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PubMed2000

Umbilical cord endothelial cells expressing large T antigen: comparison with primary cultures and effect of cell age.

A number of human endothelial cell lines from umbilical cord cells (HUVECs) have been generated by transfection with SV40 large T and small t antigen sequences. Comparison of these lines with primary cultures of HUVECs has been carried out by monitoring the expression of a number of endothelial cell markers with specific regard to cell age. The secreted levels of the protein plasminogen activator inhibitor (PAI) was found to be significantly reduced in SV40-transfected cells when compared to untransfected controls. Tissue plasminogen activator (tPA) and urokinase (uPA) levels were unchanged. As cells entered crisis, there was a rapid and significant increase in the levels of tPA, uPA, and PAl and this was observed for all clones screened. The endothelial cell marker von Willebrand Factor (vWF) was found intracellularly and was also secreted into the medium. The levels were not altered between transfected and untransfected cells. Angiotensin converting enzyme (ACE) activity was maintained in cell lines at levels found in nonimmortalized HUVECs. Both isoforms (alpha and beta) of IL-1 (interleukin-1) increased as cells approached crisis, and the presence of these cytokines may be responsible for the increased levels of tPA, PAI, and uPA. With one exception, the ability of the transfected cells to produce prostacyclin (PGI2) was lost by all clones.

Antigens, Polyomavirus Transforming↗
PubMed1992

Plasma t-PA/PAI-1 complex and blood coagulability in patients with coronary artery disease.

The t-PA/PAI-1 complex is a good indicator of the release of fibrinolysis activators and inhibitors from the vascular wall, but its clinical significance in chronic ischemic heart disease is unclear. The plasma levels of tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), and the t-PA/PAI-1 complex (including various coagulation factors) were assayed in 72 patients with coronary artery disease (CAD) and 29 control (C) subjects. The CAD patients were subdivided into 3 groups: single-vessel disease (G1, n = 30), double-vessel disease (G2, n = 20), and triple-vessel disease (G3, n = 22). The patients with triple-vessel disease had higher fibrinogen values (G3: 318 +/- 75 mg/dl, C: 263 +/- 56), factor VII activity (G3: 143 +/- 36%, C: 123 +/- 14), and t-PA antigen levels (G3: 4.7 +/- 0.8 ng/ml, C: 3.3 +/- 0.7) than controls. Patients with double- and triple-vessel disease also showed higher levels of factor VIII, vWF antigen, thrombin-antithrombin III complex (G1: 2.3 +/- 0.6 ng/ml, G2: 2.7 +/- 0.5, G3: 3.1 +/- 0.5, C: 2.0 +/- 0.5), and t-PA/PAI-1 complex (G1: 13.9 +/- 6.1 ng/ml, G2: 16.4 +/- 4.6, G3: 18.2 +/- 5.9, C: 10.7 +/- 4.9) than control subjects. The t-PA/PAI-1 complex levels were correlated significantly with the activities of factors VII and VIII and the thrombin-antithrombin III complex. These findings suggest that patients with CAD have greater blood coagulability than controls, and that this difference is related to the severity of the disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1992

Increased expression of tissue plasminogen activator and its inhibitor and reduced fibrinolytic potential of human endothelial cells cultured in elevated glucose.

In diabetic patients, elevated plasma levels of t-PA and PAI-1 accompany impaired fibrinolysis. To identify mechanisms for these abnormalities, we examined whether vascular endothelial cells exposed to high glucose upregulate t-PA and PAI-1 production and whether ambient PA activity is decreased concomitantly. In 17 cultures of human umbilical vein endothelial cells grown to confluency in 30 mM glucose, the t-PA antigen released to the medium in 24 h was (median) 52 ng/10(6) cells (range 10-384) and the PAI-1 antigen was 872 ng/10(6) cells (range 217-2074)--both greater (P less than 0.02) than the amounts released by paired control cultures grown in 5 mM glucose--29 ng/10(6) cells (range 7.5-216) and 461 ng/10(6) cells (range 230-3215), respectively. In the presence of high glucose, the steady-state levels of t-PA and PAI-1 mRNAs were increased correspondingly (median 142 and 183% of control, respectively, P less than 0.05); high glucose per se and hypertonicity contributed to the upregulation in additive fashion. The PA activity of conditioned medium from cultures exposed to high glucose was 0.4 IU/ml (range 0.2-0.6), which was significantly lower (P less than 0.02) than the PA activity of control medium (0.5 IU/ml, range 0.2-0.9). No difference was observed when comparing the PA activities of acidified conditioned media, expected to be depleted of inhibitors. Thus, high glucose coordinately upregulates endothelial t-PA and PAI-1 expression through effects exerted at the pretranslational level and enhanced by even mild degrees of hypertonicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Cells, Cultured↗
PubMed1988

The effect of body build, diet and endocrine factors on the extrinsic fibrinolytic system in healthy young women.

