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)

Heparin has been shown recently to stimulate the activity of human tissue-type plasminogen activator (t-PA). To investigate this effect further, mutant proteins lacking various domains of t-PA were screened for the ability to be stimulated by heparin. Those mutants harboring either the finger domain or the 2nd kringle were found to have enhanced enzymatic activity in the presence of heparin. Only mutants containing these structures would bind to heparin-agarose beads; monoclonal antibodies directed against these domains blocked binding. The stimulatory effect of heparin was more pronounced in finger-containing mutants than kringle-2 proteins. Earlier results had localized the fibrin-binding domains to the same two structures. Unlike heparin, the 2nd kringle was shown to be more important than the finger for fibrin stimulation. Our results have implications for producing recombinant t-PA variants for use in thrombolytic therapy.
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PMID:Structural domains of human tissue-type plasminogen activator that confer stimulation by heparin. 250 21

Twenty six patients with acute (less than 5 days) pulmonary embolism (PE) confirmed by bilateral pulmonary angiography with a Miller index greater than 15 were given tissue plasminogen activator (Alteplase) (rt-PA) intravenously (n = 20) or directly into the pulmonary artery (n = 6). The dosage was 100 mg/7 hours (bolus 10 mg + 40 mg/2 hours + 50 mg/5 hours). Heparin (5000 IV as a bolus and 1000 IV/hour) was associated in all cases. The Miller index decreased from 24 +/- 1 (n = 26) before treatment to 12 +/- 1 (n = 25) (p less than 0.001) after 100 mg of Alteplase, and from 25 +/- 0.4 (n = 14) to 22 +/- 0.5 (n = 14) (p less than 0.001) after 50 mg. The mean pulmonary arterial pressures fell from 30 +/- 2 mmHg to 21 +/- 2 mmHg after 50 mg (n = 26) (p less than 0.001) and to 14 +/- 1 (n = 25) (p less than 0.001) after 100 mg of Alteplase. A decrease in mean pulmonary artery pressures (-22%, p less than 0.001) and total pulmonary resistances (-29%, p less than 0.001) was obtained after one hour of thrombolysis in 12 monitored patients. There were no fatalities. Severe haemorrhage occurred in 6 cases. Therefore, Alteplase induced a rapid dissolution of recent intrapulmonary thrombi without inacceptable haemorrhagic complications. Its action could be particularly beneficial in patients with right ventricular failure due to life threatening pulmonary embolism.
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PMID:[Tissue plasminogen activator (alteplase) in acute massive pulmonary embolism. A pilot study]. 251 32

Heparin and a low molecular heparin fragment, injected intravenously in volunteers, increased the plasma concentrations of platelet factor 4, but did not induce platelet activation as judged from excretion of 2,3-dinor-TxB2 (a major thromboxane A2 metabolite) and beta-thromboglobulin (btg) in urine and from btg levels in plasma. Heparin prolonged, within the normal range, the bleeding time in all six subjects. Platelet aggregation in platelet rich plasma was potentiated by both heparins, but platelet number, mean platelet volume and platelet distribution width were not affected. No evidence for endothelial release of prostacyclin was obtained as judged from urinary excretion of 2,3-dinor-6-keto-PGF1 alpha (a major prostacyclin metabolite), and plasma concentrations of tissue plasminogen activator, its inhibitor (PAI-1) and the von Willebrand-factor were unchanged.
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PMID:Immediate effects of heparin and LMW heparin on some platelet and endothelial derived factors. 284 53

The effect of a selective thrombin inhibitor, (2R, 4R)-4-methyl-1-[N2-[(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl)sulfonyl]- L-arginyl]-2-piperidinecarboxylic acid (MCI-9038), on the fibrinolysis induced by t-PA and u-PA was studied in vitro and in vivo. MCI-9038 remarkably reduced the lysis time of the plasma clot generated by the addition of calcium chloride to the plasma at the concentration ranging from 0.01 to 0.3 microM. Heparin also reduced the plasma clot lysis time with a lower effect than MCI-9038. The fibrin crosslinkage in the plasma clot was inhibited by MCI-9038 or heparin. MCI-9038 potently inhibited the factor XIIIa generation from factor XIII by thrombin. The effect on the in vivo thrombolysis was studied on the arterial thrombosis generated by the endothelial cell injury of the rabbit carotid artery by acetic acid. t-PA dissolved the thrombi with the infusion at 0.96 mg/kg over 2 h without a significant activation of a systemic fibrinolysis. u-PA dissolved the thrombi with the infusion at 180,000 and 360,000 IU/kg over 2 h. At a dose of 0.48 mg/kg t-PA or 90,000 IU/kg u-PA, the thrombi were not dissolved, but the combined use of MCI-9038 at 1.2 mg/kg over 2 h effectively dissolved the thrombi. Thus, combination of MCI-9038 with plasminogen activators accelerated thrombolysis of an experimental thrombosis in rabbits.
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PMID:Effect of a selective thrombin inhibitor MCI-9038 on fibrinolysis in vitro and in vivo. 287 8

