Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human recombinant tissue-type plasminogen activator (rt-PA) has been shown to be an effective and safe agent for coronary thrombolysis in patients with acute myocardial infarction. However, thrombolysis is associated with a high rate of acute reocclusion after discontinuation of rt-PA. The goals of the present study were to assess whether reocclusion after thrombolysis is caused by intracoronary platelet aggregation and to determine the role of thromboxane A2 (TxA2) and serotonin (5HT) in mediating this phenomenon. Accordingly, coronary thrombosis was induced in anesthetized, open-chest dogs by insertion of a copper coil into the left anterior descending coronary artery (LAD). LAD blood flow was monitored throughout the experiment by means of a Doppler flow probe placed proximally to the coil. Thrombolysis was achieved with rt-PA (0.05 mg/kg bolus + micrograms/kg/min infusion) in 23 +/- 3 min. rt-PA was then discontinued and each animal received a bolus of heparin (150 U/kg) every hour. Reperfusion was followed by repeated cycles of gradual occlusions followed by spontaneous restorations of blood flow (cyclic flow variations, CFVs) before a persistent occlusion recurred. In control dogs (n = 6), heparin alone did not prevent CFVs and reocclusion time was 25 +/- 4 min. Administration of an intravenous bolus of 0.2 +/- 0.06 mg/kg SQ29548, a TxA2/prostaglandin H2-receptor antagonist, and an intravenous bolus of 0.2 +/- 0.04 mg/kg ketanserin, a 5HT2-receptor antagonist, completely abolished CFVs in six of six dogs and reocclusion time was greater than 158 +/- 14 min (p less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mediation of reocclusion by thromboxane A2 and serotonin after thrombolysis with tissue-type plasminogen activator in a canine preparation of coronary thrombosis. 312 75

The incidence of intracoronary thrombus and the effects of thrombolytic therapy were studied in 41 patients with unstable angina. All patients underwent coronary angiography 2 to 69 h (mean 19) after their last attack of chest pain. Immediately after angiography, 21 patients received intracoronary streptokinase (250,000 IU in 45 min) and were retrospectively analyzed. Twenty patients received intravenous recombinant tissue-type plasminogen activator (rt-PA) (100 mg in 3 h) and were involved in a prospective study. Eleven of the 21 patients from the streptokinase group and 11 of the 20 patients from the rt-PA group showed a decrease in the severity of the coronary stenosis on repeat angiography 1 day later. A decrease in coronary obstruction was primarily observed in 10 of 13 patients with a complete stenosis and in 6 of 9 patients with a subtotal stenosis and markedly diminished coronary flow. Improvement in coronary anatomy was not determined by the clinical characteristics of the patients. Twenty-eight of the 41 patients had angiographic evidence of intracoronary thrombus formation before and 16 had such evidence after thrombolytic treatment. Nine patients developed a small increase in serum cardiac enzymes before or during treatment. Ischemic symptoms and the incidence of surgical or angioplastic intervention were not different in patients with or without a reduction in coronary artery stenosis after fibrinolytic therapy. These observations suggest a high incidence of coronary thrombosis in patients with unstable angina. The data do not permit assessment of the clinical therapeutic efficacy of thrombolytic therapy. Better risk stratification and placebo-controlled prospective studies are required to obtain information on the risk/benefit ratio of such therapy in unstable angina.
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PMID:Effects of thrombolytic therapy in unstable angina: clinical and angiographic results. 313 80

Recombinant tissue-type plasminogen activator (rt-PA) was administered intravenously to 93 patients with acute myocardial infarction and coronary thrombosis in doses of 30 to 150 mg over 1.5 to 6 hours. During this infusion plateau levels of rt-PA in plasma ranged between 0.4 and 2.2 micrograms/ml. Activation of the plasma fibrinolytic system and fibrinogen breakdown both in vivo and in vitro was observed with this therapy. In vitro fibrinogenolysis in plasma was more effectively prevented by collection of blood samples on aprotinin (200 kallikrein inhibitor units/ml blood), a conventional serine protease inhibitor, than on either of two monoclonal antibodies against t-PA (200 micrograms/ml plasma), or on D-phenylalanyl-prolyl-arginine-chloromethyl ketone (PPACK), a newly developed synthetic inhibitor of t-PA. Results of fibrinogen measurements during infusion of rt-PA were dependent on the method of assay. In a subgroup of 36 patients after completion of a thrombolytic infusion, fibrinogen decreased in vivo by 27% when measured as total coagulable protein and by 33% with a coagulation rate assay, but increased by 26% with an automated assay system. The extent of fibrinogenolysis was proportional to the plasma level of rt-PA but substantial intersubject variation was observed. Fibrinogenolysis in vivo was also associated with alpha 2-antiplasmin depletion and was more pronounced with a two-chain (G11021) than with a single-chain preparation (G11035) of rt-PA.
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PMID:Laboratory monitoring of hemostasis during thrombolytic therapy with recombinant human tissue-type plasminogen activator. 313 34

