Gene/Protein Disease Symptom Drug Enzyme Compound
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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)

Acute and subacute deep venous thrombosis can be followed by two serious complications: pulmonary embolism feared in the early stadium and the postthrombotic syndrome (PTS) as a late complication. After a lapse of months and years there might appear a complete or incomplete recanalization, but the valves of the veins will be destroyed. Therefore it is understandable to strive first an active therapy as thrombectomy or thrombolysis to remove thrombosis. There will be released a physiological tissue plasminogen activator from the endothelium of the vein increasing a local fibrinolytic activity. But it is not strong enough to reopen the occlusion within a few days. This is only possible adding exogenous activators as streptokinase, urokinase and recently rt-PA. Heparin is well known at low-dose subcutaneously for thrombosis prophylaxis. The high doses of heparin infusion intravenously with 30-40,000 units daily are used "therapeutically" inhibiting growth-promotion of the thrombus and reducing the incidence of pulmonary embolism markedly. In respect of a postthrombotic syndrome (oedema, leg ulcers) it needs the evaluation of the early and follow up late results and the analysis of efficiency and risk of the two models of treatment. It was necessary comparing the success rate of reopening of the occluded veins after some days and follow up 5 or 6 years in clinical studies. The reopening rate in thrombolysis was about 3 times higher than in heparin therapy. But in contrast bleeding was 3 times lower in heparin therapy. For the long term follow up, physical examination, doppler-sonography phlebodynamometry and vein occlusion plethysmography were assessed. The acute intervention, regarding treatment, turned out to be the crucial prognostic parameter. Syndromes and clinical findings did indeed correlate quite well with the outcome of fibrinolytic treatment. Postthrombotic syndrome was rare in cases with complete patency. In cases where patency was only partially or not at all achieved, postthrombotic syndrome was present to a higher degree the more central and the more extensive the remaining thrombus was. In deep venous thrombosis of the lower extremity thrombolytic therapy is recommended mostly to younger patients with acute, the popliteal and the femoral vein including thrombosis, except of contraindications. More over in each of an individual case it has to be decided whether the aggressive or conservative therapy is to prefer.
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PMID:[The treatment of deep venous thrombosis. Thrombolysis vs heparin]. 209 22

Defibrotide, a deoxypolyribonuclide, has been found to modulate endothelial cell function causing increase in t-PA and decrease in PAI levels and also increase in PGI2 production. In addition, it increases platelet c-AMP levels and decreases MDA and TXB2 formation in human. Defibrotide inhibits platelet aggregate formation in vitro experiments as well as end-to-end anostomosis in rats. So, defibrotide inhibits the activation of platelets. Besides an increase of protein C and S levels a synergic action of heparin was observed in animal experiments. A strong antithrombotic effect has been observed in animal models. The drug has a beneficial effect in the cases of DVT, POVD, stroke and thromboembolism. Through its action we may say that the drug acts in a novel fashion in contrast to the other drugs used in this area. Defibrotide is a single-stranded polydeoxyribonucleotide obtained from deoxyribonucleic acid of mammalian lungs by controlled depolimerization. Since 1981 in our laboratory and in the clinical department we have been investigating a newly developed agent defibrotide in vitro experiments, animal experiments, and also its clinical pharmacology and clinical application. Some of our findings are already published and compared with literature (40, 43, 46). Because of the limited space we are not going to review the literature in detail but we are going to summarize our observations on this compound in the following order. I--in vitro experiments, II--Animal experiments, III--clinical pharmacology in human.
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PMID:The pharmacology and clinical pharmacology of defibrotide: a new profibrinolytic, antithrombotic and anti-platelet substance. 210 24

