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)

Aspirin at high but not at low doses reduces the fibrinolytic response to venous occlusion. Inhibition of vascular prostacyclin synthesis could be involved in this effect. Fish oil supplementation may redirect prostanoid metabolism toward an overall "antithrombotic" condition but with controversial effects on prostacyclin formation. In this study we investigated the effect of low-dose aspirin together with n-3 polyunsaturated fatty acid (PUFA) supplementation on the fibrinolytic response to venous occlusion. Following a double-blind, randomized, crossover design, six healthy volunteers (three men and three women, 24-37 years old) were given for 29 days 5.3 g eicosapentaenoic and docosahexaenoic acids or a corresponding dose of n-6 PUFAs as control; aspirin (40 mg/day) was then added for an additional 14 days. A 2-month washout period was allowed before the crossover. Blood was collected before and after venous stasis on days 0, 29, and 43 of each test period. A combination of aspirin with n-3 PUFAs reduced the fibrinolytic response to venous occlusion in all subjects, the mean value of fibrinolytic activity after stasis being 240 +/- 40 mm2, a value significantly lower than at baseline (366 +/- 51 mm2, mean +/- SEM, p < 0.05). Similarly, the tissue-type plasminogen activator (t-PA) antigen level was lower in the aspirin + PUFA-treated group. Plasminogen activator inhibitor activity before stasis was enhanced by n-3 PUFA supplementation (from 7.5 +/- 2 to 14.8 +/- 3 IU/ml, p < 0.05), an effect not affected by aspirin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of fibrinolytic response to venous occlusion in humans by a combination of low-dose aspirin and n-3 polyunsaturated fatty acids. 139 May 91

The role of aspirin on tissue plasminogen activator (t-PA) release was studied in rats after experimental venous occlusion. For this purpose, we developed a new experimental model which combines a vascular perfusion system (isolated rat hindquarters) with vascular stimulation, namely the application of venous stasis. Application of venous stasis for 30 min induced the release of t-PA from the vascular endothelium into the perfusate (from 0.19 +/- 0.05 to 0.39 +/- 0.05 UI/ml), reaching a peak 90 s after reperfusion. Aspirin administered to rats 60 min before the experiments (100 mg/kg i.v.), or dissolved in Tyrode solution (100 microM), suppressed 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) synthesis (0.38 +/- 0.09 in control and < 0.01 and 0.15 +/- 0.09 ng/ml, respectively, in aspirin-treated groups) but did not prevent the increase in fibrinolytic activity after venous occlusion (from 0.20 +/- 0.04 to 0.38 +/- 0.06 and from 0.07 +/- 0.03 to 0.27 +/- 0.03 IU/ml, respectively, in the aspirin-treated group). Our results suggest that the increase in fibrinolytic activity after experimental venous occlusion in isolated rat hindlegs is modulated by mechanism(s) other than the cyclooxygenase pathway in the vascular wall.
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PMID:Effect of aspirin on the fibrinolytic response in perfused rat hindquarters. 147 62

