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Query: EC:3.4.21.68 (tissue plasminogen activator)
 11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Immunogenic properties of second generation human tissue plasminogen activator (tPA) derivatives were examined in chimpanzee and mouse systems. Five species of modified tPAs (mtPAs) (designated 2660, 2663, 2810, 8000, and 9200), recombinant native tPA or bovine serum albumin (BSA) as a positive control were subcutaneously injected nine times at suitable intervals into chimpanzees, genetically the closest species to man. These animals were tested for antigen(Ag)-specific antibodies to the corresponding proteins by means of enzyme-linked immunosorbent assay and Western blot analysis. Neither 9200, one of the five mtPAs tested, nor tPA was immunogenic, although BSA and the other four mtPAs were immunogenic under these conditions. Thus, an antigenic determinant was not exposed by the modification on 9200 and this modified tPA is expected not to be immunogenic in humans. In the mouse studies, mice were immunized with mtPAs. Serum samples from these animals were tested for antibodies to the mtPAs which did not concomitantly recognize native tPA by immune adsorption of the antibodies to tPA. The amount of such antibodies after the elimination of native tPA-reactive antibodies was little or none when the serum samples from 9200 and from the other mtPAs, except 8000, were tested. Taking into consideration the results of the chimpanzee studies, it can be concluded that Ag-specific antibodies are dominantly produced to unchanged epitopes present in modified proteins in the mouse system, in which the native protein is immunogenic.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Immunogenic properties of structurally modified human tissue plasminogen activators in chimpanzees and mice. 142 14

The type of plasminogen activator (PA) secreted by bovine embryos was identified. Day 12-14 embryos were collected from estrus-synchronized, superovulated, and naturally mated crossbred beef cows. Embryos were left intact (E) or microdissected into component embryonic discs (ED) and trophoblastic vesicles (TV). Intact embryos, ED, and TV were pre-cultured for 2 days in Minimum Essential Medium Alpha (MEM alpha) with 10% heat-inactivated fetal calf serum, washed in serum-free MEM alpha, and cultured individually for 5 days in 50 microliters microdrops of MEM alpha with 15 mg/ml bovine serum albumin. At 24 hr intervals, E, ED, and TV were observed for tissue morphology and transferred to fresh microdrops, and medium was recovered and frozen at -20 degrees C. At the end of culture, blastocoelic fluid (BF) and embryonic tissues were recovered and frozen at -20 degrees C. Plasminogen activator concentrations in medium, tissues, and BF were determined by using a caseinolytic assay. Antibodies to urokinase-type PA (anti-uPA) and tissue-type PA (anti-tPA), and the urokinase inhibitor, amiloride (AMR), were used to identify the type of PA produced by bovine embryonic tissues. Intact embryos and TV released more PA (P less than 0.05) than ED, and tissues exhibiting expanded blastocoels released less PA (P less than 0.05) than tissues with collapsed blastocoels. Blastocoelic fluid from TV exhibited more PA (P less than 0.05) activity than from ED. Treatment with anti-uPA decreased PA activity (P less than 0.05) in pooled medium and tissues from E compared to treatment with nonspecific immunoglobulins and anti-tPA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Bovine embryos produce a urokinase-type plasminogen activator. 156 22

Twenty-five patients with different stages of liver cirrhosis were evaluated with regard to the degree of liver synthesis reduction, the extent of the decrease of blood coagulation factors and/or alterations of the fibrinolytic system. For the assessment of the residual level of liver synthesis we used pseudo-cholinesterase and serum albumin as references. We did not find a correlation between these quantities and antithrombin III or fibrinogen, but highly significant inverse correlations with tissue plasminogen activator activity and D-dimer concentration. We found considerable alterations in the concentrations of the coagulation and fibrinolysis factors, with the exception of fibrinogen and plasminogen activator inhibitor. Significant increases were seen for thrombin-antithrombin III complex, tissue plasminogen activator activity and D-dimer, while significant decreases were seen for antithrombin III and alpha 2-antiplasmin, compared with a group of healthy volunteers. In the group of patients with liver cirrhosis and reduced liver synthesis, as documented by lowered pseudo-cholinesterase and serum albumin, the reduction of both antithrombin III and alpha 2-antiplasmin was most prominent. Intravascular coagulation was negligibly small. For the fibrinolytic system, the increase of tissue plasminogen activator, the decrease of the fibrinolysis inhibitor (alpha 2-antiplasmin) and the elevated D-dimer concentration seem to be important. These results suggest an acceleration of fibrinolysis and the prolonged presence of cross-linked fibrin degradation products.
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PMID:The extent of diffuse intravascular coagulation and fibrinolysis in patients with liver cirrhosis. 162 24

