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PubMed1987

The pathogenesis of accelerated fibrinolysis in liver cirrhosis: a critical role for tissue plasminogen activator inhibitor.

The pathogenesis of accelerated fibrinolysis in liver cirrhosis was investigated by comparing the results of specific assays for tissue plasminogen activator (tpa) antigen, tpa activity, tpa inhibitor, and alpha-2 plasmin inhibitor (a2PI) in 12 patients with cirrhosis and markedly accelerated fibrinolysis (dilute whole blood clot lysis time (DWBCLT) less than two hours), in nine patients with cirrhosis and moderately accelerated fibrinolysis (DWBCLT two to four hours), and in nine patients with cirrhosis and normal fibrinolysis (DWBCLT greater than four hours). Mean tpa antigen was markedly increased in all three groups, but no correlation was observed between overall fibrinolytic activity as measured by the DWBCLT and the level of tpa antigen. In contrast, there was a significant correlation between overall fibrinolytic activity and tpa activity and an equally significant correlation between fibrinolytic activity and decreased tpa inhibition. Mean a2PI activity was significantly lower than normal in groups 1 and 2 but was normal in group 3. The pathogenesis of accelerated fibrinolysis in liver cirrhosis thus appears to depend critically on the capacity of plasma inhibitors to inhibit increased circulating tpa antigen. Reduced a2PI also appears to play a role.

Antigens↗
PubMed1989

The inhibitory effect of aspirin on fibrinolysis is reversed by iloprost, a prostacyclin analogue.

The reduced fibrinolytic response after aspirin intake may be due to prevention of prostacyclin production. The effect of iloprost (a stable prostacyclin analogue) was tested on the fibrinolytic activity (euglobulin lysis area on fibrin plate [E.L.A.], t-PA antigen, PAI activity and PAI-1 antigen) of plasma drawn after venous stasis test from six healthy male volunteers, who each received all the following treatments according to a single-blind randomized cross-over design: placebo, iloprost, aspirin + placebo, aspirin + iloprost. The mean E.L.A. value after venous occlusion was significantly higher than the basal level after every treatment but aspirin. Within each treatment group the t-PA antigen levels in response to venous stasis were significantly higher than the basal ones. PAI-1 antigen levels did not change significantly before and after venous stasis either within or among the treatment groups. These data are consistent with the hypothesis that the mechanism related to aspirin's effect on fibrinolysis is mediated by suppression of vessel wall prostacyclin production. Aspirin's inhibitory effect on fibrinolysis was in fact prevented by replacing endogenous prostacyclin with iloprost. Iloprost enhances fibrinolytic activity reduced by aspirin, but not by promoting t-PA release or by inhibiting release of the specific inhibitor, PAI-1.

Adult↗
PubMed1989

A role of fibrinolytic activity in angiogenesis. Quantitative assay using in vitro method.

The functional role of the fibrinolytic system in capillary growth was investigated using bovine capillary endothelial cells (BCEs) cultured on a Type I collagen gel matrix, into which the cells migrated to form capillary-like tubular structures. The length of the tubes formed were measured morphometrically using an image analyzer in the absence and presence of fibrinolytic proteases, namely plasminogen, plasminogen activators (PAs) and PA inhibitor (PAI). The addition of plasminogen (25 micrograms/ml) to the gel matrix significantly increased the length of BCE tubes found on the 9th day of culture (p less than 0.01), with a dose-dependent tendency. The simultaneous addition of a basic fibroblast growth factor (bFGF, 10 ng/ml) enhanced this tube formation as early as the 3rd day of culture (p less than 0.01). Cultured BCEs secreted both tissue-type and urokinase-type PAs (tPA and uPA) and PAI-1 into the culture medium, and the secretion of both PAs was enhanced by the addition of bFGF. However, the secreted tPA was composed mostly of an inactive form of tPA.PAI-1 complex, and the PA activity was derived mostly from uPA. Inhibitors of plasmin suppressed the enhancing effect of plasminogen on angiogenesis. In addition, anti-uPA IgG markedly inhibited the enhancing effect of plasminogen on the 4th and 7th days of culture (p less than 0.01), whereas anti-tPA IgG showed an inhibitory tendency only on the 4th day of culture (p less than 0.05). These findings indicate that the plasminogen-PAs system, especially uPA synthesized and secreted by BCEs, plays an important role in regulating angiogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex↗
PubMed1989

Plasminogen activators and plasminogen activator inhibitors in liver deficiencies caused by chronic alcoholism or infectious hepatitis.

