduction of perioperative blood loss. While tranexamic acid had no effects on the other important fibrinolytic inhibitors like PAI-1 and alpha2-antiplasmin.     

Hepatic synthesis and clearance of components of the fibrinolytic system in healthy volunteers and in patients with different stages of liver cirrhosis

We determined plasma levels of tissue-type plasminogen activator (t-PA) antigen, urokinase-type plasminogen activator (u-PA) antigen, and activity of the fast acting inhibitor of plasminogen activator (PAI-1) in patients with different stages of liver cirrhosis (Child A, B, and C) and in age and sex-matched healthy controls to investigate the contribution of the liver to the metabolism of these main components of the fibrinolytic system. For control purposes routine clotting parameters were also determined. In patients with the most severe form of liver cirrhosis (Child C) t-PA antigen levels were significantly elevated as compared to patients with Child A or Child B (p less than 0.05) or to controls (p less than 0.01). Furthermore, Child C patients exhibited significantly decreased PAI-1 plasma levels (p less than 0.05) as compared to controls. We were not able to demonstrate, however, any significant correlation between liver function and u-PA plasma levels. Furthermore, t-PA antigen and albumin plasma levels were negatively correlated (r = 0.48; p = 0.0015) and t-PA antigen and bilirubin were positively correlated (r = 0.46; p = 0.0022) thus indicating that the liver is mainly involved in the clearance of t-PA antigen. PAI-1 activity, however, seems to depend partially on synthesis by the liver as demonstrated by a positive correlation between PAI-1 and albumin (r = 0.33; p = 0.037). These physiologic liver functions are both progressively attenuated in severe liver damage and an increase of t-PA plasma levels and a decrease of PAI-1 might contribute to the higher fibrinolytic tendency observed in those patients.     

Tissue plasminogen activator release in chronic venous hypertension due to heart failure.

In order to study the effects of chronic venous hypertension due to heart failure on blood fibrinolytic activity, tissue plasminogen activator (t-PA) antigen, plasminogen activator inhibitor 1 (PAI-1) antigen, t-PA activity and PAI activity were measured before and after venous occlusion of the arm for 20 min in 15 patients with right-sided heart failure, 15 patients with left-sided heart failure, and 30 control healthy subjects. Central venous pressure, measured by observing the jugular veins, was above 15 cm of the blood column in all patients with right-sided heart failure, and normal (below 8 cm) in all patients with left-sided heart failure and control subjects. There was no difference in the basal concentrations of t-PA (11.0, 10.2 and 10.8 ng/ml; all values medians) and PAI-1 antigens and their activities between right and left-sided heart failure and the control subjects. After the occlusion, t-PA antigen increased significantly less in right-sided heart failure (28.6 ng/ml) than in left-sided heart failure and the control subjects (54.5 and 45.9 ng/ml, respectively). It was concluded that the poor increase in fibrinolytic activity that had already been reported in patients with heart failure, was due to low t-PA release during occlusion and not to a high basal PAI level. It was limited to the patients with right-sided heart failure and was probably the consequence of chronic systemic venous hypertension.     

The effect of red wine on the fibrinolytic system and the cellular activation reactions before and after exercise

The effect of red wine drinking was tested on fibrinolytic parameters and blood cells in nine healthy students at rest and after acute exercise. The subjects were randomly assigned in a crossover design to one of three treatment regimes: control situation, low-dose wine group, and high-dose wine group. Blood samples were drawn just prior to experimental start, at 2 and 4 hours, and the next morning at 8:00 a.m., at 8:30 a.m. just after exercise, and 2 hours after exercise. The fibrinolytic potential was measured by whole blood clot lysis time (WBCLT), tissue plasminogen activator, and plasminogen activator inhibitor-1 (PAI-1) antigens in plasma. A whole blood system was used to test the reactivity of blood cells by stimulating hirudinized blood with 5 ng/mL lipopolyusaccharide (LPS) for 2 hours at 37 degrees C and measurements of tissue necrosis factor alpha and interleukin-8 (IL-8) in the plasma. Intake of red wine caused impaired fibrinolysis shown by prolonged WBCLT (3.6, 20.7, and 55.7%, respectively, for control, low- and high-dose wine groups) due to increase in PAI-1 antigen (-0.8, 4.8, and 11.0 ng/mL, respectively, in the three groups). There was no effect of the red wine the next morning on the fibrinolytic system. A strong correlation was observed between WBCLT and PAI-1 antigen (p<0.0001). Acute exercise caused an immediate rise in both tissue plasminogen activator antigen and PAI-1 antigen levels and WBCLT was significantly shortened. In contrast to that of the wine groups, 2 hours after exercise WBCLT was prolonged in the control group, but not significantly so. Thus the red wine has a negative effect on the fibrinolytic system during rest, but may have a positive effect after strenuous exercise. The red wine had no immediate effect on LPS-induced tissue necrosis factor alpha or IL-8 production, although there was a tendency for higher cytokine production in the control group compared to the wine groups during and just after intake of wine. The next morning after exercise, the LPS-induced IL-8 production increased 137, 89, and 96%, respectively, in control, low-, and high-dose wine groups, probably due to a rise in epinephrine and activation of platelets. Although not significantly so, there was a tendency for red wine intake in the evening to suppress the reactivity of the cells after physical exercise the subsequent morning. It is suggested that the negative effect of red wine ingestion may be due to the toxic effect of ethanol on hepatocytes or adipose tissue and subsequent release of PAI-1, whereas the positive effect may be due to the red wine suppression of platelet activation and release of PAI-1 from activated platelets. It is proposed that at least part of the beneficial effect of red wine ingestion may be associated with the downregulation of cytokine production.     

