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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular or tissue-type plasminogen activator (TPA) is a key enzyme in physiologic fibrinolysis. To study the role of prostaglandins in modulating the synthesis and release of TPA in vivo, we prospectively studied the effect of aspirin (650 mg/d X 2) on TPA activity in 13 human subjects before and after 10 min of forearm venous occlusion. TPA activity was quantified by a newly developed enzyme-linked immunosorbent assay that both measures and differentiates between TPA and urokinase (UK)-like plasminogen activator activity. This assay is based on the observation that the concentration of alpha 2-plasmin inhibitor-plasmin complexes in Reptilase-clotted plasma increases linearly in proportion to the amount of activator added. Resting TPA activity was higher in women than in men (0.56 +/- 0.59 vs. 0.15 +/- 0.11 U/ml, P = 0.049). Venous occlusion induced an eightfold rise in TPA activity in women (to 4.5 U/ml, P = 0.006) and a 15-fold rise in men (to 2.28 U/ml, P = 0.004), whereas UK activity was not detected. Aspirin inhibited the rise in TPA activity after venous occlusion by 69% in men (P = 0.004) and 70% in women (P = 0.014). In contrast, aspirin had no effect on pre- or post-occlusion hematocrits or Factor VIII-related antigen levels. There was no correlation between plasma salicylate level and percentage inhibition of TPA. Neither exogenous aspirin (0-1 microgram/ml) nor salicylate (0-70 micrograms/ml) inhibited the generation of alpha 2-plasmin inhibitor-plasmin complexes by exogenous TPA or interfered with the assay system. We conclude that aspirin may have an antifibrinolytic effect in man that has not been previously described.
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PMID:Aspirin inhibits vascular plasminogen activator activity in vivo. Studies utilizing a new assay to quantify plasminogen activator activity. 623 45

Considering the enormous increase in the use of thrombolytic therapy over the last decade, many of the early concepts of thrombolytic therapy have proved to be remarkably robust. Early and sustained restoration of coronary patency remains the ultimate goal. Streptokinase is still extensively used despite evidence that alteplase may, under some conditions, be more effective. Aspirin is of proven efficacy, heparin is important with alteplase but less so with streptokinase. The benefits of early thrombolysis, even if this means pre-hospital administration, have been repeatedly confirmed. On the debit side, more effective thrombolysis seems to go hand in hand with increased bleeding risk, and primary angioplasty seems to be emerging as a viable alternative in high risk patients. More effective regimens tend to be more complex, and the proportion of eligible patients receiving thrombolytic therapy is still relatively low. Better early diagnosis, by methods independent of the electrocardiogram, and simplified but effective treatment regimens using improved thrombolytic agents are likely developments in the near future.
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PMID:Thrombolytic therapy of acute myocardial infarction. 754 70

The adult mammalian central nervous system (CNS) lacks the capacity to support axonal regeneration. There is increasing evidence to suggest that astrocytes, the major glial population in the CNS, may possess both axon-growth promoting and axon-growth inhibitory properties and the latter may contribute to the poor regenerative capacity of the CNS. In order to examine the molecular differences between axon-growth permissive and axon-growth inhibitory astrocytes, a panel of astrocyte cell lines exhibiting a range of axon-growth promoting properties was generated and analysed. No clear correlation was found between the axon-growth promoting properties of these astrocyte cell lines with: (i) the expression of known neurite-outgrowth promoting molecules such as laminin, fibronectin and N-cadherin; (ii) the expression of known inhibitory molecules such tenascin and chondroitin sulphate proteoglycan; (iii) plasminogen activator and plasminogen activator inhibitor activity; and (iv) growth cone collapsing activity. EM studies on aggregates formed from astrocyte cell lines, however, revealed the presence of an abundance of extracellular matrix material associated with the more inhibitory astrocyte cell lines. When matrix deposited by astrocyte cell lines was assessed for axon-growth promoting activity, matrix from permissive lines was found to be a good substrate, whereas matrix from the inhibitory astrocyte lines was a poor substrate for neuritic growth. Our findings, taken together, suggest that the functional differences between the permissive and the inhibitory astrocyte cell lines reside largely with the ECM.
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PMID:An analysis of astrocytic cell lines with different abilities to promote axon growth. 758 24