Plasma concentrations of tissue-type plasminogen activator (t-PA), urokinase (u-PA), plasminogen activator inhibitor 1 (PAI-1) and PAI-2 were studied in 53 patients with liver deficiency caused by chronic alcoholism (n = 40), viral hepatitis (n = 10) or malignant disease of the liver (n = 3) and compared to that of a control group (n = 20) of healthy subjects. u-PA and PAI-1 levels were significantly increased in all patients with chronic alcoholism, whereas high t-PA was only observed in combination with disturbed liver function tests or with liver cirrhosis (two and six-fold above control values, respectively). A good correlation was observed between t-PA and gamma glutamyl transferase (r = 0.615; p less than 0.001). In patients with infectious hepatitis or with malignant disease of the liver t-PA was normal whereas u-PA and PAI-1 were increased. PAI-2 levels were close to or below the detection limit (15 ng/ml) in the control group and in most patients. However, in two patients with alcohol induced cirrhosis PAI-2 levels were approximately 45 ng/ml and in one patient with hepatocarcinoma even 66 ng/ml. Thus, in liver disease, marked elevations of t-PA, u-PA and PAI-1 levels may occur, with increased PAI-1 as an early marker of liver defects and t-PA a marker of severe liver defects.

Female↗
PubMed1989

[Relation of an increase of von Willebrand factor in the blood, acute myocardial infarction, unstable angina and coronary thrombosis].

Forty six patients admitted for precordial chest pain were included in this study. The clinical, electrocardiographic, enzymatic and angiographic features allowed retrospective identification of 6 subgroups (nos 1 to 6): all transmural myocardial infarction (Q-MI) (Group 1), Q-MI without intracoronary thrombus (Group 2), Q-MI with intracoronary thrombus (Group 3), acute non-Q wave infarction (non Q-MI) (Group 4), unstable angina (Group 5) and atypical chest pain (Group 6). Several blood clotting factors were studied; von Willebrand factor (VWF), fibrinogen, tissue plasminogen activator (t-PA) and its inhibitor (PAI-1) and factor VII. There was no significant difference in the fibrinogen, t-PA, PAI-1 or factor VII levels between the 6 groups. On the other hand, the VWF was increased in the all transmural myocardial infarction (Q-MI) groups (n. 1). In Group 3 with visible intracoronary thrombus the VWF was high or very high in all patients, attaining three times the normal values. The values were lower in Group 5 (unstable angina) patients in whom no thrombus was observed on coronary angiography. The differences between Group 1 and Groups 4, 5 and 6 were statistically significant (p less than 0.05). The VWF was higher in the Q-MI group with intracoronary thrombus than in the group without thrombus, but the difference was not statistically different. In conclusion, the VWF may be considered to be a marker for thrombus and/or endothelial activation but a larger study population would be required to identify more accurately the subgroups with thrombosis or risk of thrombosis.

Adult↗
PubMed1989

Inhibition of tissue plasminogen activator activity by aspirin in vivo and its relationship to levels of tissue plasminogen activator inhibitor antigen, plasminogen activator and their complexes.

The observation that aspirin inhibits the increment in tissue plasminogen activator (t-PA) activity induced by venous occlusion of the forearm became controversial with the publication of several nonconfirmatory studies. The current study was performed to confirm the original observation and determine the mechanism by which aspirin suppresses the incremental t-PA activity induced by venous occlusion. Aspirin (650 mg/d X 2) caused no change in resting levels of t-PA antigen (t-PA:Ag) or activity, plasminogen activator inhibitor 1 antigen (PAI-1:Ag), or activity or t-PA-PAI-1 complexes. In contrast, aspirin reduced the increments induced by venous occlusion as follows: t-PA:Ag by 45% (P = .001); t-PA activity (euglobulin lysis time, ELT) by 43% (P = .006); and t-PA activity (alpha 2-plasmin inhibitor-plasmin complexes, PIPC) by 41% (P = .003). The inhibition of incremental t-PA activity measured as ELT or PIPC was linearly correlated with the inhibition of incremental t-PA:Ag (respectively, r = .75, P less than .02; r = .67, P less than .05). Aspirin had no effect on the increment in PAI-1:Ag induced by venous occlusion, but similar to the effect on t-PA:Ag, aspirin induced a 51% inhibition of the increment in t-PA-PAI-1 complex formation. Aspirin did not alter the ability of alpha 2-plasmin inhibitor to bind plasmin, nor the ability of plasma to support the fibrin-catalyzed generation of plasmin by t-PA, nor the subsequent formation of PIPC. Aspirin inhibits the t-PA activity induced by venous occlusion primarily by inhibiting the release of t-PA antigen.