To investigate the possibility that a hypercoagulable state develops during autologous bone marrow transplantation (BMT), we measured levels of circulating natural anticoagulants and fibrinolytic proteins before and weekly during the hospital course of 18 patients undergoing autologous BMT for Hodgkin's and non-Hodgkin's lymphoma. Patients received either weekly (standard dose group) or daily (high dose group) vitamin K supplements with their total parenteral nutrition. By day 14 there had been a significant drop in protein C activity (mean of 95% of normal to 52%), protein C antigen (mean of 105% of normal to 70%), and antithrombin 3 activity (111% of normal to 83%), and an increase in fibrinogen (471-621 mg/dl) and tissue plasminogen activator (6.9-13.8 ng/ml). No changes were seen in free or total protein S, plasminogen activator inhibitor, prothrombin time or partial thromboplastin time. The decreases in protein C and antithrombin 3 persisted through day 28 after transplantation. The drop in protein C correlated strongly with decrease in serum albumin, suggesting impaired synthesis of these proteins by the liver. No differences were seen in any of these parameters between the standard and high dose groups. Deficiencies in anticoagulant proteins antithrombin 3 and protein C and a rise in fibrinogen without a concomitant improvement in fibrinolytic variables create a potentially hypercoagulable state which may contribute to the thrombotic complications of autologous BMT.
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PMID:High frequency of antithrombin 3 and protein C deficiency following autologous bone marrow transplantation for lymphoma. 179 Apr 30

A new continuous flow electrophoretic separator for cells and macromolecules was built and tested in laboratory experiments and in the microgravity environment of space flight. Buffer flows upward in a 120-cm long flow chamber, which is 6 cm wide X 1.5 mm thick in the laboratory version and 16 cm wide X 3.0 mm thick in the microgravity version. Electrophoretic subpopulations are collected in 197 fractions spanning 16 cm at the upper end of the chamber. The electrode buffer is recirculated through front and back cooling chambers, which are also electrode chambers. Ovalbumin and rat serum albumin were used as test proteins in resolution and throughout tests; resolution of these two proteins at 25% total w/v concentration in microgravity was the same as that found at 0.2% w/v concentration in the laboratory. Band spreading caused by Poiseuille flow and conductance gaps was evaluated using polystyrene microspheres in microgravity, and these phenomena were quantitatively the same in microgravity as in the laboratory. Rat anterior pituitary cells were separated into subpopulations enriched with cells that secrete specific hormones; growth-hormone-secreting cells were found to have high electrophoretic mobility, whereas prolactin-secreting cells were found to have low electrophoretic mobility. Cultured human embryonic kidney cells were separated into several electrophoretic subfractions that produced different plasminogen activators; a medium-high-mobility subpopulation and a medium-low-mobility subpopulation each produced a different molecular form of urokinase, whereas a high- and an intermediate-mobility subpopulation produced tissue plasminogen activator. Canine pancreatic islets of Langerhans cells were separated into subpopulations, which, after reaggregation into pseudoislets, were found to be enriched with cells that secrete specific hormones; insulin-secreting beta cells were found in lowest mobility fractions, whereas glucagon-secreting alpha cells were found in the highest mobility fractions. Results of particle electrophoresis experiments were comparable in microgravity and in the laboratory, since cell densities that overloaded the carrier buffer (resulting in zone sedimentation) were avoided, and a 500-fold increase in protein throughput was achieved without compromising resolution in microgravity.
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PMID:Continuous flow electrophoretic separation of proteins and cells from mammalian tissues. 244 May 79