Plasminogen activators convert the proenzyme plasminogen to the active serine protease plasmin by hydrolysis of the Arg560-Val561 peptide bond. Physiological plasminogen activation is however regulated by several additional molecular interactions resulting in fibrin-specific clot lysis. Tissue-type plasminogen activator (t-PA) binds to fibrin and thereby acquires a high affinity for plasminogen, resulting in efficient plasmin generation at the fibrin surface. Single-chain urokinase-type plasminogen activator (scu-PA) activates plasminogen directly but with a catalytic efficiency which is about 20 times lower than that of urokinase. In plasma, however, it is inactive in the absence of fibrin. Chimeric plasminogen activators consisting of the NH2-terminal region of t-PA (containing the fibrin-binding domains) and the COOH-terminal region of scu-PA (containing the active site), combine the mechanisms of fibrin specificity of both plasminogen activators. Combination of t-PA and scu-PA infusion in animal models of thrombosis and in patients with coronary artery thrombosis results in a synergic effect on thrombolysis, allowing a reduction of the therapeutic dose and elimination of side effects on the hemostatic system.
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PMID:Mechanisms of plasminogen activation by mammalian plasminogen activators. 313 4

The concepts of acute, potentially reversible coronary artery thrombosis and myocardial salvage by early coronary thrombolysis using pharmacologic agents and/or percutaneous transluminal coronary angioplasty have evolved rapidly since 1980. Broad, general application of these methods awaited clear data on efficacy and safety of proposed treatment regimens, and in May 1987 streptokinase was recommended for approval by the Food and Drug Administration for intravenous use in patients with acute myocardial infarction. A second, more promising drug, recombinant tissue-type plasminogen activator, was approved by the FDA in November 1987. Thrombolysis is now accepted therapy for patients with acute myocardial infarction. Rapid identification of the patient with acute myocardial infarction plays an important role in treatment, because thrombolytic therapy is maximally effective if begun within four hours of the onset of symptoms. Care must be taken in selecting patients for treatment to ensure that an acute myocardial infarction is in evolution and that a medical condition predisposing to hemorrhage is not present. Cost of treatment and risk of complications must be considered before initiating therapy. In many patients, thrombolytic therapy can be considered only the first step in treatment, because of the relatively frequent occurrence of reocclusion and reinfarction after initial thrombolysis. If cardiac catheterization, angioplasty, and open heart surgery facilities are not readily available, transfer to a tertiary care center is indicated for high-risk patients, such as those with large anterior infarction, vacillating pain, or previous myocardial infarction. Transfer is safe if carried out promptly by critical care transport teams experienced in cardiac care.
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PMID:Identification and transport of patients with acute myocardial infarction for thrombolytic therapy. 314 15

The blood of 30 patients who received recombinant tissue-type plasminogen activator for lysis of acute coronary thrombosis was examined to identify the effects of this enzyme on the fibrinolytic and coagulation systems. Doses ranged from 20 to 80 mg and duration of infusion ranged from 15 minutes to 4.5 hours. Doses of 60 mg or less and duration of infusion of 2 hours or less caused only mild fibrinogenolysis, a 28% drop from baseline plasma fibrinogen concentrations to nadir. In contrast, higher doses or longer infusion periods led to significantly lower fibrinogen levels, a 61% decrease of fibrinogen levels at nadir (p less than 0.01), and this effect was sustained. Dosing by weight led to less appreciable fibrinogen breakdown. A strong negative correlation was seen between plasma plasminogen activator and fibrinogen levels (r = -0.83, p less than 0.001) during the infusion. In-vitro studies showed the enzyme to deplete fibrinogen rapidly, and this activation was blocked with a protease inhibitor.
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PMID:Coronary thrombolysis with recombinant tissue-type plasminogen activator. A hematologic and pharmacologic study. 393 95

To determine whether tissue-type plasminogen activator (t-PA) may prevent coronary thrombosis or accelerate the lysis of clot formed under conditions in which increased concentration of the activator is present before thrombosis, clot lysis studies were undertaken in vitro and in vivo. In vitro, exogenous t-PA (6 to 100,000 ng/ml) accelerated the lysis of clot in a dose-dependent fashion when the clot was formed either from whole plasma or from euglobulin fractions (n = 316 determinations). Adding t-PA before clot formation shortened the time to lysis by at least threefold with euglobulin fractions and by at least 10-fold with whole plasma clots, which is consistent with the presence of inhibitors of fibrinolysis in whole plasma and with the binding of t-PA to nascent fibrin. In an intact dog preparation of coronary thrombosis (n = 25), occlusive thrombus formation was prevented when t-PA was present in subthrombolytic concentrations (430 to 1200 ng/ml, n = 5). Occlusive thrombus formation occurred after only discontinuation of the t-PA infusion and clearance of t-PA. Lower concentrations of t-PA (147 to 427 ng/ml, n = 6) significantly delayed occlusion (26 +/- 6.5 vs 7.8 +/- 2.8 min for controls). In animals with t-PA concentrations of less than 140 ng/ml (n = 4), the time to occlusion was unaltered (7.7 +/- 4.5 min). The present study demonstrates that t-PA present before clot formation inhibits thrombosis or accelerates thrombolysis depending on concentration, and that subthrombolytic doses of t-PA can prevent thrombus formation in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prevention of coronary thrombosis with subthrombolytic doses of tissue-type plasminogen activator. 393 49