Antifibrinolytic Agents↗
PubMed1986

Advances in clinical fibrinolysis.

The discovery of a fast-acting plasminogen activator inhibitor has resulted in the notion that the balance between tissue-type plasminogen activator and its inhibitor determines the net fibrinolytic activity of blood. The inhibitor shows a rapidly fluctuating acute-phase pattern, which may be important in relation to thrombosis in acute disease. Other newly discovered modulators of the fibrinolytic system include histidine-rich glycoprotein, tetranectin and thrombospondin. The role of fibrin as a cofactor in its own dissolution is further elucidated with emphasis on local aspects. Therapeutic inhibition of overactive fibrinolysis by various drugs needs careful monitoring. Prophylactic stimulation of fibrinolysis is possible, e.g. by stanozolol or other drugs that lower inhibitor levels, but its proven value is as yet limited. Results of clinical trials with activators of the fibrinolytic system as thrombolytic agents are discussed in relation to the physiology of the fibrinolytic system.

Coronary Disease↗
PubMed1986

The fast-acting inhibitor of tissue-type plasminogen activator in plasma is also the primary plasma inhibitor of urokinase.

We have compared the ability of a plasminogen activator inhibitor (PA-inhibitor) in human plasma, to form complexes with radioiodinated tissue-type plasminogen activator (t-PA) and high molecular weight urokinase (HMr-UK). Addition of 125I-t-PA (final concentration 10 IU/ml) or of 125I-HMr-UK (2 IU/ml) to a plasma containing 33 U/ml of PA-inhibitor resulted in the rapid formation of a 110,000 Mr complex of 125I-t-PA or a 95,000 Mr complex of 125I-HMr-UK with PA-inhibitor. Upon prolonged incubation of the plasma with 125I-HMr-UK a secondary complex of a Mr of 88,000 was observed, which probably derives from limited degradation of the 95,000 complex. Preincubation of the plasma with unlabelled t-PA, HMr-UK or LMr-UK at higher concentrations prevented the subsequent formation of complexes between radiolabelled PAs and the PA-inhibitor. These results thus demonstrate that t-PA and UK form complexes with the same PA-inhibitor. The rate of complex formation of 125I-t-PA or of 125I-HMr-UK with the plasma PA-inhibitor was similar (second order rate constant of association with PA-inhibitor in the order of 10(7) M-1s-1).

Glycoproteins↗
PubMed1986

A sensitive assay, specific for endothelial cell type plasminogen activator inhibitor in blood plasma.

A polyclonal antibody raised against plasminogen activator (PA-)inhibitor from endothelial cells fully precipitates the PA-inhibitor in endothelial cell conditioned medium but only a part of the PA-inhibitory activity in blood plasma. This indicates that the PA-inhibitory activity in blood plasma is not due to a single inhibitory component. Performing the assay for PA-inhibitory activity in plasma both in the presence and absence of saturating concentrations of anti-endothelial cell PA-inhibitor antibodies, allows the determination of endothelial cell type PA-inhibitor in plasma. The assay gives a linear dose-response curve of amount of plasma added versus t-PA neutralised. Values for endothelial cell type PA-inhibitor in plasma of a group of 20 healthy individuals are in the range of 0.0-16.8 IU/ml and are not normally distributed (median value 3.0 IU/ml). This method also reveals a second, so far unidentified, PA-inhibitory component in human plasma.

Blood Vessels↗
PubMed1986

Inhibition of tissue-type plasminogen activator in plasma of women using oral contraceptives and in normal women during a menstrual cycle.

