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PubMed1988

Plasminogen activator inhibitor activity in bacterial infection.

It has been experimentally shown that endotoxin induces a marked increase in the levels of a fast-acting inhibitor of plasminogen activator (PAI). The plasma PAI activity and tissue-type plasminogen activator (t-PA) concentrations were measured in 61 patients with human septicaemia and results were compared with those observed in healthy controls. There was a markedly significant increase of PAI in plasma and platelet extracts of patients with septicaemia as compared to controls (p less than 0.0001). No correlation between PAI and endotoxin concentration was observed. Fibrin autography of plasma samples confirmed that activator inhibition was associated with the formation of an enzyme-inhibitor complex. t-PA activity was similar in patients and controls, whereas t-PA Ag showed a significant increase in patients (p less than 0.0001). A significant inverse correlation between t-PA activity and PAI was observed (p less than 0.05). PAI activity was higher in patients with positive blood cultures (p less than 0.0001) and gram-negative septicaemia (p less than 0.0001). There was also a significant increase of PAI levels in patients with disseminated intravascular coagulation (DIC) as compared with patients without DIC (p less than 0.001). We conclude that there is a marked increase of PAI in patients with sepsis. Increased PAI activity may contribute to the pathogenesis of DIC associated with septicaemia.

Adolescent↗
PubMed1988

Impaired fibrinolysis in obstructive jaundice--evidence from clinical and experimental studies.

Microvascular thrombosis is considered an important pathogenetic factor in renal failure associated with obstructive jaundice but the mechanisms leading to fibrin deposition are still unknown. The plasma levels of plasminogen activator inhibitor (PAI) in 29 patients with obstructive jaundice were found significantly increased as compared to 20 nonjaundiced patients. Fibrin autography of plasma supplemented with tissue plasminogen activator (t-PA) revealed that in icteric samples most of the added activator migrated with an apparent Mr of 100 kDa, corresponding to t-PA-PAI complex, whereas in control samples virtually all t-PA migrated as free enzyme. PAI activity detected in icteric samples is similar to the endothelial type PAI since it is neutralized by a monoclonal antibody against PAI-1. Venous stasis in jaundiced patients was neither associated with an increase in blood fibrinolytic activity nor with a decrease in PAI activity. Immunologic assay showed that t-PA release was impaired in 3 out of 4 patients. In controls, venous occlusion induced an increase in both fibrinolytic activity and t-PA antigen and a reduction in PAI activity. Bile duct recanalization in jaundiced patients subjected to surgery was accompanied by a decrease in plasma PAI activity which paralleled the decrease in serum bilirubin levels. In nonjaundiced patients, surgical treatment did not cause significant changes in either parameter. Rabbits made icteric by bile duct ligation showed an early and progressive increase in plasma PAI activity indicating that obstructive jaundice itself causes the elevation of circulating PAI. it is concluded that obstructive jaundice is associated with a severe impairment of fibrinolysis which might contribute to microvascular thrombosis and renal failure.

Adult↗
PubMed1985

Immunoradiometric assay to measure the binding of a specific inhibitor to tissue-type plasminogen activator.

A functional, immunoradiometric assay for a specific plasminogen activator inhibitor (PAI) was developed. This assay was based on the ability of the PAI to bind rapidly and strongly to immobilized tissue-type plasminogen activator (tPA). The extent of binding was quantified by incubating the PAI-tPA complex first with rabbit antiserum to the PAI and then with 125I-labeled goat anti-rabbit IgG. The interaction between tPA and the PAI was rapid, time- and concentration-dependent, sensitive over a broad range of PAI concentrations (1 to 100 ng/ml), and competed by urokinase but not streptokinase. The widespread application of this new technique was indicated by its ability to detect an immunologically related PAI not only in a number of other cell types, but also in platelets from which it can be released by thrombin, and in blood. This assay thus provides a quantitative approach for assessing the role of this PAI in a variety of fibrinolytic processes.

Adenocarcinoma↗
PubMed1993

Fibrin induction of tissue plasminogen activator expression in corneal endothelial cells in vitro.

