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PubMed1995

Acute dynamic exercise increases fibrinolytic activity.

The influence of acute bouts of dynamic exercise on plasma tissue plasminogen activator (tPA), plasminogen activator inhibitor (PAI) and fibrinogen was investigated on nine healthy non-smoking men aged 23 to 37 years. Subjects performed maximal and two submaximal (duration 30 min, intensity 50% [aerobic threshold] and 78% [anaerobic threshold]VO2max) bicycle ergospirometry tests separated by seven days. The order of the submaximal tests was randomized. Blood samples were drawn before, immediately after and 24 h after each test. Plasma tPA and PAI activities were measured amidolytically, and fibrinogen concentration by thrombin method. All postexercise values were corrected for the change in plasma volume. The pre-exercise tPA and PAI activities and fibrinogen concentration were similar in each tests. tPA activity increased during each test (from 2.0 [SEM 0.24] IU/ml to 20.3 [3.14] during maximal, 2.0 [0.22] to 19.0 [2.59] during anaerobic threshold test, 1.8 [0.22] to 5.5 [0.82] during aerobic threshold; p < 0.001 during all tests, p = 0.01 aerobic threshold vs maximal and anaerobic threshold). PAI activity decreased during maximal (from 6.6 [2.51] AU/ml to 2.0 [2.00], p < 0.05) and anaerobic threshold (5.0 [2.07] to 0.2 [0.22], p < 0.01) tests but not during aerobic threshold test (7.0 [3.69] to 4.5 [2.93], p = 0.123). One subject had clearly higher pre-exercise PAI activity and smaller tPA response to exercise as compared to other subjects. All 24 h post-exercise activities were similar to pre-exercise values. Plasma fibrinogen concentration did not change during any tests.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

[Effects of guan-mai-shu on tissue-type plasminogen activator and plasminogen activator inhibitor in the plasma of patients with coronary heart disease].

Effects of Guan-Mai-Shu (GMS), a traditional Chinese medicine preparation, on tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI) in the plasma of patients with coronary heart disease were studied. It was found that those patients had a significant decrease in t-PA activity (P < 0.05) and a significant increase in PAI activity (P < 0.01) compared to healthy subjects. After treatment of GMS, t-PA activity significantly increased (P < 0.001), while PAI activity decreased (P < 0.001). These results indicated that GMS could raise t-PA activity and reduce PAI activity in the plasma of patients with coronary heart disease.

Adult↗
PubMed1993

[Effect of qigong on plasma coagulation fibrinolysis indices of hypertensive patients with blood stasis].

The levels of plasma tissue-type plasminogen activator (tPA), plasminogen activator inhibitor (PAI), VIII factor related antigen (VIIIR:Ag) and anti-thrombin (AT-III) were determined in 40 hypertensive patients with Blood Stasis. The results indicated that the function of coagulation-fibrinolytic system was disturbed. After one year of practising Qigong, plasma PAI and VIII R:Ag levels were decreased, while plasma tPA and AT-III levels increased. It suggested that Qigong could improve the function of coagulation-fibrinolytic system.

Aged↗
PubMed1993

Retinoids increase urokinase-type plasminogen activator production by human retinal pigment epithelial cells in culture.

PURPOSE: To examine the effect of two retinoids, all-trans-retinoic acid (tretinoin) and all-trans-9-(4-methoxy-2,3,6- trimethylphenyl)-3,7-dimethyl- 2,4,6,8-nonatetraenoic acid (acitretin) on the production of plasminogen activators and plasminogen activator inhibitors by human retinal pigment epithelial cells in culture. METHODS: Cultures of human retinal pigment epithelial cells were incubated with either of the retinoids at a concentration of 1 microM for 24-72 hours. The media were assayed using solid-phase immunocapture assays and zymography. RESULTS: Both retinoids caused a twofold to sevenfold increase in urokinase-type plasminogen activator in the medium. The effect was seen after 24 hours in culture and was further augmented up to 72 hours. No significant amounts of tissue-type plasminogen activator were detected. The plasminogen activator inhibitor activity was unaffected by the retinoids. Proliferation and morphology of retinal pigment epithelial cells were also unaffected by the retinoids in incubations for up to 72 hours. CONCLUSIONS: Retinoids profoundly affect the extracellular proteolysis of retinal pigment epithelial cells in culture. This effect may be related to the differentiation-inducing activity of retinoids seen in other cell types, often connected with changes in extracellular proteolysis. It is possible that retinoids may modulate dedifferentiation, proliferation, and migration of retinal pigment epithelial cells seen in vitro, as well as in the pathogenesis of retinal disease.