We performed a randomized trial comparing two dosing regimens of recombinant tissue plasminogen activator (rt-PA) plus heparin vs heparin alone in the treatment of acute proximal deep vein thrombosis in 83 patients. Of 12 patients who received 0.5 mg/kg rt-PA plus heparin over 4 h, seven (58 percent) had greater than 50 percent lysis of the thrombus, compared with none of 12 who received placebo plus heparin (p = 0.002). Of 28 patients who received 0.5 mg/kg rt-PA over 8 h, repeated in 24 h, six (21 percent) had greater than 50 percent lysis, compared with two (7 percent) of 30 patients who received placebo plus heparin (p = 0.11). The 4-h infusion of rt-PA produced a 40 percent reduction and the 8-h infusion an 11 percent reduction in plasma fibrinogen concentration. At long-term follow-up, three (25 percent) of 12 patients in whom greater than 50 percent lysis was achieved had symptoms of the postphlebitic syndrome, compared with 19 (56 percent) of 34 patients in whom lysis was less than 50 percent (p = 0.07).
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PMID:Tissue plasminogen activator (rt-PA) vs heparin in deep vein thrombosis. Results of a randomized trial. 210 55

Two promising novel recombinant tissue-type plasminogen activator (rt-PA) regimens for pulmonary embolism (PE) are being actively investigated: 100 mg/2 h as a continuous peripheral intravenous infusion, and bolus rt-PA, adjusted to weight, as a 2-min infusion. For deep venous thrombosis (DVT), less progress has been made in finding an optimal dosing regimen of rt-PA. Our mandate for the 1990s is to use the best possible thrombolytic dosing regimens in large clinical trials of PE and DVT. The primary objective of these planned clinical studies is to determine which patients with PE and DVT will benefit the most from thrombolysis followed by anticoagulation rather than anticoagulation alone.
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PMID:Thrombolysis in venous thromboembolism. An international perspective. 210 56

Using a monoclonal antibody-based assay, we measured the fibrin degradation product release in the supernatant of plasma clots obtained before and after venous occlusion (VO) in 30 patients with definite or suspected vascular thrombosis (19 definite and 2 suspected deep vein thrombosis, 6 recurrent superficial thrombophlebitis, 3 arterial occlusions of lower limbs). tPA and PAI-1 concentrations were determined using ELISA assays; the post-occlusion values were corrected for haemoconcentration. The increase in tPA during VO was correlated with haemoconcentration (r = 0.74), but 3 patients had ineffective VO (less than 2% increase in proteins). The fibrinolytic response to VO was evaluated using the shortening of the time necessary for the release of 200 micrograms of fibrin degradation products per mg of fibrinogen (delta T 200). Two among the 27 patients with effective VO were bad responders with a delta T 200 less than 3 h (whereas all the others had delta T 200 greater than 10 h). These patients had respectively a deficient tPA release (delta tPA = 1 ng/ml) and an elevated PAI-1 level at rest (33 ng/ml). Several other patients were bad responders in terms of tPA release or of shortening of the euglobulin clot lysis time but they had a normal delta T 200. This plasma clot test reflects the ability of free tPA to bind to fibrin (the amount of which depends on the level of tPA and PAI-1), and may be useful in the diagnosis of a hypofibrinolytic state.
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PMID:A plasma clot lysis assay based on the release of fibrin degradation products: application to the diagnosis of hypofibrinolytic states. 211 Oct 50

Recombinant tissue plasminogen activator (rt-PA) is a thrombolytic agent characterized by elevated but not absolute fibrin specificity. However, its therapeutic dose is high and associated with a variable degree of systemic activation of the fibrinolytic system. Thrombolytic drugs are widely used in acute myocardial infarction and have now begun to be considered for deep vein thrombosis (DVT), pulmonary embolism (PE), and peripheral artery thrombosis (PAT) as well. Although anticoagulant therapy is effective in reducing the immediate complications of venous thromboembolism, thrombolytic therapy has various advantages over anticoagulant therapy, including lysis of thrombi with recanalization of venous circulation, reduction of venous valve damage and prevention of post-phlebitic syndrome. The different dosage regimens of rt-PA recently evaluated (0.71 to 1.76 mg/kg/24 h for 2-4 days) in DVT have caused consistent thrombolysis but also excessive bleeding. The optimal therapeutic range for rt-PA in DVT remains to be determined. Thrombolytic therapy is superior to heparin treatment only in hemodynamically compromised patients with massive PE. The minor systemic fibrinolytic effect and the faster action on thrombi of rt-PA compared with the first generation thrombolytic agents, streptokinase (SK) and urokinase (UK), are very interesting and explain the positive results recently obtained in PE with this drug (50 mg over 2 h, followed, if necessary, by 40-50 mg over 4-5 h) by Goldhaber and Verstraete.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[rt-PA in extracardiac thromboembolic vascular occlusions]. 211 73