PURPOSE: Fibrin is deposited in the anterior chamber of the eye in response to injury and can damage corneal endothelial cells (CEC). Fibrin degradation is plasmin dependent and is regulated by the balance between plasminogen activators (PA), tissue-PA (t-PA), urokinase-PA (u-PA), and their inhibitors (PAI). Although several factors can modulate PA/PAI expression in cells, the effect of fibrin is inconclusive. We hypothesized that fibrin can regulate fibrinolysis in the anterior segment by modulating PA/PAI expression in CEC. METHODS: Bovine CEC (BCEC) were treated for 3 to 72 hours with in situ polymerized fibrin (2 mg/ml) +/- 35S-methionine, cycloheximide, or actinomycin D. Polymerization was thrombin catalyzed, and control BCEC were incubated with or without thrombin or polymerization by-products. PA and PAI in conditioned medium, fibrin matrix, and cell fractions were analyzed by PA-specific zymographic and enzymatic assays. RESULTS: Fibrin treatment induced a dramatic (> 20-fold) accumulation of extracellular, fibrin-bound PA. This activity was identified as t-PA by its Mw (70 kD) affinity for fibrin and sensitivity to inhibition by Erythrina. Induction of t-PA was not observed in control BCEC under any condition. Fibrin induction of t-PA was selective because the levels of u-PA (45 kD), PAI-1 (50 kD), or protein synthesis in general were unaffected. Fibrin induction of t-PA was not accompanied by changes in cellular t-PA levels and was dependent on both RNA and protein synthesis. CONCLUSIONS: Fibrin selectively induces t-PA expression in CEC. Induced t-PA is released extracellularly and binds exclusively to the fibrin matrix. These findings suggest a role for fibrin and CEC in the regulation of fibrinolysis in the anterior segment of the eye.

Animals↗
PubMed1993

[Pathogenesis of skin pathologic changes and ulceration].

Twenty-six patients with venous insufficiency and 15 normal controls were studied by local skin pathological and ultrastructure changes. Transcutaneous oxygen tension (Tcpo2) and tPA, PAI of venous blood were measured. Biopsies from the ulcerating and liposclerosis area showed pericapillary fibrins. The patients with severe venous disease resulting in liposclerosis or ulceration of the goiter area had Tcpo2 levels lower than the controls and patients with venous insufficiency but no skin changes. The more serious the skin changes in patients with venous insufficiency, the lower the fibrinolysis activity. We conclude that extravascular deposition of fibrins in patients with venous disease which block the diffusion and exchanges of oxygen between the blood and tissue is an important factor in the development of venous ulcerations. The decrease of fibrinolysis activity led to the decrease of removing pericapillary fibrins deposition, combined with extravascular fibrin caused venous ulceration.

Aged↗
PubMedDate not supplied

[Tissue plasminogen activator (T-PA) and tissue plasminogen activator inhibitor (PAI-1) in patients after head injury].

The following factors of fibrinolysis: tissue plasminogen activator (t-PA) and tissue plasminogen activator inhibitor-1 (PAI-1) play an important role in patients after trauma. Their possible mechanisms in head-injured patients remain unknown. We studied the maintenance of those markers of fibrinolysis in the plasma and cerebrospinal fluid of 19 patients after severe head injury (initially GCS less than 8 p) without intracranial haematoma. We measured changes of the level of t-PA antigen and PAI-1 activity in days 0-3, 4-6 and later. T-PA antigen level in the plasma was higher than normally (4-8 ng/ml). T-Pa was present in the cerebrospinal fluid, but its level reached only 30% of the plasma level. In the days following injury the t-PA antigen level decreased. The PAI-1 activity in the plasma was normal (0-15 IU/ml). However, its activity in csf was high and reached, 80% of the plasma level and systematically increase in the following days particularly in patients who died. PAI-1 activity can be connected with the presence of damaged brain tissue and its necrosis and its increase can be a marker of poor prognosis.

Adult↗
PubMed1999

Protein movement during complex-formation between tissue plasminogen activator and plasminogen activator inhibitor-1.