This study was performed to characterize selected pharmacologic properties and effects on the fibrinolytic system of tissue-type plasminogen activator synthesized by recombinant DNA technology (rt-PA) in 12 patients treated for coronary thrombosis. rt-PA was infused parenterally (by the intracoronary route in four patients and intravenously in eight) in doses of 8.3, 12.5, or 16.7 micrograms/kg/min for 30 to 60 min, yielding a total dosage of 20 to 40 mg/patient. The drug induced coronary thrombolysis in 10 of the 12 patients treated (83%), including six of the eight given rt-PA intravenously. No bleeding complications were encountered. Serial blood samples were obtained before, during, and after infusion of rt-PA and analyzed for t-PA antigen (i.e., immunoassayable rt-PA protein), functional fibrinolytic activity attributable to rt-PA, fibrinogen, plasminogen, alpha 2-antiplasmin, fibrinogen degradation products, prothrombin time, activated partial thromboplastin time, and protamine-corrected thrombin time. Pretreatment plasma t-PA antigen levels averaged 16.5 +/- 5(SD) ng/ml. Peak plasma values were generally proportional to dose, averaging 3330 +/- 1201 ng/ml. Approximately 90% of peak level was reached in 30 min, with a plateau at peak reached within 40 min. Functional t-PA activity increased monotonically in a comparable fashion. Curves for disappearance of both t-PA antigen and functional activity from plasma were monoexponential for at least two half-lives (r = .99 for both) and were concordant. The observed half-lives were similar, averaging 8.3 and 9.1 min, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Clinical pharmacology in patients with evolving myocardial infarction of tissue-type plasminogen activator produced by recombinant DNA technology. 403 68

Occlusive thrombus was produced by thrombin-induced coagulation in the left anterior descending coronary artery (LAD) of 16 open-chest baboons. In six control animals, occlusive thrombosis persisting over a period of 4 h as evidenced by coronary arteriography resulted in large transmural infarction (63.1 +/- 3.5% of the perfusion area). In 10 animals, tissue-type plasminogen activator obtained by recombinant DNA technology (rt-PA) was infused systemically at a rate of 1,000 IU (10 micrograms)/kg per min for 30 min after 30-80 min of coronary thrombosis. Reperfusion occurred within 30 min in nine animals. In one animal, intravenous infusion was followed by an intracoronary infusion at the same rate, which resulted in thrombolysis within 8 min. In the rt-PA group, mean duration of occlusion before reperfusion was 77 +/- 24 min. Reocclusion occurred in one animal. Recanalization resulted in an overall reduction of infarct size (37.8 +/- 5.9%, P less than 0.05 versus controls). Residual infarction was related to the duration of occlusion (r = 0.80, P less than 0.01). Reperfusion was associated with reduced reflow. Myocardial blood flow in the perfusion area of the LAD was only 70% of normal after 4 h despite perfect angiographic refilling. The infusion of rt-PA was not associated with systemic activation of the fibrinolytic system, fibrinogen breakdown, or clinically evident bleeding. It is concluded that intravenous infusion of rt-PA may recanalize thrombosed coronary vessels without inducing systemic lysis. The extent of residual infarction is closely related to the duration of coronary artery occlusion before thrombolysis.
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PMID:Coronary thrombolysis and infarct size reduction after intravenous infusion of recombinant tissue-type plasminogen activator in nonhuman primates. 403 6

On a theoretical basis, delayed fibrinolysis has always been assumed to allow a harmless, or rather, useful clotting process to develop into manifest thrombosis. Since the early sixties, when most modern concepts on fibrinolysis were postulated, the evidence for a causal relationship between impaired fibrinolysis and venous thrombosis has not become much stronger. On the other hand, several observations indicate an association between impaired fibrinolysis and arterial thrombosis. Recent years have witnessed a flare-up of interest in fibrinolytic therapy, especially of acute coronary artery thrombosis, and thanks to the availability of human tissue-type plasminogen activator, expansion of its field of application is to be expected. However, with drugs for maintenance enhancement of fibrinolysis still being out of reach, we rely on the well-established oral anticoagulant regimen for the prophylaxis of thrombosis in patients with an obvious thrombotic disposition.
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PMID:Delayed fibrinolysis: a cause of thrombosis? 404 26


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