In this study, the importance of anthropometric, nutritional and endocrine variables on the plasma concentrations of tissue plasminogen activator antigen (tPA) and plasminogen activator inhibitor (PAI-l) were investigated. Tissue plasminogen activator concentration and PAI-l activity in plasma were studied in 24 healthy young women after diet periods which caused depletion or filling of hepatic glycogen stores. Plasminogen activator inhibitor levels in the glycogen-depleted state and the glycogen-repleted state were positively correlated, as were also tPA levels. In fasting subjects with repleted glycogen stores, tPA values correlated with fasting insulin concentration and blood pressures. In fasting subjects depleted of glycogen stores, PAI-l correlated with tPA, plasma insulin, triglycerides, and waist-to-hip girth ratio; triglycerides and waist-to-hip girth ratio also correlated with tPA. Over a 4-h period following intake of a test-meal, the glucose and insulin responses were not correlated with the fibrinolytic variables. Multivariate regression analysis suggested that waist-to-hip girth ratio and diastolic blood pressure were independently associated with tPA concentrations both in subjects with depleted and repleted glycogen stores. Thus, both constitutional factors such as anthropometric variables and blood pressure, and nutritional status of the subjects may be related to tPA and PAI- levels in plasma. This should be taken into account in clinical studies on fibrinolysis.

Adult↗
PubMed1991

Increased levels of fibrinolysis reaction products (D-dimer) in patients with decompensated alcoholic liver cirrhosis.

We studied the activation of coagulation and fibrinolysis in the blood of patients with compensated (n = 25) and decompensated (n = 25) liver cirrhosis. We observed increased blood concentrations of thrombin-antithrombin III (TAT) complexes (p less than 0.001) and of D-dimer (p less than 0.001) in both groups of patients compared with healthy volunteers (n = 25). The blood levels of tissue-type plasminogen activator (t-PA) activity (p less than 0.001) and the concentrations of t-PA antigen (p less than 0.001) were also significantly raised in both groups of patients compared with controls, whereas plasminogen activator inhibitor did not deviate. There were no significant differences in the determined variables between the two groups of patients except that the concentrations of D-dimer were significantly higher (p less than 0.001) in patients with decompensated liver cirrhosis. The ratio between D-dimer and TAT did not deviate between patients with compensated liver cirrhosis and healthy volunteers but was significantly increased in patients with decompensated liver cirrhosis. These observations indicate that efflux from the extravascular space (for example, ascitic fluid) contributes to the high concentrations of fibrin degradation products (D-dimer) in patients with decompensated liver cirrhosis. In addition, we conclude that patients with liver cirrhosis have an enhanced activation of both coagulation and fibrinolysis but that the balance between these two systems is not significantly displaced compared with healthy volunteers.

Aged↗
PubMed1995

Plasma von Willebrand factor, tissue plasminogen activator, plasminogen activator inhibitor, and antithrombin III levels in Behçet's disease.

Sixty-three patients with Behçet's disease (BD), 30 patients with recurrent oral ulcer and 30 healthy individuals as control group were included in the study. ISG criteria was used for the diagnosis of BD and patients were classified as active and inactive and evaluated accordingly. In the patient and control groups, von Willebrand factor (vWF), tissue plasminogen activator (tPA), and plasminogen activator inhibitor (PAI) levels were determined using ELISA method and antithrombin III (AT-III) by nephelometric methods. High levels of endothelial product, vWF in the active Behçet patient group (p < 0.005) supports endothelial destruction due to vasculitis related with BD. In the active patient group tPA levels were significantly lower (p < 0.05) than the inactive and control groups with higher levels of PAI (p < 0.05 and p < 0.01) respectively. In Behçet disease, besides the decrease in tPA synthesis, high PAI levels also can affect tPA decrease and lead to inhibition of fibrinolytic activity. In active Behçet group, levels of AT-III were low and no significant difference was observed in recurrent oral ulcer and control groups. This situation may arise from the excessive use of AT-III in active disease. In conclusion, high levels of vWF in Behçet patients is thought to arise from vasculitis and high levels of PAI from the accumulation of thrombocytes on the damaged surface of endothelium leading to a decrease in tPA levels and inhibition of fibrinolytic activity.

Adolescent↗
PubMed1990

Association between tissue plasminogen activator and serum lipids in healthy volunteers.