Plasminogen activator inhibitor-1 (PAI-1) rapidly inactivates tissue plasminogen activator (tPA). After initial binding and cleavage of the reactive-centre loop of PAI-1, this complex is believed to undergo a major rearrangement. Using surface plasmon resonance and SDS-PAGE, we have studied the influence of a panel of monoclonal antibodies on the reaction leading to the final covalent complex. On the basis of these data, we suggest the mechanisms for the action of different classes of inhibitory antibodies. We propose that the antibodies which convert PAI-1 into a substrate for tPA do this by means of preventing the conversion of the initial PAI-1/tPA complex into the final complex by sterical intervention. Moreover, the localisation of the binding epitopes on free PAI-1, as well as on the PAI-1/tPA complex, suggests that tPA in the final complex cannot be located near helices E and F, as has previously been proposed.

Antibodies, Monoclonal↗
PubMed1986

A new, ideal technique to monitor thrombolytic therapy.

In an earlier article we have reported a technique which allows the measurement of haemostasis from whole blood by the "tube bleeding" principle. The technique is now progressed by using non-anticoagulated blood and therefore clotting-time is also measured. We report here that the technique allows a simple thrombolytic assay to perform from the same blood sample used for haemostasis measurement by detecting the length of time until the haemostatic plugs crack or are expelled. Evidence is presented that this "spontaneous" expulsion is mainly due to thrombolysis. Generation of thrombin during haemostasis is indicated by the inhibitory effect of hirudin. 125I-fibrinogen accumulates (28-fold) in the haemostatic plugs. Plasminogen activators (streptokinase and urokinase) reduce while inactivation of plasminogen by specific antibody greatly prolongs the expulsion-time. The effect of cytochalasin B shows that the retraction of the haemostatic plug is not a decisive factor of the expulsion. As the technique allows the simultaneous measurement of haemostasis, thrombolysis and clotting, it seems ideal for monitoring thrombolytic therapy.

Adolescent↗
PubMed1980

The binding of tumor localizing porphyrins to a fibrin matrix and their effects following photoirradiation.

The binding of two tumor localizing porphyrins, meso-tetra (4-carboxyphenyl) porphine (TCPP) and meso-tetra (4-sulfonatophenyl) porphine (TPPS4) to fibrin clots was determined in vitro. Both TCPP and TPPS4 were found to bind extensively, although weakly, to fibrin. No appreciable binding by Hematoporphyrin IX to the fibrin matrix was detectable. Similar results were obtained whether the clot was non-crosslinked or crosslinked with factor XIII. Photoirradiation of a porphyrin-impregnated non-crosslinked clot rendered it urea insoluble. Electrophoretic analysis indicated that the alpha chain of the fibrinogen molecule was most affected by photoirradiation. This was manifested as a loss of the alpha chain intensity and a concomitant increase of high molecular weight components, suggesting the formation of crosslinks. No substantial differences were noted in susceptibility to plasmin lysis between photoirradiated and non-irradiated clots. Photoirradiated clots were, however, significantly more resistant to lysis induced by the plasminogen activators urokinase and streptokinase, suggesting that inactivation of plasminogen within the clot matrix had occurred during photoirradiation. The relevance of porphyrin binding to fibrin with regard to tumor localization and destruction is also discussed.

Binding Sites↗
PubMed1991

Induction of plasminogen activator inhibitor 1 biosynthesis by hyperthermia.

Hyperthermia is a clinical sign of inflammation and constitutes in itself an adaptive defense mechanism. The fibrinolytic system, a highly regulated proteolytic system, is involved in inflammatory processes. Plasminogen activator inhibitor 1 (PAI-1) is the principal inhibitor of the two activators of the fibrinolytic system: tissue- and urokinase-type PAs (t-PA and u-PA). Our present paper provides the first evidence that hyperthermia can directly induce PAI-1. A moderate heat stress, sufficient to induce heat shock protein 70 mRNA approximately 100-fold, resulted in a two- to three-fold increase in functionally active PAI-1 in the conditioned medium of human HT-1080 fibrosarcoma and Hep G2 hepatoma cells. Exposure of these cells to 42 degrees C led to a similar two-fold and two- to five-fold induction of PAI-1 mRNA expression in HT-1080 and Hep G2 cells, respectively, as has been determined by using both oligo d(T) selected and total RNA preparations. These results suggest that the observed increase in PAI-1 accumulation is due to an induction of PAI-1 biosynthesis. Run-on transcription analysis indicates that the induction of PAI-1 biosynthesis by hyperthermia is mediated by a stimulation of PAI-1 gene transcription. No significant effect of hyperthermia was found on t-PA or u-PA at the level of antigen accumulation, mRNA, and gene transcription in human HT-1080 fibrosarcoma cells. These results point to an additional regulatory mechanism of fibrinolysis in the context of inflammation.