Hypofibrinolysis in patients with a history of idiopathic deep vein thrombosis and/or pulmonary embolism.

An impaired fibrinolytic activity after a venous occlusion test is the most common abnormality associated with thomboembolic disease. To better characterize the causes of abnormal responses we have measured different fibrinolytic parameters, before and after 10 and 20 min of venous occlusion, in 77 patients with a history of idiopathic deep vein thrombosis and/or pulmonary embolism and in 38 healthy volunteers. The patients had a lower mean fibrinolytic response to venous occlusion than the controls and higher antigen levels of tissue-type plasminogen activator (t-PA:Ag) and plasminogen activator inhibitor type 1 (PAI-1:Ag). Before venous occlusion, PAI-1 levels were at a molar excess over those of t-PA in all patients and controls. After 20 min of venous occlusion, the release of t-PA from the vascular endothelium resulted in a molar excess of t-PA over PAI-1 in the majority of controls (72%) but only in a minority of patients (39%). To identify patients with fibrinolytic abnormalities, reference intervals (RI) for fibrinolytic activity, t-PA:Ag and PAI-1:Ag were established in healthy controls. None of the patients had low levels of t-PA:Ag, but 17 (22%) had elevated PAI-1:Ag levels before venous occlusion and 12 (16%) exhibited low fibrinolytic activity after 20 min of venous occlusion. Ten of these were among the 17 subjects with high PAI-1:Ag levels before venous occlusion. Thus, the measurement of PAI-1:Ag levels before venous occlusion (i.e. in samples taken without any stimulation) is a sensitive (83%) and specific (89%) assay for the detection of patients with an impaired fibrinolytic response to venous occlusion.     

Heparin induced increase of t-PA antigen plasma levels in patients with unstable angina: No evidence for clinical benefit of heparinization during the initial phase of treatment

Patients with unstable coronary artery disease were randomly treated either with a combination therapy consisting of nitrates and calcium-channel blockers without or with addition of clinical grade heparin administered subcutaneously; in order to evaluate the effect of heparin treatment on the fibrinolytic system, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) plasma levels were related to the clinical course of the disease. In heparinized patients thrombin time was prolonged more than 3-fold the normal range indicating effective heparin treatment. Heparinization led to a significant increase in t-PA antigen plasma levels (p <0.0001) within approximately four hours while PAI-1 activites remained unaltered. However, the measurable increase of the anticoagulant and pro-fibrinolytic activities of heparin did not result in a short-term benefit for the heparinized patients because the number of further ischemic attacks per patient during the observation period of three days was not different between the two study groups.     

Mild hyperhomocysteinemia is associated with a decreased fibrinolytic activity in patients after ST-elevation myocardial infarction

BACKGROUND: Elevated homocysteine (Hcy) levels have been associated with increased risk for cardiovascular disease and it has been shown that hyperhomocysteinemia is associated with increased levels of t-PA antigen in individuals without evidence for coronary artery disease (CAD). The aim of this study was to examine if Hcy plasma levels are associated with plasma levels of fibrinolytic factors in patients with CAD and a history of acute myocardial infarction. METHODS: We measured in 56 patients with CAD, 1 month after their first ST-elevation myocardial infarction, plasma levels of Hcy, the fibrinolytic parameters tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-type-1 (PAI-1), and t-PA-PAI-1 complexes. RESULTS: Hcy plasma levels inversely correlated with t-PA activity (r=-0.303, p<0.05). Patients with mild hyperhomocysteinemia (Hcy>15 micromol/L, n=8) showed significantly lower plasma levels of t-PA activity (p<0.05). Regression analysis revealed that out of cardiovascular risk factors and medical treatment only Hcy was significantly associated with t-PA activity. CONCLUSIONS: Patients with CAD after a first myocardial infarction and hyperhomocysteinemia show a reduced t-PA activity independently from cardiovascular risk factors and medical treatment. Homocysteine lowering therapies may increase fibrinolytic activity and thereby may help to avoid atherothrombotic events in patients with CAD after a first myocardial infarction.     