Antistasin is a 119-amino acid protein initially isolated from salivary glands of the Mexican leech, Haementeria officinalis, that exhibits potent anticoagulant properties resulting from selective inhibition of blood coagulation factor Xa. The comparative antithrombotic efficacies of recombinant antistasin (rATS), standard heparin (Hep), and aspirin (ASA) administered adjunctly with recombinant tissue-type plasminogen activator (tPA) on thrombolytic reperfusion and reocclusion were determined in a canine model of femoral arterial thrombosis. An occlusive thrombus was formed by insertion of a thrombogenic copper coil into the femoral artery, and blood flow velocity was monitored directly and continuously by Doppler flowmetry. Sixty minutes after occlusion, dogs received an intravenous infusion of either saline (vehicle) or rATS (0.31, 1.25, or 2.5 micrograms/kg/min), intravenous boluses of Hep (100 units/kg + 50 units/kg/hr or 200 units/kg + 150 units/kg/hr), or a single intravenous bolus of ASA (2.0 mg/kg), followed 45 minutes later by tPA (0.8 mg/kg i.v. over 90 minutes). The saline and rATS infusions were discontinued 60 minutes after termination of tPA, and the last Hep boluses were given 105 minutes after termination of tPA. All dogs achieved reperfusion. The time to reperfusion in the ASA group was similar to that in the vehicle group (50 +/- 9 versus 50 +/- 6 minutes, respectively). Reperfusion times were slightly decreased by the low and high doses of Hep (34 +/- 6 and 31 +/- 4 minutes, respectively) and the rATS doses of 0.31 and 1.25 micrograms/kg/min (37 +/- 4 and 36 +/- 5 minutes, respectively). However, the time to reperfusion was dramatically reduced with the 2.5 micrograms/kg/min rATS dose (15 +/- 3 minutes, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Acceleration of recombinant tissue-type plasminogen activator-induced reperfusion and prevention of reocclusion by recombinant antistasin, a selective factor Xa inhibitor, in a canine model of femoral arterial thrombosis. 157 36

Having previously shown in the Heparin Aspirin Reperfusion Trial that the empiric use of early intravenous heparin after recombinant tissue-type plasminogen activator (rt-PA) is an important component in the overall treatment strategy, we examine in this report the specific relation between the degree of prolongation of activated partial thromboplastin time and coronary artery patency. To evaluate the hypothesis that arterial patency after administration of rt-PA for acute myocardial infarction is sustained by effective anticoagulation, activated partial thromboplastin time of heparin recipients was determined 8 and 12 h after the start of thrombolysis. Mean activated partial thromboplastin time was higher among patients with an open infarct-related artery than in those with a closed artery (81 +/- 4 vs. 54 +/- 9 s, p less than 0.02). Only 45% of patients with values less than 45 s at both 8 and 12 h had Thrombolysis in Myocardial Infarction (TIMI) flow grade 2 or 3 in the infarct-related artery at 18 h. In contrast, 88% of patients with activated partial thromboplastin time greater than 45 s and 95% of those with values greater than 60 s had an open infarct-related artery at 18 h (p = 0.003 and 0.0006, respectively). Among patients with an initially patent infarct-related artery who underwent repeat angiography at 7 days, activated partial thromboplastin time was similar in those with a persistently patent artery and those with late reocclusion. Excessive anticoagulation did not appear to increase hemorrhagic risk except that access site-related hemorrhage was more common in patients with activated partial thromboplastin time greater than 100 s at 8 h.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Heparin-induced prolongation of partial thromboplastin time after thrombolysis: relation to coronary artery patency. HART Investigators. 160 35

Multiple clinical trials have demonstrated that thrombolytic treatment early in the course of acute myocardial infarction significantly reduces mortality. Patients under 75 years of age who have had chest pain for no longer than six hours and who demonstrate ST-segment elevation on electrocardiogram are the best candidates for this therapy. Recent studies suggest that there is little difference in effectiveness among streptokinase, alteplase and anistreplase. However, streptokinase is 10 times less expensive than the other agents and causes fewer intracranial bleeds, the major serious adverse effect of thrombolytic therapy. An advantage of anistreplase is that it can be given in a five-minute bolus injection, compared with a one-hour infusion for streptokinase and a three-hour infusion for alteplase. Thrombolytic therapy is contraindicated in patients with known pregnancy, active internal bleeding, uncontrolled hypertension, aortic dissection, intracranial neoplasm or a history of hemorrhagic stroke. Heparin should be administered with both alteplase and streptokinase. Aspirin, beta blockers, nitrates and lidocaine are useful adjunctive therapies in the setting of an acute myocardial infarction.
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PMID:Thrombolytic therapy in acute myocardial infarction. 173 49