Base Sequence↗
PubMed1992

The relationship between cardiovascular complications of estrogen therapy and fibrinolysis in patients with prostatic cancer.

To determine the relationship between cardiovascular complications of estrogen therapy and fibrinolysis, fibrinolysis parameters plasminogen, urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA), and plasminogen activator inhibitor-1 (PAI-1), were assessed in 12 prostatic cancer patients before and 6 weeks after the onset of estrogen therapy. The levels of plasminogen, u-PA, and PAI-1 in the patients treated with the estrogen therapy were significantly higher than those in the patients before the therapy. The t-PA level in the patients during the therapy was significantly lower than that before the treatment. Cardiovascular complications were found in two patients (16.7%) during estrogen therapy. In the two patients, marked elevation of PAI-1 and decreased level of t-PA were observed during the therapy. These results indicate that cardiovascular complications of estrogen therapy in patients with prostatic cancer may be related to hypofibrinolysis resulting from changes of PAI-1 and t-PA.

Aged↗
PubMed1993

The effect of different exercise intensities on the fibrinolytic system.

The effects of moderate 30-min cycle ergometer exercise (aerobic metabolism) followed by short-term exercise at maximal capacity (anaerobic metabolism) on fibrinolytic activity were investigated in ten female and ten male healthy, untrained subjects. The following parameters of fibrinolytic activity were measured initially (t0), at the end of the aerobic phase (t1), at the end of the anaerobic phase (t2) and after a 30-min recovery period (t3): tissue plasminogen activator (PAt) activity, PAt concentration, plasminogen activator (PAt) activity, PAt concentration, plasminogen activator inhibitor (PAi) activity, and D-Dimer concentration. Moderate long-term exercise caused a slight but significant increase in PAt concentration and PAt activity (t1; P < 0.01), whereas short-term exercise at maximal capacity (t2) produced a substantial elevation in both these parameters (P < 0.01). This would suggest that PAt was not inhibited totally by PAi which would itself seem to be consumed during exercise. In addition, a slight exercise intensity-dependent increase in D-Dimer concentration was measured--circumstancial evidence not only for elevated fibrinolytic potential, but also for an actual increase in fibrin degradation (t2: P < 0.01). After t3 both PAt activity and D-Dimer concentration were still slightly but significantly increased. The results obtained in the tests of fibrinolytic activity showed no significant difference between the men and the women. It would seem that the release of PAt is more markedly stimulated by short-term intense physical exercise than by long-term moderate exercise and actually causes increased fibrin degradation.

Adult↗
PubMed1994

Impaired fibrinolysis in the hemolytic-uremic syndrome of childhood.

Thrombotic obstruction of glomerular capillaries causes acute renal failure in patients with hemolytic-uremic syndrome (HUS). Recanalization of occluded vessels normally occurs by activation of the endogenous fibrinolytic system, mediated by plasminogen activators, which are stored and synthesized in the endothelial cells. However, endothelial injury is considered the primary event in the pathogenesis of HUS, and this may result in impaired fibrinolysis. In five children with HUS we performed a prospective study of plasminogen activator activity and two plasminogen activator antigens: tissue-type plasminogen activator and urokinase-type plasminogen activator before and after intravenous desmopressin. Plasminogen activator inhibitor type-1 antigen was also studied. In the acute stage of HUS plasminogen activating activity was low, in spite of elevated levels of total plasminogen activator antigens. This decrease of plasminogen activating activity was due to high levels of the plasminogen activator inhibitor. Improvement of fibrinolysis paralleled recovery from HUS. We conclude that decreased fibrinolysis is an important pathophysiologic feature of HUS.

Adolescent↗
PubMed1988

[Persistent changes in tissue-type plasminogen activator and plasminogen activator inhibitor fibrinolytic parameters in patients following juvenile ischemic cerebral infarct].