In a prospective, randomized controlled study, tissue plasminogen activator (t-PA) and tissue plasminogen activator antigen (t-PA:ag) were measured pre- and postoperatively in 40 consecutive patients undergoing total hip replacement. Patients received either a subcutaneous injection of low molecular weight heparin or placebo once daily. Deep vein thrombosis was diagnosed by bilateral phlebography. Patients who developed postoperative thromboembolic complications had significantly lower preoperative t-PA activity levels than patients who did not develop such complications. No difference was observed between the two groups with respect to t-PA:ag. Thromboprophylaxis with low molecular weight heparin did not cause any significant changes in t-PA activity and t-PA:ag. This study in high risk patients indicates that impaired fibrinolysis may be associated with development of thromboembolic complications after operation.
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PMID:Association between plasma levels of tissue plasminogen activator and postoperative deep vein thrombosis--influence of prophylaxis with a low molecular weight heparin. The Venous Thrombosis Group. 216 77

In this review, an attempt has been made to present new data on the mechanisms that can be involved in DVT and to emphasize the role of the cell in these processes. It has been demonstrated that cells can mediate the relevant expression of tissue factor without cell disruption and that the fibrinolytic responses can also be modulated by the cells. It has also been demonstrated that the fibrinolytic system seems to be designed to work on the cell surface based upon (1) the existence of specific receptors, (2) the modulation of the expression of these receptors and (3) the comprehensive increase in plasmin generation by up-regulating, for example, the plasminogen receptors. It could also be worthwhile to attempt to explain some beneficial effects of drugs such as heparins by studying their action on these compartments. It is important to note that recently Rosenfeld et al. have described an increase in t-PA and u-PA binding to endothelium by pre-incubation of endothelial cells with unfractionated heparin. This work would be a first step in a very exciting and interesting new era in the prevention of venous thromboembolism.
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PMID:Biochemical aspects of the pathogenesis of venous thrombosis. 228 80

This study comprised 50 patients subjected to major abdominal surgery, of which 13 developed deep vein thrombosis (DVT) according to the 125I-fibrinogen test. Plasma was sampled preoperatively, for the specific analysis of tissue plasminogen activator (t-PA) before and during venous occlusion. The recently described fast t-PA inhibitor and plasmin alpha 2-antiplasmin complex (PAP) were also measured. The result of the laboratory analyses were correlated to the development of DVT. From the data obtained it is concluded that the evaluation of t-PA release during venous occlusion is a poor predictive factor for the occurrence of DVT after major abdominal surgery. The level of the t-PA inhibitor appears to be raised in these patients, but the values obtained in this material were not related to the development of postoperative DVT. Patients with elevated PAP levels, as shown previously, have a lesser tendency to develop postoperative DVT.
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PMID:Relationship between preoperative status of the fibrinolytic system and occurrence of deep vein thrombosis after major abdominal surgery. 241 Oct

An enzyme-linked immunosorbent assay for free tissue-type plasminogen activator (t-PA) in human blood was developed based on a murine monoclonal antibody directed against the active site of t-PA. The lower limit of sensitivity of the assay applied to plasma is 2 ng/mL for one-chain t-PA but only 100 ng/mL for two-chain t-PA. Free t-PA in plasma taken at rest was found in 6 of 21 healthy subjects (4.5 +/- 0.8 ng/mL, mean +/- SD) and increased to 14 +/- 7.0 ng/mL after venous occlusion in 18 of these individuals. A linear correlation between total t-PA and free t-PA was observed with r = 0.92 (n = 18) and a slope of 1.08, indicating that t-PA released from the vessel wall circulates in the blood as the one-chain form. In 16 of 18 patients with deep vein thrombosis, the increase of total t-PA antigen after venous occlusion was comparable to that observed in controls, but the free t-PA was significantly lower or undetectable. The present assay for free t-PA may be useful for the investigation of the release and inhibition of t-PA under physiological, pharmacological, or pathological conditions in humans.
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PMID:Measurement of free, one-chain tissue-type plasminogen activator in human plasma with an enzyme-linked immunosorbent assay based on an active site-specific murine monoclonal antibody. 243 30


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