Acitretin↗
PubMed1993

Fibrinolytic and hemostatic parameter response after resistance exercise.

These experiments were designed to study the effect of resistance exercise on parameters pertinent to the hemostatic and fibrinolytic systems. Seven normal healthy subjects (6 male, 1 female, 25 +/- 3 yr mean SD) were studied under three conditions: control (C) [no exercise], high volume resistance exercise (HVRE), and low volume resistance exercise (LVRE), which were randomized for each subject, with 7 d separating tests. Both HVRE and LVRE trials encompassed the performance of five sets of nine exercises. After establishing one repetition maximum (1 RM), the HVRE involved the performance of moderate resistance, higher repetition, and shorter resting periods, whereas LVRE involved the use of high resistance, lower repetition, and longer resting intervals. Heart rate (HR) was monitored at rest and continuously during trials and venous blood was removed with minimum stasis, before and immediately after HVRE, LVRE, and before and after 38 min of supine rest (C). The blood was enzymatically analyzed for lactic acid (LA) and assayed using chromogenic substrates for the determination of tissue plasminogen activator (t-PA), plasminogen activator inhibitor (PAI), and Factor VIII (FVIII) activities. Global fibrinolysis (GF) was also screened in the fibrin plate and hematocrit ratios were employed to calculate percent plasma volume changes. Values were corrected for changes in plasma volume then data were analyzed using repeated measures ANOVA. There were no significant (P > 0.05) changes in the parameters measured in the resting condition over the three testing occasions and no significant differences (P > 0.05) were observed during the control experiment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

[An analysis on the activity status of fibrinolytic system in Chinese patients with acute cerebral infarction].

The fibrinolytic activity status of the patients with cerebral infarction can affect their clinical prognosis. In this case-controlled study, the plasma fibrinolytic system activities in 30 cases of cortical artery territory cerebral infarction (CACI) and 32 cases of perforating artery territory cerebral infarction (PACI) with a disease duration less than 3 days were assayed with a comprehensive panel including the plasma tPA activity, PAI activity, tPA releasing capacity from vascular endothelium and PAI/tPA ratio values. 30 subjects without cardiovascular and cerebrovascular disorders were served as control. The results showed that the plasma fibrinolytic system activities of the patients with aforementioned two subtypes of cerebral infarction were significantly lower than those of the controls, the results provide a theoretical basis for carrying out thrombolytic therapy in patients with ischemic stroke and suggest that recurrent cerebral infarction might be related to the high activity of plasma PAI.

Adult↗
PubMed1996

[The indices of the fibrinolysis, blood coagulation and lipid transport systems in hypertension patients].

Lipid spectrum, basal insulin concentration, the activity of coagulation factor VII and inhibitor of plasminogen tissue activator, content of plasminogen tissue activator antigen were assessed in 54 hypertensive patients with left ventricular hypertrophy (mean age 48.9 +/- 0.9 years, mean duration of the disease 15.7 +/- 1.1 years) after discontinuation of hypotensive therapy. A correlation was found between a rise in thrombogenic, atherogenic and a fall in fibrinolytic potential of blood. These findings suggest an essential role of insulin in regulation of thrombogenesis and fibrinolysis in hypertensive patients.

Biological Transport↗
PubMed1996

[Tissue plasminogen activator (t-PA) in aqueous humor of patients with cataract].