Angina presents itself to us as a continuous spectrum of ischemic syndromes. The disease is multifactorial, and within the same patient different pathophysiological mechanisms may occur at different times and in succession. Several factors may be causative at a particular moment of the disease process and the very next moment a different mechanism may prevail or spontaneous improvement may occur. Among these are stable atheroma with episodic increased vasomotor tone, fissured plaques with intraluminal and/or intraintimal thrombus, thrombocyte aggregation in greater than 70% intraluminal narrowing from ulcerated plaques, as well as frank spasm of vessels without major atherosclerosis. Consequently, there will never be one therapy for every case of (un)stable angina nor will there ever be a best therapy for all. Rather, a stepped approach appears the most likely to be successful. This begins with bed rest and requires vasodilator therapy with nitrates and/or Ca2+ antagonists and beta blockade. If this triple therapy does not "cool" the symptoms within 6-12 hours, semiurgent arteriography is indicated. Depending on the pathophysiology found, thrombolytic therapy with streptokinase or tissue plasminogen activator, percutaneous transluminal coronary angioplasty (PTCA), or coronary artery bypass grafting (CABG) must be carried out early. Heparin in the short term and aspirin in the long term protect best against late complications. The moment is now here when infarction or death after an attack of angina pectoris should be rare.
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PMID:Calcium antagonists for angina pectoris. 289 19

The amidolytic plasmin activity of a mixture of tissue plasminogen activator (tPA) and plasminogen is enhanced by heparin at therapeutic concentrations. Heparin also increases the activity in mixtures of urokinase-type plasminogen activator (uPA) and plasminogen but has no effect on streptokinase or plasmin. Direct analyses of plasminogen activation by polyacrylamide gel electrophoresis demonstrate that heparin increases the activation of plasminogen by both tPA and uPA. Binding studies show that heparin binds to various components of the fibrinolytic system, with tight binding demonstrable with tPA, uPA, and Lys-plasminogen. The stimulation of tPA activity by fibrin, however, is diminished by heparin. The ability of heparin to promote plasmin generation is destroyed by incubation of the heparin with heparinase, whereas incubation with chondroitinase ABC or AC has no effect. Also, stimulation of plasmin formation is not observed with dextran sulfate or chondroitin sulfate A, B, or C. Analyses of heparin fractions after separation on columns of antithrombin III-Sepharose suggest that both the high-affinity and the low-affinity fractions, which have dramatically different anticoagulant activity, have similar activity toward the fibrinolytic components.
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PMID:Interaction of heparin with plasminogen activators and plasminogen: effects on the activation of plasminogen. 294 15

It is now generally well accepted that heparin and related substances increase the fibrinolytic activity in vivo. The stimulation of the amidolytic, plasminogenolytic and fibrinogenolytic activity of tissue plasminogen activator and urinary plasminogen activator through heparin was investigated in vitro. A concentration-dependent stimulation of the plasminogenolytic and fibrinogenolytic activity of both urinary and tissue-type plasminogen activators was observed in the presence of heparin. No heparin dependence was observed in the amidolytic assay. Heparin stimulates the plasminogenolytic activity of tissue plasminogen activators in the same manner as fibrin. Both activators form complexes with heparin; the heparin-binding-site seems to be identical or related with the fibrin-binding-site of tissue plasminogen activator. The physiological role of these interactions is discussed.
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PMID:Study on the mechanism of action of heparin and related substances on the fibrinolytic system: relationship between plasminogen activators and heparin. 308 55