Hemovasal produced by Manetti-Roberts, Florence, Italy, is a glycosaminoglycan obtained from porcine intestinal mucosa which belongs to the family of heparan sulfates. The substance was examined On 36 male survivors of myocardial infarction with an interval of at least 6 months after the acute event. No anticoagulants were given and ASA was withdrawn at least 2 weeks before the trial. Hemovasal was administered in 3 different i.m. doses as single injections. A further group received a daily oral dose of 300 mg for one week. A comparable placebo group of patients as well as a group of healthy volunteers was run in parallel. The coagulation profile showed only a slight prolongation of the aPTT, a trace of diminution of Antithrombin III and no activation of Heparin cofactor II. The fibrinolytic system showed an enhancement of the diurnal increase of t-PA without an alteration of the total increase of this activity. There was a considerable and highly significant diminution of the PAI-1 activity. This was dose dependent and could be found after i.m. as well as after oral administration. It was assumed that the thrombolytic effect which was repeatedly described was a consequence of the diminution of PAI-1.
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PMID:On the action of a heparan-like glycosaminoglycan (Hemovasal) on the mechanism of haemostasis and fibrinolysis. 763 1

An early, complete, and sustained patency of the infarct related artery achieved by thrombolytic therapy reduces mortality in patients with acute myocardial infarction. In the ISIS-3-study there was no difference in mortality between t-PA, APSAC, and streptokinase. In contrast, in the GUSTO-trial, a "front-loaded" regimen of t-PA (100 mg/90 min) lead to a reduced inhospital mortality compared to streptokinase. This was most likely due to the higher early patency-rate of the infarct-related artery after the front-loaded t-PA. The search for new, more effective, thrombolytic regimens lead to a double-bolus injection of t-PA (2 x 50 mg) which revealed high early patency rates (> 80% TIMI-3 after 90 min). R-PA, a new recombinant plasminogen activator with a prolonged half-life, given as double bolus (2 x 10 MU), also produced high patency rates after 90 min without an increased incidence of reocclusions. Acetylsalicylic acid should be given routinely in every thrombolytic therapy. An anticoagulation with heparin seems to improve the efficacy of the more fibrin-specific thrombolytics t-PA, r-PA, and pro-urokinase. In dose-finding studies the specific thrombin inhibitor hirudin has been shown to significantly reduce reocclusions and reinfarctions compared to heparin. An "optimal thrombolysis" most likely can only be achieved by a thrombolytic agent with a very high early patency combined with an effective adjunctive therapy with platelet aggregation- and thrombin-inhibition.
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PMID:[Different therapeutic regimens in thrombolysis of acute myocardial infarct]. 786 5

Thrombolytic therapy has revolutionized the treatment of acute myocardial infarction by reducing mortality and preserving left ventricular function. It is relatively safe and cost-effective. However, it is currently underused in most countries. Patients in whom thrombolysis is indicated include those with ST elevation on the electrocardiogram or bundle branch block pattern who present within 12 hours of myocardial infarction; the indications should be widened to include the elderly, patients who have undergone nontraumatic cardiopulmonary resuscitation, and women during menstruation. The risk-benefit ratio should be assessed for the individual patient. Prehospital thrombolytic treatment has been shown to be feasible with the support of well-trained staff and resuscitation equipment, and may be cost-effective in communities with time delays before hospitalization greater than 1 hour. The most important strategy is to shorten the "door to needle" time in hospital. The importance of full infarct-related artery flow (Thrombolysis in Myocardial Infarction [TIMI] grade 3 flow) for preservation of ventricular function and survival has been documented in the second Thrombolysis Trial of Eminase in Acute Myocardial Infarction (TEAM 2) and the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) studies. Aspirin and heparin are beneficial adjunctive regimens to thrombolytic therapy but optimal epicardial reperfusion is achieved in only about half of patients. Improved thrombolytic, adjunctive antiplatelet, and antithrombotic regimens are required to achieve early full reperfusion, which is crucial to improve survival and quality of life.
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PMID:Thrombolytic therapy in acute myocardial infarction. 791 92

Radioactively labeled human fibrin clots were placed into veins of Macaca arctoides monkeys. Thrombolysis was recorded by the disappearance of radioactivity and by angiography. Streptokinase (SK) and urokinase (UK) induced thrombolysis was potentiated by low dose aspirin (ASA) and pentoxifylline (PE). Studies on the mechanisms of action revealed that PE inhibits platelet aggregation, releases tissue plasminogen activator (t-PA) from the endothelium, increases red cell deformability and inhibits white cell adhesion. Thrombolysis by pro-urokinase (pro-UK) was potentiated by low dose SK probably because of streptokinase-plasmin activation of pro-UK to UK. Platelet aggregation inhibitory effects, disaggregation of platelet aggregate inducing effects, and the t-PA releasing activity of PE was demonstrated in patients with obstructive cardiovascular disease. Pharmacodynamic studies suggested that PE metabolites one and five are most effective from this point of view. These metabolites are currently studied in combination with thrombolytic enzymes.
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PMID:Potentiation of thrombolytic therapy by enzyme combinations and with aspirin or pentoxifylline. 799 60