PURPOSE: The purpose of the examination was evaluation of tissue plasminogen activator (t-PA) concentration and plasminogen activator inhibitor (PAI) activity in aqueous humor of the eye and plasma of blood in patients operated on cataract. MATERIAL AND METHODS: In aqueous humor and citrate plasma of 24 patients undergoing cataract surgery the concentration of t-PA (Imulyse Biopool) and the activity of PAI-1 (Spectrolyse Biopool) were determined. RESULTS: In aqueous humor of 90% patients the concentration of t-PA-Ag in mean value 1.5 +/- 2.7 ng/ml was ca 20% of the level present in plasma. In aqueous humor of nearly all patients no PAI-1 activity could be detected. In a little group of persons because of small amounts of aqueous humor, other fibrinolytic parameters were also estimated and the presence of urokinase-type plasminogen activator (u-PA), alfa-2 antiplasmin (alfa-2AP) and plasmin-alfa-2 antiplasmin (PAP) complexes but no activity of protein C were observed. CONCLUSION: The presence of PAP complexes in aqueous humor indicates on intensive plasminogenesis in vivo. Our examinations confirm the role of fibrinolytic process in physiological and pathological processes occurring in the eye.

Aged↗
PubMedDate not supplied

Effect of nonionic and ionic contrast media on fibrinolysis in patients undergoing angiography.

Radiologic contrast media may influence processes of hemostasis resulting in increased thrombotic or bleeding tendency. A number of clinical case reports suggest that the use of nonionic contrast media is associated with thrombotic complications. In vitro studies have indicated that nonionic contrast media may induce generation of thrombin in blood whereas ionic contrast agents do not show such an effect. Not much is known about the effects of contrast media on the coagulation and fibrinolytic systems in vivo. The aim of this study was to evaluate the systemic effects of markers for activation of fibrinolysis with a nonionic contrast medium (Iopromid/Ultravist-300/Schering AG) and ionic contrast medium (Uropolinum, Polfa) in 82 patients undergoing angiography. We measured tissue plasminogen activator (t-PA) and tissue plasminogen activator inhibitor (PAI), using COA-SET, t-PA and COA-TEST PAI (Chromogenix). Fibrinogen concentration and euglobulin lysis time (ELT) were also estimated. Both contrast agents caused a significant decrease in fibrinogen concentrations. A marked difference was seen for PAI activity. A statistically significant increase was seen in the Iopromid group and no statistically significant rise was seen in the Uropolinum group. t-PA activity remained virtually unchanged in both groups. ELT has been significantly prolonged in patients who received Iopromid but not in those who received Uropolinum. It is likely that nonionic contrast medium could release PAI from platelets and endothelial cells. The changes in fibrinolysis may result from endothelial cell dysfunction.

Contrast Media↗
PubMed1997

[Plasminogen tissue activator and plasminogen tissue inhibitor in type II diabetes].

The aim of study was the evaluation of tissue plasminogen activator (t-PA) and its inhibitor (PAI-1) in the II type diabetes on the base of the common fibrinolytic system tests as euglobulin lysis time (ELT) and the concentration of fibrin/fibrinogen products (FDP). The studies were performed in 21 outpatients suffering of II type diabetes aged 38-65 (median 56.0) years treated with diet and sulphonylcarbamide derivates. The control group contained 18 healthy persons aged 33-65 (median 42.0) years. In the blood the following determinations were performed: antigen of t-PA and PAI-1, ELT and FDP. In the blood of patients with II type diabetes increased. t-PA Ag and PAI-1 Ag concentrations were observed.

Adult↗
PubMed1996

[Tissue plasminogen activator and plasminogen activator inhibitor in aqueous humor].

BACKGROUND: In the anterior segment of the eye, fibrin clots must be rapidly resorbed to prevent fibrosis. Tissue-type plasminogen activator (t-PA), a serine protease that catalyzes the conversion from plasminogen to plasmin, plays an important role in the fibrinolytic system and has therefore in recent years attracted attention in the field of ophthalmology. MATERIAL AND METHODS: The aqueous humor of patients undergoing cataract surgery was analyzed for the presence of components of the fibrinolytic cascade. The quantities of t-PA and plasminogen-activator inhibitor (PAI) were determined using enzyme-linked immunosorbent assays. We determined t-PA and PAI in the aqueous humor of 64 patients between 59 and 82 years of age. RESULTS: The t-PA levels ranged from 0.65 to 1.75 ng/ml and PAI activity from 3.24 to 5.1 AU/ml. Association between t-PA levels and PAI activity and accompanying diseases or metabolic disorders was noted. The highest concentration of t-PA and the lowest activity of PAI has been observed in aqueous humor of patients with senile cataract. The knowledge about the presence of t-PA in aqueous humor is significant for the recognition of pathological events following intraocular fibrin formation and may be an important basis for therapeutic use of t-PA.