The statistical association between tissue plasminogen activator (t-PA) activity, antigen, plasminogen activator inhibitor-1 (PAI-1) antigen and lipids levels in blood samples used for medical check ups in 111 volunteers attending hospital for health examinations was examined. The t-PA activity level of 111 volunteers was 0.08-0.56 ng/ml (5% trimmed range) (normal range: 0.08-0.70 ng/ml); t-PA antigen concentrations were 2.4-9.2 ng/ml (normal range: 1.0-7.0 ng/ml); PAI-1 antigen concentrations were 5.2-57.4 ng/ml (normal range: 5.2-45.0 ng/ml). The volunteers with the lowest t-PA activity in blood (group E) had higher concentrations of serum total cholesterol (P less than 0.001), triglycerides (P less than 0.001), or t-PA antigen (P less than 0.001) and lower concentrations of high-density lipoprotein cholesterol (P less than 0.001) than those having normal serum lipids and t-PA activity level (group A). These results show that t-PA activity, antigen and PAI-1 antigen in blood obtained from the healthy volunteers are influenced significantly by the concentrations of lipids in blood.

Adult↗
PubMed1990

[Tissue-type plasminogen activator and its inhibitor (PAI-1) in plasma in cases of non-insulin-dependent diabetes mellitus (NIDDM)].

Parameters of fibrinolysis, including plasminogen, alpha 2 plasmin-inhibitor (alpha 2 PI), tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) antigens, and fibrinogen were assayed in 53 patients (28 women and 27 men; mean age: 64 years, age range: 32-87 years) with non-insulin-dependent diabetes mellitus (NIDDM). The control group was similarly aged (mean age: 60.4 years, age range: 38-81). The levels of t-PA and t-PA/PAI-1 ratio of the diabetic group (mean +/- SD; 9.8 +/- 4.3 ng/ml, 0.94 +/- 0.47, respectively) were significantly higher than that of the control group (5.5 +/- 2.5 ng/ml, 0.51 +/- 0.23, respectively). The increased levels of t-PA antigen and t-PA/PAI-1 ratio in diabetics mean that free t-PA has been released. However, there was no significant difference in the level of PAI-1 between the diabetic group (12.9 +/- 6.4 ng/ml) and the control group (12.1 +/- 5.6 ng/ml). Levels of fibrinogen, plasminogen and alpha 2 PI in plasma were not different in the two groups. Duration of the disease, levels of glycosylated hemoglobin, differences in treatment and presense of diabetic nephropathy or retinopathy did not affect the fibrinolytic parameters. The levels of fibrinogen was higher in those with nephropathy than in the diabetics without nephropathy and retinopathy (p less than 0.05). There were no significant differences in the levels of t-PA, t-PA/PAI-1 ratio and PAI-1 between younger (less than 65 years) and older (65 years or more) subjects, in either the control or diabetic groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Plasminogen activator regulation by transforming growth factor-beta in normal and neoplastic human urothelium.

Plasminogen activators (PA) are thought to participate in the invasive and metastatic processes of malignancies and are known to be modulated by certain growth factors (Danø, K; Andreasen, P.A.; Grondahl-Hansen, J.; Kristensen, P.; Nielsen, L.S.; Skriver, L. Adv. Cancer Res. 44:139-266; 1985 and Laiho, M.; Keski-Oja, J. Cancer Res. 49:2533-2553; 1989). This report describes the effect of TGF-beta on the regulation of secreted PA activity produced by human fetal urothelium and neoplastic urothelial cell lines. Epidermal growth factor was previously shown to induce substantially different effects on PA production by normal versus neoplastic urothelial (Dubeau, L.; Jones, P.A.; Rideout, W.M.; Laug, W.E. Cancer Res. 48:5552-5556; 1988). This report demonstrates that log phase normal urothelium, but not transformed cells, responded to TGF-beta (1-10 ng/mL) by diminishing the total secreted PA activity. Northern and western analyses showed that the reduction in protease activity resulted from an increased level of plasminogen activator inhibitor-1 (PAI-1) mRNA and protein. Additionally, northern analysis of total mRNA levels at varying cell densities demonstrated modulation of tPA, PAI-1, and TGF-beta transcripts in normal urothelial cells as a function of growth in vitro, suggesting the presence of an intact regulatory pathway to control extracellular proteolysis.

Blotting, Western↗
PubMed1995

[Tissue type plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI) in transplanted kidneys].