1. This study compares a cyclo-oxygenase inhibitor (aspirin), a 5-HT2 antagonist (ZM170809) and a combined thromboxane synthase inhibitor/receptor antagonist (ZD1542) as adjuncts to tissue plasminogen activator (rt-PA). 2. Application of an anodal current (332 +/- 4.1 microA) to the stenosed left circumflex coronary artery of 20 anaesthetized dogs produced a stable platelet-rich occlusive thrombus. 3. After initial i.v. administration of recombinant human tissue type plasminogen activator (rt-PA, 3 mg bolus +2 mg kg-1 h-1 for 30 min) thrombolysis occurred in 15 out of 20 dogs. All 15 dogs reoccluded. 4. The second i.v. administration of rt-PA in the presence of either aspirin, ZM170809, ZD1542 or saline resulted in thrombolysis in all 20 dogs. 5. Both the combined thromboxane synthase inhibitor/receptor antagonist (ZD1542) and 5-HT2 antagonist (ZM170809) significantly (P < 0.05) reduced the time taken to lyse the thrombus compared with the saline group. The times were 14.4 +/- 2.7 min, 18.0 +/- 3.9 min and 36.8 +/- 6.2 min for ZD1542, ZM170809 and saline respectively. 6. Aspirin did not offer any additional benefit to using rt-PA alone. The times to thrombolysis were 36.8 +/- 8.4 min for aspirin and 36.8 +/- 6.2 min for the saline group. 7. The number of dogs in which the circumflex coronary artery reoccluded within 60 min of terminating the second infusion of rt-PA were five for saline, four for aspirin, two for ZD1542 and two for ZM170809. 8. These results indicate that both ZD1542 and ZM170809 are more effective adjuncts than aspirin in thrombolysis and may provide an improvement in current clinical practice.
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PMID:Comparative effects of anti-platelet agents as adjuncts to tissue plasminogen activator in a dog model of occlusive coronary thrombosis. 803 50

Ridogrel, a compound with the dual property of inhibiting the synthesis of thromboxane and blocking the receptors of thromboxane/prostaglandin/endoperoxides, has been shown to accelerate the speed of recanalization and to delay or prevent reocclusion during systemic thrombolysis with tissue plasminogen activator in experimental animals. Ninety patients who had not taken any antiplatelet drugs within the last 10 days were randomized to either intravenous ASA 250 mg immediately before the thrombolytic treatment and 100 mg once a day orally thereafter or ridogrel 300 mg i.v. before thrombolytic treatment and 300 mg b.i.d. orally thereafter. All patients were given intravenous heparin concomitantly with alteplase. The patency of the infarct-related artery was determined by coronary angiography before the administration of the thrombolytic agent and by repeated coronary angiography every 15 min until the end of the administration of alteplase. A final angiogram was obtained 48 to 72 h later. At 90 min, the recanalization and patency rates were the same in the two treatment groups with no intergroup difference in the speed of recanalization.
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PMID:Ridogrel does not increase the speed and rate of coronary recanalization in patients with myocardial infarction treated with alteplase and heparin. 805 7

Adjuncts to thrombolytic agents have improved coronary patency and prevented early reocclusion after thrombolysis in acute myocardial infarction. The aim of this study was to compare in a canine thrombolysis model the effects of Ro 43-5054 = N-(N-[N-(p-amidinobenzoyl)-beta-alanyl]-L-alpha-aspartyl)-3- phenyl-L-alanine-trifluor-acetate, a new glycoprotein IIb-IIIa receptor antagonist with aspirin or heparin. Six groups of 10 dogs each were studied. A platelet-rich coronary thrombus was induced in open-chest dogs by electrical stimulation. In addition to recombinant tissue-type plasminogen activator (30 micrograms/kg.min during 60 min), the dogs received 1) saline, 2) heparin 200 U/kg + 50 U/kg.hr i.v., 3) aspirin 10 mg/kg i.v., 4) heparin+aspirin, 5) Ro 43-5054 (3 micrograms/kg.min) and 6) heparin+Ro 43-5054. The overall reperfusion rate was 70% (range, 60-90%) and comparable in all the six groups. During the 120-min observation period, episodes of reocclusion were observed in the absence of antiplatelet therapy (group 1 and 2) irrespective of heparin treatment. Aspirin prevented coronary reocclusion in half of the reperfused dogs (group 3 and 4). However, after reinforcement of the thrombogenic stimulus, 80% of the reperfused dogs treated with aspirin showed reocclusion, whereas none of them reoccluded when treated with Ro 43-5054. Thus, inhibition of platelet activation by the selective, nonpeptidic glycoprotein IIb-IIIa receptor antagonist Ro 43-5054, although without effect on the time to reperfusion, better protected than aspirin against early reocclusion after thrombolytic therapy.
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PMID:Effects of heparin, aspirin and a synthetic platelet glycoprotein IIb-IIIa receptor antagonist (Ro 43-5054) on coronary artery reperfusion and reocclusion after thrombolysis with tissue-type plasminogen activator in the dog. 842 48


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