Aged↗
PubMed1998

Effect on plasma lipids and lipoproteins of replacing partially hydrogenated fish oil with vegetable fat in margarine.

We have compared the effects on lipoproteins and haemostatic variables of two hard margarines with similar functional properties, one traditional margarine containing partially hydrogenated fish oil (PHFO), and one experimental margarine based on vegetable oil (VO). Both were all-purpose cooking margarines with nearly identical functional properties. Trans fatty acids from PHFO in the traditional margarine were replaced mostly by saturated, monounsaturated and trans fatty acids of vegetable origin in the new formulation. Both test margarines contained approximately the same amount of cis polyunsaturated fatty acids. Sixteen female normolipidaemic students consumed each diet with the two test margarines for 14 d in random order (crossover design). The amount of fat was 31% energy in the PHFO diet and 32% energy in the VO diet. The test margarines provided approximately 26% energy in both diets. In the PHFO diet 7.8% of the energy was derived from trans fatty acids and 9.2% from saturated fatty acids (12:0, 14:0 and 16:0) while in the VO diet, 1.1% energy was derived from trans fatty acids and 13.3% from saturated fatty acids (12:0, 14:0 and 16:0). The natural content of cholesterol in PHFO was deliberately not balanced by addition of cholesterol to the VO diet, thus the PHFO diet contained 215 mg and the VO diet 86 mg cholesterol per 8.5 MJ. LDL-cholesterol concentration was 19% higher in subjects on the PHFO diet compared with the VO diet (P < 0.01). The ratio LDL-cholesterol:HDL-cholesterol was 12.6% higher in subjects on the PHFO diet compared with the VO diet (P < 0.01). The level of apolipoprotein (apo)A-I was 6% lower in subjects on the PHFO diet compared with the VO diet (P < 0.01). The ratio apoB:apoA-I was 10.4% higher in subjects on the PHFO diet than on the VO diet (P < 0.01). There were no significant differences in total cholesterol, HDL-cholesterol, triacylglycerols, apoB, lipoprotein(a) and haemostatic variables between the diets. Our results demonstrate that PHFO, with its unfavourable effects on plasma lipids, can be replaced by vegetable oils in margarine without appreciable loss of functional properties but with significant improvement in the effects on plasma lipoproteins.

Adult↗
PubMed1995

Visualization of thrombi in pulmonary arteries with radiolabeled, enzymatically inactivated tissue-type plasminogen activator.

BACKGROUND: Despite the high frequency of pulmonary thromboembolism and its significant morbidity and mortality, diagnosis remains suboptimal. We have been developing a method for prompt detection with the use of radiolabeled, inactivated tissue-type plasminogen activator (TPA) and performed the present study to determine whether its use permits rapid scintigraphic visualization of pulmonary thrombi in vivo. METHODS AND RESULTS: The thrombolytic, but not fibrin-binding, property of TPA was inactivated with a tripeptide chloromethyl ketone (YPACK) that had already been iodinated with 123I to radiolabel the TPA. Pulmonary arterial thrombosis was induced in nine dogs with the use of guide wires modified to provide thrombogenic tips. 123I-YPACK-TPA (1.1 to 7.8 mCi, 0.5 to 7.8 mg) was infused for 5 minutes into either the systemic or the pulmonary circulation. Clearance of radioactivity from the blood was rapid and indistinguishable from that of unlabeled, thrombolytically active TPA, with only 6.7 +/- 1.0% (mean +/- SEM) of peak radioactivity remaining after 60 minutes and minimal release of labeled fragments from the liver during this interval. Thrombi were visualized with single photon emission computed tomography and/or planar imaging 40 to 120 minutes after infusion of tracer in all seven animals given at least 3.7 mCi of 123I-YPACK-TPA. Ratios of radioactivity in thrombus (wet mass, 610 +/- 64 mg) to blood were high (14 +/- 3:1). CONCLUSIONS: The use of radiolabeled TPA in which thrombolytic activity is inactivated permits prompt scintigraphic detection of thrombi in pulmonary arteries in vivo.