Tissue-type plasminogen activator (t-PA) inhibition in plasma was assessed in 15 normal women and in 10 women using oral contraceptives (OC) containing 30 micrograms ethinyl oestradiol and 150 micrograms levo-norgestrel. The levels of t-PA inhibition were significantly lower in the OC group with marked fluctuations related to the hormone cycle. Normal women had only minor fluctuations.

Adult↗
PubMed1987

Evaluation of fibrinolytic capacity by a combined assay system for tissue-type plasminogen activator antigen and function using monoclonal anti-tissue-type plasminogen activator antibodies.

An assay system has been developed that allows consecutive quantification of tissue-type plasminogen activator (t-PA) activity and t-PA antigen in the same plasma sample. In the first step t-PA is bound to an immobilized IgM monoclonal anti-t-PA antibody and functional activity of bound t-PA is quantified by its plasminogen-activating activity. In the second step the amount of bound t-PA antigen is determined by using a different peroxidase-labeled monoclonal anti-t-PA antibody. In this combined assay system t-PA functional activity was found to depend not only on the amount of t-PA antigen but also on the amount of plasminogen activator inhibitor (PAI), whereas in the t-PA antigen assay PAI did not affect the results. In plasma samples obtained from normal controls t-PA activity was detected only in post-venous occlusion plasma (3.7 +/- 2.5 IU/ml), whereas 2.7 +/- 0.5 ng/ml t-PA antigen was found before and 12.6 +/- 4.4 ng/ml after venous occlusion. Using this combined assay system to study plasma samples from patients who did not respond to venous occlusion with shortening of the euglobulin clot lysis time (ECLT), it was possible not only to confirm that in none of these patients could t-PA activity be detected in the postocclusion plasma samples but also to subdivide that group of patients into a group of about 39% not reacting with normal t-PA antigen release to venous occlusion and into a second group of about 61% that reacted with normal t-PA antigen release.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Increased plasminogen activator inhibition levels in malignancy.

Plasminogen activator(PA)-tissue and urokinase type-and PA-inhibition in plasma were investigated in 52 consecutive cancer patients with a variety of tumors. At first patients were analyzed as one group. Secondly patients were subdivided into two groups, one with (n = 42) and one without (n = 10) metastasis. Our results show that tissue-type-PA antigen (t-PA-antigen) and PA-inhibition were both significantly increased irrespective of the presence or absence of tumor metastasis (p less than 0.001 compared to age matched healthy controls. In the group without metastasis a significantly decreased level of t-PA activity was found (p less than 0.001) but in the group with metastasis t-PA activity was normal. These data seem to reject the hypothesis that decreased plasma fibrinolytic activity is one of the prerequisites for tumor metastasis.

Antigens↗
PubMed1987

Transforming growth factor-beta induction of type-1 plasminogen activator inhibitor. Pericellular deposition and sensitivity to exogenous urokinase.

The human tumor cell line HT-1080 was used as a model system to study the effects of transforming growth factor-beta (TGF beta) on polypeptide synthesis and proteolytic activity of malignant cells. Confluent cultures were exposed to TGF beta under serum-free conditions, and alterations in the production of proteins were examined by metabolic labeling and polypeptide analysis. TGF beta induced the synthesis and secretion of the Mr 47,000 endothelial type plasminogen activator inhibitor (PAI-1) as shown by reverse zymography, immunblotting, and immunoprecipitation analyses. TGF beta-induced PAI-1 was rapidly deposited in the growth substratum of the cells as shown by metabolic labeling and extraction of the cultures with sodium deoxycholate. Using pulse-chase experiments, we found a relatively fast turnover of substratum-associated PAI-1. Exogenously added urokinase released PAI-1 from the substratum even in the presence of the plasmin inhibitor aprotinin, suggesting a direct effect of urokinase. Immunoreactive complexes of higher molecular weight were subsequently detected in the medium. Epidermal growth factor, transforming growth factor-alpha, platelet-derived growth factor, and insulin did not elicit similar effects on the amount of PAI-1. TGF beta also inhibited the anchorage-independent growth of HT-1080 cells at the same concentrations at which it induced PAI-1. These results indicate that TGF beta can modulate the extracellular proteolytic activity of cultured cells by enhancing the secretion and deposition of PAI-1 into their microenvironment. It remains to be established whether TGF beta inhibition of anchorage-independent growth of these cells is associated with the induction of PAI-1.

Animals↗