We have studied the involvement of fibrinolysis in acute rejection after kidney transplantation by analyzing changes in urinary levels of substances such as FDP, D-dimer, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI). Fibrinolytic activity was found to be low (that is, PAI is dominant) during acute rejection, and it was elevated (that is, PA became dominant) as acute rejection subsided. It appears that the dominance of PA leads to an increase in the products of fibrinolysis and an elevation in the D-dimer/FDP ratio, resulting in disappearance of the acute rejection. Based on these findings, we thought it necessary to administer t-PA to kidney recipients so that PA becomes dominant earlier and the acute rejection can be reduced. It is necessary for us to directly study the phenomena within the kidneys. Therefore, we recently conducted a histochemical study of the distribution of t-PA, Urokinase type PA (u-PA) and PAI in transplanted kidneys. Transplanted kidney, which functioned well or showed signs of acute or chronic rejection, were biopsied. These renal samples as well as control samples (biopsied from normal nongrafted kidney) were examined as to distribution of t-PA, u-PA and PAI by the indirect enzyme complement method. In conclusion, t-PA, u-PA and PAI were detected in the glomeruli, arterioles, tubule and interstices of the control kidneys, well functioning grafts, acutely rejected grafts chronically rejected grafts. All samples showed intense chromatic responses in the arterioles and part of the tubules. On the whole, the chromatic response tended to be more intense in the acute rejection group than in the other group.

Fibrinolysis↗
PubMed1997

[Changes of serum TNF-alpha level, t-PA activivty and PAI activity in patients with silent myocardial ischemia or silent cerebral ischemia].

Tumor necrosis factor-alpha (TNF-alpha) level, tissue-typed plasminogen activator(t-PA) activity and PA inhibitor (PAI) activity were determined in three groups: (1) 25 NIDDM patients with silent myocardial ischemia (SMI) or silent cerebral ischemia (SCI); (2) 18NIDDM patients without SMI or SCI; (3) 20 age-matched normal controls. Diagnosis of SMI or SCI was based on the finding of ischemic evidence by SPECT of myocardiotomograph or cerebrotomograph. All patients ECG and blood pressure were normal, and they had no history of clinical symptoms and signs of MI or CI. The result showed that the TNF-alpha level and PAI activity in the ischemia group were the highest and the t-PA activity in the ischemia group was the lowest, as compared with those in the other two groups respectively. It suggests that in NIDDM patients who have high TNF-alpha, high PAI activity, low t-PA, and even no symptoms and signs of MI or CI, anticoagulant therapy might be useful to prevent the progression of diabetic macroangiopathies.

Brain Ischemia↗
PubMed1998

[Relationship of lipoprotein(a) to fibrinolytic activities in healthy subjects].

Plasma tissue-type plasminogen activator(tPA) and plasminogen activator inhibitor(PAI-1) and lipoprotein(a) [Lp(a)] in 133 healthy subjects were determined. The results demonstrated that PAI-1 activity was higher in Lp(a) > or = 0.3 g.L-1 group than Lp(a) < 0.3 g.L-1 group (P < 0.05). Univariate statistical analyses showed Lp(a) concentration was positively associated with PAI-1 activity (P < 0.01), but not with age, sex, body mass index, blood lipids or tPA activity.

Adult↗
PubMed1997

Changes of plasma tPA and PAI activities in patients with diabetic retinopathy.

PURPOSE: To investigate the relationship between the diabetic retinopathy (DR) and the activity of plasma tissue plasminogen activator (tPA) and plasminogen activator inhibitor (PAI). METHODS: tPA and PAI activities were measured by chromatogenous substrate assay in plasma samples obtained from patients with and without diabetic retinopathy (n = 42). Retinopathy was determined by stereoscopic color fundus photographs graded according to a modification of Chinese National Fundus Disease Academic Meeting. And 21 sex-age matched normal people were as controls. This study was in a masked fashion. RESULTS: 1. tPA activity was lower and PAI activity was higher in all of diabetic patients than those in controls (P < 0.001); 2. tPA activity was lower and PAI activity was higher in proliferative DR (PDR) subgroup than those in non-DR (NDR) and background-DR (BDR) subgroups (P < 0.01, respectively); 3. there was no significant difference between BDR and NDR subgroups (P > 0.05); and 4. the results also suggested that the severity of DR and duration of diabetes were correlated negatively with the activity of tPA but positively with that of PAI (r = -0.564, -0.416, 0.671, 0.442; P < 0.01, respectively). CONCLUSIONS: Reduced plasma tPA activity and enhanced PAI activity in diabetic patients, probably is one of the causes for thromboembolic diseases and are related to the severity of DR and duration of diabetes. Therefore, the change and imbalance between activities of plasma tPA and PAI might play a role in developing and progression of DR.

Adolescent↗
PubMed2000

[Exploration on parameters of TCM syndrome in acute cerebral infarction through investigating active factors of vascular endothelium cells].