Plasma levels of t-PA free PAI-1 and a complex of t-PA with PAI-1 in human males and females at various ages

The concentration of tissue plasminogen activator (t-PA), plasminogen activator inhibitor 1 (PAI-1) and the complex of t-PA and PAI-1 (t-PA-PAI-1 complex) were measured using an enzyme immunoassay, where the first antibody was monoclonal antibody against PAI-1 and the second one was polyclonal anti-t-PA Fab' antibody. Plasma levels of t-PA and t-PA-PAI-1 complex increased with increase in age in the total population of males and females, but there was no age related change in free and total PAI-1. Plasma levels of t-PA antigen were higher in males than in females, and those in females gradually increased with increase in age, reaching the same levels as those of males at their 60s. Plasma levels of t-PA-PAI-1 complex were also higher in males than in females, but the difference was low at their 50s and no difference was observed at their 60s. Plasma levels of free PAI-1 were higher in males than in females, but those of males declined at age group higher than their 50s. At their 60s plasma levels of free PAI-1 were higher in females than in males. These results indicate that fibrinolytic parameters such as t-PA and PAI-1 were balanced at higher levels in plasma in males than in females.     

Plasma PAI-1 levels in obese children--effect of weight loss and influence of PAI-1 promoter 4G/5G genotype

An association between an increase in plasminogen activator inhibitor type 1 (PAI-1) and obesity, and also between elevated levels of PAI-1 and the presence of PAI-1 promoter 4G allele has been described in adults and can contribute to increased risk of cardiovascular disease. It has also been suggested that in adults a decrease in adiposity has beneficial effects on the haemostatic system. However, less information is available regarding adiposity and fibrinolysis in children. The aim of the present study is to evaluate the effect of weight loss and the influence of the PAI-1 promoter 4G/5G genotype on the fibrinolytic system and lipid parameters in obese children. The clinical groups included 102 obese children and 105 controls of similar age and sex distribution. A significant decrease in fibrinolytic activity due to a significant increase in PAI-1 antigen and activity levels was observed in the obese children in comparison with the control group. In obese children, no significant differences in PAI-1 levels between the PAI-1 4G/5G genotypes were obtained. A significant correlation was observed between PAI-1 antigenic and functional levels and body mass index (BMI), as well as between PAI-1 levels and both triglyceride and insulin levels. No correlation between PAI-1 levels and either cholesterol or glucose levels was observed. After a three-month period of treatment to reduce weight, an increase in fibrinolytic activity due to a decrease in PAI- levels was observed in the obese children who had reduced their BMI in comparison with the group of obese children who did not show a decrease in their BMI. No significant differences between the two groups with respect to the variations in tissue type plasminogen activator and fibrinogen levels were obtained after three months of intervention to reduce weight. A significant correlation was observed between variations in BMI and variations in PAI-1 levels, and a significant inverse correlation was also observed between previous PAI-1 levels and variation in PAI-1 levels. Therefore, the largest decrease in PAI-1 levels was observed in the obese children with the highest previous PAI-1 levels. In conclusion, a decrease in BMI in obese children shows a favourable effect on the fibrinolytic system due to a decrease in PAI-1 levels. However, no influence of 4G/5G genotype on PAI-1 levels was observed.     

Fibrinolytic potential and antiphospholipid antibodies in systemic lupus erythematosus and other connective tissue disorders.

We studied the fibrinolytic response before and after venous occlusion (VO) in 30 patients with systemic lupus erythematosus (SLE), 25 with rheumatoid arthritis (RA) and 25 with different connective tissue disorders. Results were compared in patients with and without antiphospholipid antibodies (APA) and a history of either thrombosis or abortions. Before occlusion plasma levels of tissue-type plasminogen activator (t-PA) antigen and its inhibitor (PAI-1) were significantly higher in the patient group (p < 0.001). After occlusion, a low fibrinolytic activity on fibrin plates (p < 0.005) was observed in the same group. t-PA capacity and t-PA release were similar in relation to controls. The plasma PAI-1 activity was significantly elevated in each group of patients (p < 0.005) as compared to the control group. No significant differences with respect to t-PA and PAI-1 were observed in patients as to the presence or absence of thrombosis. There was also no correlation between the fibrinolytic changes and the presence of APA. It is concluded that an impairment of the fibrinolytic system, mainly related to increased PAI-1 levels, is present in most patients with connective tissue disorders, although these changes did not correlate with the presence of APA or the incidence of thrombosis.     