In diseases associated with thrombotic or thromboembolic complications, a reduction in the fibrinolytic potential may contribute to the risk to develop thrombosis. To investigate whether juvenile cerebral infarction is associated with a permanent defect of the fibrinolytic system we measured the main components of the fibrinolytic system, tissue plasminogen activator (t-PA) and its fast acting inhibitor (PAI) in plasma samples of 21 patients (aged 21-44 years) 3-24 months after the acute event. The data obtained were compared to those from thirteen healthy young volunteers (22-46 years). A direct effect of known risk factors on the fibrinolytic system could be excluded because patients avoided their risk factors immediately after the ischemic cerebral attack. Hypertension and the combination of oral contraceptives and smoking had been the most striking original risk factors. Levels of t-PA antigen and t-PA activity before and after venous occlusion, or PAI activity were not different between patients and controls suggesting that at least a permanent decrease in the activity of the fibrinolytic system does not exist in these patients. However, our findings do not exclude that a temporary defect in fibrinolysis might have contributed to the acute onset of the thrombotic cerebral event possibly induced by the risk factors originally present.

Adult↗
PubMed1997

The concentration of u-PA and PAI-1 antigen in tissue extracts of nasopharyngeal carcinoma.

We measured the antigen levels of urokinase-type plasminogen activator (u-PA) and plasminogen activator inhibitor-1 (PAI-1) in tissue extracts from nasopharyngeal carcinomas. An increase in u-PA antigen was observed with the advanced stages of disease. However, the levels of PAI-1 antigen decreased with each advanced stage. These results suggest that local administration of antiplasminic agents may be effective in suppressing tumor invasion.

Adult↗
PubMed1991

Leukocyte elastase inhibition and t-PA-induced coronary artery thrombolysis in dogs: beneficial effects on myocardial histology.

Leukocyte-derived elastase is released following coronary artery occlusion and reperfusion and may contribute to reperfusion-related myocardial injury. Leukocyte infiltration into the reperfused myocardium may also contribute to ischemic injury following reflow. In the present study, we examined the effects of tissue-plasminogen activator (t-PA, 1 mg/kg over 20 minutes) given intravenously with either saline or a leukocyte elastase inhibitor (ICI 200,880, 5 mg/kg) in dogs with electrically-induced coronary artery thrombosis. ICI 200,880 administration increased elastase inhibitory activity without affecting t-PA and plasminogen activator inhibitor (PAI-1) activities. Time to reflow, magnitude of peak coronary blood flow, and duration of reflow were not different in dogs given t-PA with saline or with the elastase inhibitor. However, administration of the elastase inhibitor decreased the histologically-determined leukocyte infiltration and severity of myocardial injury in dogs subjected to coronary artery thrombosis and subsequent thrombolysis. These early observations suggest that elastase release during reperfusion may be an important mediator of anoxia-reoxygenation-mediated tissue injury.

Animals↗
PubMed1992

Circadian fluctuations of tissue plasminogen activator antigen and plasminogen activator inhibitor-1 antigens in vasospastic angina.

To elucidate the circadian variation of fibrinolytic components in vasospastic angina, plasma levels of tissue plasminogen activator antigen (t-PA), free plasminogen activator inhibitor antigen (free PAI-1), t-PA/PAI-1 complex, and total PAI-1 were measured in venous plasma samples. Samples were taken every 6 hours (6:00 AM, noon, 6:00 PM, and midnight) for 24 hours in 14 patients with vasospastic angina, in 9 patients with exertional angina, and in 19 normal subjects. Twenty-four-hour Holter monitoring (Holter monitor, Del Mar Avionics, Irvine, Calif.) was also carried out in all subjects. All of the fibrinolytic components showed circadian variation, with a peak level at 6:00 AM in every study group except for the t-PA/PAI-1 complex in the group of patients with exertional angina. The values for all or the fibrinolytic components at each sampling time were higher in patients with coronary artery disease than in normal subjects. In particular, the mean value of free PAI-1 at 6:00 AM in patients with vasospastic angina was significantly higher than that in normal subjects and that in patients with exertional angina. This value of free PAI-1 in patients with vasospastic angina was closely associated with the duration of ischemic attacks. These results suggested that the circadian fluctuation of fibrinolytic components may be an important factor that leads to coronary thrombosis at the time of coronary spasm, especially in the early morning.

Acetylcholine↗