In 10 patients with nephrotic syndrome (NS), the coagulation inhibitors, the fibrinolytic system and several functions of the fibrinogen-fibrin molecule were studied. Among the coagulation inhibitors, only antithrombin III (AT III) was found decreased and correlated with serum-albumin levels. Venous occlusion test provoked a normal tissue plasminogen activator (tPA) release in all patients. The plasminogen activator inhibitor (PAI) had an increased activity in 5 out of the 10 patients. Thrombin and reptilase times were found abnormal in most patients. The thrombin time (TT) prolongation correlated with serum albumin levels and was corrected by adding purified albumin. The fibrinogen was purified from each of the 10 patients' plasma. Only 2 of them showed abnormal polymerization in purified system, suggesting dysfibrinogenaemia. Other functions (thrombin binding, tPA stimulating activity, lysis by purified plasmin) were found normal except in one of the 2 patients with dysfibrinogenaemia whose fibrinogen lysis by plasmin was delayed. It is concluded that an abnormal fibrinogen molecule is not the most frequent explanation for thrombin time prolongation in NS.
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PMID:A study of fibrinogen and fibrinolysis in 10 adults with nephrotic syndrome. 314 81

Nephrotic syndrome is associated with numerous blood coagulation abnormalities and a marked propensity to thromboembolism. The present study was undertaken to examine the status of the fibrinolytic system in this hypercoagulable state. We measured the antigen concentrations or activities of plasminogen, tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor (PAI), alpha 2-antiplasmin, alpha 1-antitrypsin, and alpha 2-macroglobulin as well as total antiplasmin activity and D-dimer concentration in the plasma of 39 patients with nephrotic syndrome and 32 normal controls subjects. In addition, antigen concentrations of plasminogen, alpha 2-antiplasmin, alpha 1-antitrypsin, and alpha 2-macroglobulin were measured in the urine of the study populations. The nephrotic group showed marked elevations of plasma t-PA, plasminogen, alpha 2-macroglobulin, and D-dimer and a significant reduction of plasma alpha 2-antiplasmin and alpha 1-antitrypsin as compared with the normal control group. Plasma alpha 2-macroglobulin was directly related to 24-hour urinary protein excretion and inversely related to serum albumin concentration. None of the proteins measured were detectable in the urine of normal controls. However, substantial amounts of plasminogen, alpha 2-antiplasmin, and alpha 1-antitrypsin and small amounts of alpha 2-macroglobulin were recovered in the urine of patients with nephrotic syndrome. Despite the lack of clinically demonstrable thrombosis, plasma D-dimer was markedly elevated in the nephrotic group, suggesting concurrent activation of coagulation and fibrinolytic pathways. In addition, the study revealed multiple abnormalities of the plasma fibrinolytic proteins and documented their urinary excretion in patients with nephrotic syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Plasma levels and urinary excretion of fibrinolytic and protease inhibitory proteins in nephrotic syndrome. 751 91