Amino Acid Chloromethyl Ketones↗
PubMed1986

Rapid inactivation of the plasminogen-activator inhibitor upon secretion from cultured human endothelial cells.

In conditioned medium (CM) from cultured human endothelial cells, two forms of plasminogen-activator inhibitor (PA-inhibitor) can be demonstrated: a fast-acting active form and an immunologically related, inactive form. Evidence is presented that endothelial cells produce active PA-inhibitor which is rapidly inactivated upon secretion into the medium. This inactivation can, at least partly, be prevented by culturing cells with excess of tissue-type plasminogen activator (t-PA). This results in the formation of large amounts of t-PA-PA-inhibitor complex at the cost of accumulation of inactive PA-inhibitor. No complex was detectable when inactive PA-inhibitor preparations were incubated with t-PA either in the absence or in the presence of cells. Furthermore, in cell extracts, predominantly functionally active PA-inhibitor was present. PA-inhibitor derived from the t-PA-PA-inhibitor complex showed an Mr approx. 4000 lower by polyacrylamide-gel electrophoresis than that of the inactive form. The rapid inactivation seems to be confined to newly synthesized molecules, since PA-inhibitor molecules in CM are inactivated much more slowly (even with cells or cell homogenates) than necessary to explain the excessive production of inactivated PA-inhibitor by cells. It could not be prevented by inhibitors of oxidative processes, like butylated hydroxytoluene, dithiothreitol, superoxide dismutase and catalase.

Cells, Cultured↗
PubMed1985

Minactivin expression in human monocyte and macrophage populations.

Adherent monolayer cultures of human blood monocytes, peritoneal macrophages, bone marrow macrophages, and colonic mucosa macrophages were examined for their ability to produce and secrete minactivin, a specific inactivator of urokinase-type plasminogen activator. All except colonic mucosa macrophages produced and secreted appreciable amounts of minactivin, but only blood monocytes were stimulated by muramyl dipeptide (adjuvant peptide) to increase production. The minactivin from each of these populations could be shown to preferentially inhibit urokinase-type plasminogen activator and not trypsin, plasmin, or "tissue"-type plasminogen activator (HPA66). A plasminogen-activating enzyme present in monocyte cultures appeared unaffected by the presence of minactivin and could be shown to be regulated independently by dexamethasone.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1991

Combinatorial mutagenesis of the reactive site region in plasminogen activator inhibitor I.

Plasminogen activator inhibitor (PAI-I) rapidly inactivates tissue plasminogen activator (t-PA) and urokinase (UK) with nearly identical association rate constants. The contributions of Ser344, Ala345, and Arg346 (P3, P2, and P1 residues, respectively) in PAI-I to inhibition of UK and t-PA were evaluated using combinatorial mutagenesis of the human PAI-I cDNA. A bacteriophage lambda expression library potentially encoding the 8000 unique PAI-I species were screened for inhibitory activity against UK using a fibrin indicator gel. 390 plaques demarcated by zones of retarded fibrinolysis were analyzed to determine the DNA sequences of their associated active PAI-1 species. We found 134 unique PAI-1 variants that retained inhibitory activity towards UK; they contained a variety of amino acids in their P3 and P2 positions but only Arg or, infrequently, Lys in their P1 position. Each of the unique active PAI-1 were assayed for inhibitory activity towards UK or t-PA; many substitutions differentially affected the ability of the inhibitor to inactivate UK and t-PA. For example, replacement of Ser344 and Ala344 with Val and Pro, respectively, yielded a PAI-1 variant exhibiting an association rate constant that was unchanged for t-PA but decreased 23-fold for UK, relative to native PAI-1. In general, the PAI-1 variants were more potent inhibitors of t-PA than UK. Hence, t-PA appears more tolerant than UK of structural diversity present in the P3 and P2 positions of the PAI-1 variants.