The fibrinolytic system was investigated in 120 patients with spontaneous or recurrent deep vein thrombosis (DVT) without any known organic disease able to explain by itself the occurrence of a thrombosis and without any known defect of antithrombin III, Heparin Cofactor II, Protein C, or Protein S. The assays included: Euglobulin fibrinolytic activity (EFA), tissue-type plasminogen activator related antigen (t-PA-Ag) and plasminogen activator inhibitor activity (PA inhibitor), which were measured before and after 10 min of venous occlusion (V.O.). On the basis of the results, the patients could be classified in 3 groups: good responders with an at least two-fold increase of EFA after venous occlusion (n = 76), poor responders with a lesser increase of EFA due to deficient release of t-PA (n = 12), and poor responders with a normal t-PA release but an increased level of PA-Inhibitor (n = 32). The poor responders due to deficient t-PA release (10% of total) had a higher incidence of recurrence of deep vein thrombosis, than the other groups (p less than 0.01). An overall correlation was found between the level of PA-Inhibitor activity and the triglyceride level (r = 0.40, p less than 0.01), suggesting that these elevations may be due to a common cause, at least in some of the patients. It is concluded that a poor fibrinolytic response to venous occlusion occurs in 35 percent of DVT patients.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Deficient t-PA release and elevated PA inhibitor levels in patients with spontaneous or recurrent deep venous thrombosis. 310 59

Coronary thrombolysis with t-PA is generally implemented with concomitant administration of heparin. However, results of studies in vitro suggest that heparin competes with fibrin for binding of tissue-type plasminogen activator (t-PA), augments activation of free plasminogen, decreases fibrin specificity, and impairs thrombolysis. To define the biological implications of these observations, we characterized effects of therapeutic concentrations of heparin on the binding of t-PA to thrombi formed in whole blood, effects of heparin on activation of plasminogen by t-PA in plasma, and effects of heparin on thrombolysis induced by t-PA in a clot lysis system designed to simulate conditions in vivo. The amount of t-PA bound to thrombi was not affected by heparin (0, 0.5, 1.0, and 5.0 U/mL). When t-PA activity was selectively and irreversibly inhibited by D-Phe-Pro-Arg-chloromethyl ketone (PPACK) the amount of t-PA-PPACK bound was similarly unaffected by heparin. Thrombolysis measured by 125I-fibrin(ogen) release and by reduction of mass of thrombi were not altered by heparin. Heparin did not affect plasminogen consumption induced by t-PA. Plasma concentrations of alpha-2-antiplasmin after exposure of blood to t-PA were less depressed with increasing concentrations of heparin. Thus, heparin in therapeutic concentrations does not interfere with binding of t-PA to thrombi, augment activation of free plasminogen, or inhibit thrombolysis. Accordingly, it appears likely that concomitant administration of heparin will not impair thrombolysis with t-PA implemented clinically.
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PMID:Lack of interference by heparin with thrombolysis or binding of tissue-type plasminogen activator to thrombi. 312 47

Purified preparations of recombinant tissue-type plasminogen activator (t-PA) from the recombinant Bowes melanoma cell line TRBM6 were shown to contain multiple species of plasminogen activator. Using a combination of chromatography on Sephadex G25, Sephadex G75 and Heparin Sepharose CL6B we have isolated two fibrinolytically active species, which, under non-reduced SDS PAGE, have apparent Mr = 38,000 and 56,000. Double immunodiffusion studies indicated that both species were closely related to both the t-PA B chain and t-PA itself. N-terminal sequencing identified the Mr = 38,000 species as ala160- t-PA (essentially delta FGKI t-PA) and the Mr = 56,000 species as ser1-tyr2-gln3-glyx-cys51 t-PA (delta F t-PA), the latter probably produced by alternative splicing of the t-PA gene. The pharmacokinetic properties of N,N dimethyl-4-aminobenzoyl (DAB) derivatives of these activators and native t-PA were determined in the guinea pig. Whereas DAB----delta F t-PA showed a similar, rapid plasma disappearance profile to that of DAB----t-PA, DAB----delta FGKI t-PA was cleared significantly slower. These results suggest that a rapid clearance recognition site resides on either the growth factor or kringle 1, or both, domains of t-PA.
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PMID:Isolation, identification and pharmacokinetic properties of human tissue-type plasminogen activator species: possible localisation of a clearance recognition site. 314 86


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