Pro-urokinase is a natural plasminogen activator that displays a clot-lysis activity through a fibrin-dependent mechanism. It seems to be a promising agent for the treatment of coronary thrombosis. Like tissue-type plasminogen activator and two-chain urokinase-type plasminogen activator, pro-urokinase has a very short half-life in circulation. It has been described that conjugation of serum albumin with pro-urokinase in plasma may occur that could protect this protein from degradation. In this study we describe the insertion of an extra cysteine residue in the N-terminal end of des-(C11-K135)-pro-urokinase (delta 125-proUK), a pro-urokinase deletion mutant lacking amino acids 11-135. We have expressed and purified the new mutein [H5K, S9C, N10T] des-(C11-K135)-pro-urokinase (Cys-delta 125-pro-urokinase) and chemically conjugated it with serum albumin via the extra cysteine of Cys-delta-pro-urokinase. The purified conjugate obtained has a lower specific amidolytic activity (72,000 U/mg) than unconjugated Cys-delta 125-pro-urikinase (240,000 U/mg) due to its higher molecular mass and has a similar fibrinolytic activity in a clot lysis test to that of delta 125-pro-urokinase. We established an ELISA to measure the concentration of the conjugate in plasma and to follow the pharmacokinetics of the conjugate in monkeys after bolus injection. The conjugate displays significant lysis of human plasma clots in vivo and a dramatic increase of the half-life in the circulation, with respect to pro-urokinase and delta 125-pro-urokinase. Therefore, preliminary biological characterisation of this conjugate indicates that it could be a good candidate to inject as a bolus, compared with the infusion regimen needed with pro-urokinase.
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PMID:Prolonged half-life in the circulation of a chemical conjugate between a pro-urokinase derivative and human serum albumin. 764 55

Recently there has been a renewed interest in the possibility that lipoprotein(a)--Lp(a)--may be important in the pathogenesis of thrombosis-related disease. In nephrotic syndrome, hyperlipidemia is a common finding, and thrombosis is a major complication. With this regard, if Lp(a) levels increase concomitantly with low-density lipoprotein and/or very-low-density lipoprotein levels in nephrotic syndrome, this may be considered a thrombogenic factor. To probe this possibility and to corroborate the relationship between Lp(a) and fibrinolytic profiles, we measured the Lp(a) levels in patients with nephrotic syndrome (n = 43), in patients with chronic glomerulonephritis with less proteinuria than in nephrotic syndrome (n = 28), and in healthy controls (n = 50) and observed the relation between Lp(a) levels and tissue-type plasminogen activator (t-PA) activity, euglobulin fibrinolytic activity, and t-PA antigen. The Lp(a) levels were significantly higher in the patients with nephrotic syndrome as compared with both patients with chronic glomerulonephritis and healthy controls (p < 0.001). There was a direct correlation with serum cholesterol level (r = 0.780; p = 0.0001), triglyceride level (r = 0.445; p = 0.0001), and urine protein level (r = 0.675; p = 0.0001) and a reverse correlation with serum albumin levels (r = 0.566; p = 0.0001). The Lp(a) levels showed a reverse correlation with t-pA activity (r = 0.627; p = 0.0001), total fibrinolytic activity in euglobulin fraction (r = 0.458; p = 0.0001), and t-PA activity divided by the t-PA antigen (r = 0.567; p = 0.0001), but no correlation with t-PA antigen.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Lipoprotein(a) levels and fibrinolytic activity in patients with nephrotic syndrome. 874 69

A recombinant endotoxin-neutralizing protein, rBPI23, was shown to partially prevent endotoxin-induced activation of the fibrinolytic and coagulation systems in experimental endotoxemia in humans. In a placebo-controlled, blinded crossover study, eight volunteers were challenged twice with an intravenous bolus injection of endotoxin (40 EU/kg of body weight) and concurrently received either rBPI23 (1 mg/kg) or placebo (human serum albumin, 0.2 mg/kg). rBPI23 treatment significantly lowered the endotoxin-induced fibrinolytic response, ie, reduced the release of tissue-type plasminogen activator, urokinase-type plasminogen activator, plasminogen activator inhibitor antigen, and complex formation of plasmin alpha 2-antiplasmin (P = .0078 for each). Plasminogen activator inhibitor activity was also reduced, but not significantly according to the Hochberg method (P = .0304). The endotoxin-induced activation of the procoagulant state as reflected by increase in F1 + 2 fragments and TAT complexes was blunted by rBPI23 infusion (P = .0391 [not significant according to the Hochberg method] and .0078, respectively). These results indicate that rBPI23 is capable of reducing both the activation of the fibrinolytic and the coagulation systems after low-dose endotoxin infusion in humans.
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PMID:Inhibition of endotoxin-induced activation of the coagulation and fibrinolytic pathways using a recombinant endotoxin-binding protein (rBPI23). 778 Jan 31


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