Increased procoagulant and antifibrinolytic activities in the lungs with idiopathic pulmonary fibrosis

To elucidate the pathophysiology of idiopathic pulmonary fibrosis (IPF), we examined procoagulant (tissue factor:TF), fibrinolytic (tissue type plasminogen activator:t-PA and urokinase type plasminogen activator:u-PA) and antifibrinolytic (plasminogen activator inhibitor-1:PAI-1 and PAI-2) activities in bronchoalveolar lavage (BAL) supernatant fluids and BAL cell lysates obtained from IPF patients. The results indicated that TF levels in BAL supernatant fluids from IPF patients were higher than those of normal subjects, especially in patients with progressive disease, suggesting that TF levels in the lung correlate with disease activity. PAI-1 levels in BAL supernatant fluids were significantly higher in IPF patients than in normal subjects (1.7 ± 4.1 vs 0 ng/mg protein). PAI-2 levels in BAL cell lysates were also significantly higher in IPF patients than those in normal subjects (14.4 ± 12.2 vs 3.0 ± 3.0 ng/mg protein). However, u-PA levels in both BAL supernatant fluids and BAL cell lysates did not differ between the two groups. These observations suggest that u-PA inhibition exceeded u-PA activity in alveolar lining fluid resulting in an antifibrinolytic condition. Immunohistochemical analysis showed that TF was intensely stained in cuboidal epithelial cells and PAIs were positively stained in alveolar macrophages (AMs) and cuboidal epithelial cells, suggesting that cuboidal epithelial cells as well as AMs contribute to the increased procoagulant and antifibrinolytic activities in the lungs of IPF patients.     

No Influence of acute hypertriglyceridemia on plasma t-PA in healthy male volunteers.

Dietary effects on liver blood flow may have biased the previously observed effects of hypertriglyceridemia on systemic tissue-type plasminogen activator (t-PA) concentrations. Therefore, in this study the effects of hypertriglyceridemia on plasma t-PA were determined by inducing hypertriglyceridemia with an intravenous fat emulsion (Intralipid) infusion. In a randomised crossover fashion, eight healthy male volunteers received Intralipid 10% (1.5 ml/min) or 0.9% saline for 2 h and 45 min. After 2 h of infusion, t-PA antigen, t-PA activity, t-PA/plasminogen activator inhibitor (PAI-1) complex, and PAI-1 activity were determined. Concomitantly, the effects of Intralipid t-PA clearance were determined from steady-state t-PA antigen concentrations of a 45-min recombinant tissue-type plasminogen activator (rt-PA) infusion (31.25 microg/min). Liver blood flow was assessed from steady-state concentrations of a continuous sorbitol infusion. Differences between treatments were calculated using the prevalue as the covariate. No significant differences were observed in mean+/-S.D. endogenous concentrations of t-PA antigen, 4.5+/-0.9/4.1+/-0.9 ng/ml (Intralipid vs. saline infusion; difference of 0.3 ng/ml, 95% confidence interval, CI: -0.2, 0.8); t-PA activity, 0.69+/-0.21/0.68+/-0.21 U/ml (difference of 0.04 U/ml, CI: -0.17, 0.25); t-PA/PAI-1 complex, 2.0+/-1.3/1.6+/-1.0 ng/ml (difference of 0.1 ng/ml, CI: -0.8, 0.6); and PAI-1 activity, 7.3+/-5.1/7.1+/-5.1 U/ml (difference of 0.26 U/ml, CI: -3.7, 4.3). Mean t-PA clearance and liver blood flow were unaffected by the Intralipid infusion. These results indicate that acute hypertriglyceridemia does not alter plasma fibrinolytic parameters in healthy male volunteers.     

Changes in fibrinolysis following exercise above and below lactate threshold

This study sought to compare fibrinolytic responses to exercise above lactate threshold (LT) to longer-duration, equicaloric exercise below LT. Fifteen males performed cycle ergometer tests above (77% VO(2)peak) and below LT (41% VO(2)peak) to comparatively evaluate tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) responses. tPA activity significantly (P < 0.05) increased during the >LT test (pre-exercise = 1.57 +/- 0.44 IU ml(-1), post-exercise = 3.85 +/- 4.72 IU ml(-1)), but not the LT (pre-exercise = 8.32 +/- 4.48 ng ml(-1), post-exercise = 14.23 +/- 5.40 ng ml(-1)) and LT test. PAI-1 activity significantly (P < 0.05) decreased during both the >LT (pre-exercise = 15.00 +/- 2.73 AU ml(-1), post-exercise = 10.12 +/- 2.90 AU ml(-1)) and LT test. Our results suggest that exercise 相似文献