OBJECTIVE: To explore the multiple parameters of TCM Syndrome-types and the acute cerebral infarction (ACI) with blood stasis type. METHODS: Sixty-six acute cerebral infarction patients with blood stasis Syndrome, various vascular active factors such as tissue plasminogen activator (t-PA), the activity of plasminogen activator inhibitor (PAI), the concentration of prostaglandin F1 alpha (6-keto-PGF1 alpha) etc. were determined. RESULTS: (1) In Incidental Syndrome, those "Phlegm" and "stasis" predominant, mainly manifested as Wind-Phlegm-Blood stasis (WPBS), Qi deficiency-blood stasis (QDBS) and Phlegm-Heat-bowel excess (PHBE) Syndrome all showed t-PA activity lowered, among them, QDBS Syndrome lowered more obviously (P < 0.01); and in fundamental deficiency predominant Syndrome such as Yin-deficiency and Wind-move (YDWM) Syndrome, the active t-PA content increased (P < 0.05); in Liver Yang ascending (LYA) Syndrome and YDWM Syndrome, the 6-keto-PGF1 alpha lowered very significantly. (2) Through regression analysis, although influencing the severity of acute blood stasis was related with 3 factors (t-PA activity, nervous system defect score and age growth), but single factor linear relationship analysis indicated that did not existed positive-negative relationship. (3) Through statistical analysis, the factor influencing nervous system defect scores was positively related with blood stasis score (r = 0.70, P < 0.01). CONCLUSION: (1) The basis of WPBS, QDBS and PHBE Syndrome mainly was fibrinolytic system activity lowering, and YDWM and LYA Syndrome prostaglandin system activity lowering. Comprehensive analysis of multiple parameters would be helpful to differentiate the ACI blood stasis stage. (2) Single parameter would not help to differentiate the types of ACI blood stasis stage, its change merely denoted the existence of blood stasis, its type should be differentiated after comprehensive analysis. (3) Those influencing nervous system scoring, mainly was blood stasis score, which suggested that the importance of activating blood circulation to remove stasis in preventing and treating ACI. (4) Put forward ACI blood stasis, and the quantification for new standard of Syndrome for discussion.

6-Ketoprostaglandin F1 alpha↗
PubMed1999

[Plasma Lp (a) levels and correlation of Lp (a) with fibrinolysis activation in chronic renal failure].

Plasma Lp (a) concentration and activation of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1(PAI-1) were determined in 50 patients with chronic renal failure (CRF) and in 50 healthy subjects. The results demonstrated that plasma concentration of Lp(a) was significantly higher and plasma t-PA activation was significantly lower in CRF patients than in healthy subjects. With multivariate analyses, plasma Lp(a) concentration was positively correlated with the total amount of 24 h uric protein, plasma BUN and uric protein concentration. Moreover, a negative significant correlation between plasma Lp(a) levels and t-PA activation was observed. Plasma Lp(a) levels did not show a correlation to PAI-1 activation. It is indicated that renal function may contribute to moderate plasma Lp(a) concentration and elevated Lp(a) levels may be related with fibrinolytic impairment.

Adult↗
PubMed1992

Peritoneal fluid and plasma fibrinolytic activity in women with pelvic inflammatory disease.

Previous studies have shown that the fibrinolytic activity of peritoneum is depressed in local inflammation. We measured fibrinolytic parameters in peritoneal fluid and in plasma of 10 women with pelvic inflammatory disease (PID). Nine women, in whom laparoscopy for sterilisation was performed, served as a control group. In the peritoneal fluid of women with PID, PAI-Ag, t-PA-Ag and u-PA-Ag were many times higher than in the control group. In contrast to the antigens which may be present in inert complexes, the potentially active compounds, measured as t-PA activity and plasmin-activable scu-PA, were not significantly different in the two groups, and in none of the samples was the active enzyme tcu-PA detectable. Nevertheless, the mean peritoneal fluid TDP and FbDP concentrations were about twenty times higher in the PID group than in the control group. In plasma of PID patients, none of the parameters except u-PA-Ag differed from those in the control group. The difference between control and patient plasma u-PA-Ag was statistically significant, but too small to attach any relevance to the observation. Our data suggest that, in contrast to the classical concept of decreased fibrinolytic activity as a cause of adhesion formation, intraperitoneal fibrinolysis is enhanced in peritoneal inflammation through stimulation of the local production of t-PA and u-PA. Despite concomitant production of PAI, fibrinolysis occurs at a high rate, resulting in high levels of fibrin degradation products. Since this activated fibrinolysis does not meet the demand, therapeutic enhancement should be considered to prevent adhesions.

Adolescent↗