Amino Acid Sequence↗
PubMed1995

Effects of disruption of the plasminogen gene on thrombosis, growth, and health in mice.

BACKGROUND: Circumstantial evidence suggests that the plasminogen/plasmin system plays a role in many biological processes, including hemostasis, cell migration, and development. METHODS AND RESULTS: The in vivo function of the plasminogen/plasmin system was studied by generation of plasminogen-deficient (Plg-/-) mice. Inactivation of the murine plasminogen-gene (Plg) was achieved by replacing, via homologous recombination in embryonic stem cells, genomic sequences encoding the exons containing the catalytic site amino acids His605 and Asp648 with a neomycin phosphotransferase expression cassette. Germline transmission of the mutated allele, as determined by Southern blot hybridization and polymerase chain reaction, was obtained via blastocyst injection. Mendelian inheritance of the inactivated plasminogen allele was observed, and homozygous-deficient mice (Plg-/-) displayed normal viability but retarded growth up to at least 12 weeks of age. At 8 weeks of age, body weight was 21.8 +/- 1.2 g (n = 10) for wild-type (Plg+/+) mice, 21.0 +/- 1.1 g (n = 16) for heterozygous-deficient (Plg+/-) mice, and 17.4 +/- 1.3 g (n = 12) for Plg-/- mice; P < .05 versus Plg+/+ or Plg+/-. None of 36 Plg+/+ or 65 Plg+/- mice but 7 of 37 Plg-/- mice (19%) developed rectal prolapse at 7.4 +/- 0.6 weeks of age (P = .03 versus Plg+/+ and P = .003 versus Plg+/-); 4 of 37 Plg-/- mice (11%) became runted and apathic at 5.3 +/- 0.3 weeks of age (P = .041 versus Plg+/-); and 6 of 37 Plg-/- mice (16%) died prematurely at 8.8 +/- 1.7 weeks of age (P = .057 versus Plg+/+ and P = .029 versus Plg+/-). Although male and female Plg-/- mice were able to sire offspring, the fertility of Plg-/- female mice was reduced, possibly owing to their impaired health. Levels of plasminogen-related antigen in plasma, measured by ELISA, were 84 +/- 8 micrograms/mL (n = 4) in Plg+/+, 35 +/- 2 micrograms/mL (n = 3) in Plg+/-, and 0.076 +/- 0.032 microgram/mL (n = 6) in Plg-/- mice (P < .001 versus Plg+/- and Plg+/+). Plasmin activity generated by urokinase activation was unmeasurable in Plg-/- mice (< 5% of Plg+/+ mice). Plasminogen-specific immunoreactivity was observed in hepatocytes from Plg+/+ mice but not from Plg-/- mice (< 10% of Plg+/+ mice). Neither native nor variant plasminogen mRNA nor translation products could be identified by Northern or Western blot of liver extracts from Plg-/- mice. Spontaneous lysis within 24 hours of a 125I-fibrin-labeled pulmonary plasma clot was 85 +/- 5% (n = 5) in Plg+/+ mice, 62 +/- 7% (n = 3) in Plg+/- mice, and -2 +/- 1% (n = 3) in Plg-/- mice (P < .001 versus Plg+/- and Plg+/+). Delayed clot lysis within 72 hours was 33 +/- 1% (n = 3) in tPA-/- mice and 26 +/- 2% (n = 3) in Plg-/- mice (P = .054). Histological examination of several organs revealed fibrin deposition in the liver; lung; and in the stomach, associated with gastric ulcers, in 6- to 12-week-old Plg-/- mice but not in Plg+/+ or Plg+/- littermates. CONCLUSIONS: Plasminogen-deficient mice survive embryonic development but develop spontaneous fibrin deposition due to impaired thrombolysis and suffer retarded growth and reduced fertility and survival. The Plg-/- phenotype is reminiscent of the combined tPA-/-:uPA-/- phenotype, which suggests that there is no significant additional pathway for physiological plasminogen activation in mice.

Animals↗