Coronary thrombolysis is the treatment of choice for patients with acute Q-wave myocardial infarcts who have no contraindications to such therapy. However, the time required for thrombolysis and the possibility of reocclusion of the infarct-related artery remain problematic. Herein are described experimental animal studies and clinical evaluations in which attempts have been made to develop adjunctive therapies that, when coupled with available thrombolytic interventions, might shorten the time to thrombolysis and delay or prevent reocclusion. From the studies conducted to date, it is clear that a combined thromboxane synthesis inhibitor and receptor antagonist with a serotonin receptor antagonist and heparin shorten the time to thrombolysis and delay or prevent coronary artery reocclusion in experimental canine models with copper coil-induced coronary artery thrombi. A monoclonal antibody to the platelet glycoprotein IIb/IIIa receptor coupled with tissue plasminogen activator (t-PA) and heparin also shortens the time to thrombolysis and delays or prevents reocclusion in experimental canine models. Thrombin inhibitors, including heparin and synthetic inhibitors, given with t-PA and aspirin, appear to shorten the time to thrombolysis and delay or prevent coronary artery reocclusion in experimental canine models. Aspirin coupled with intravenous streptokinase reduces mortality in patients with presumed acute myocardial infarction, and a combination of heparin and t-PA results in infarct-artery patency more frequently than t-PA without heparin. Data from these studies are encouraging with regard to the possibility of developing effective and relatively safe thrombolytic regimens that shorten the time to thrombolysis and delay or prevent coronary artery reocclusion.
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PMID:Role of new antiplatelet agents as adjunctive therapies in thrombolysis. 199 Jul 81

Malignant tumors are generally characterized by extensive local tissue invasion and destruction of ECM which may be due to increased constitutive expression and activity of secreted proteases. Moreover, a large number of diverse protease activities may be constitutively over-expressed in a simultaneous or co-ordinated fashion, thereby significantly increasing cellular invasive potential of the cells. To explore this relationship, we have measured steady-state levels of mRNA coding for urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA), transin and tissue-specific inhibitor of metalloproteinases (TIMP); as well as gelatinolytic, caseinolytic and plasminogen activator activities secreted by SPI, a non-metastatic mouse mammary carcinoma cell line and 4 metastatic sublines derived from it. mRNA encoding metalloproteinase transin was increased 15- to 20-fold, while TIMP transcripts were decreased 3-fold in the metastatic sublines compared to parental SPI tumor cells. Metastatic sublines secreted higher levels of gelatinase (i.e., 92 kDa and 64 kDa) as well as proteases with caseinolytic activity (i.e., 115 kDa and 57 kDa) when compared with SPI cells. Moreover, these enzymes were identified as neutral metalloproteinases. Although the amount of uPA mRNA appeared to be the same in SPI and the metastatic sublines, the latter secreted 1.5-3 times more uPA activity into the culture supernatants. Metastatic competence in the SPI tumor model is therefore associated with increased secretion of several metalloproteinase activities and uPA, as well as decreased TIMP expression, consistent with a more invasive phenotype.
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PMID:Constitutive expression and secretion of proteases in non-metastatic SP1 mammary carcinoma cells and its metastatic sublines. 204

Aspirin has been shown to be beneficial in the prophylaxis of arterial thromboembolic disease. The rationale for its use as an antithrombotic drug lies in its inhibition of thromboxane A2-dependent platelet function. However, the effect of aspirin on coagulation and fibrinolysis during chronic therapy has not been studied. We have measured a range of haemostatic and platelet functions in 49 patients with transient ischaemic attacks randomly allocated to aspirin 300 mg a day, aspirin 1,200 mg a day or placebo. All had been taking their allocated treatment for between 9 months and 4 years prior to investigation. Bleeding time was prolonged, serum thromboxane diminished and platelet aggregation to arachidonic acid but not ADP was abolished by both 300 mg and 1,200 mg aspirin, in a non-dose dependent fashion. Serum salicylate increased with the dose of aspirin ingested. No effect was seen with either dose of aspirin on urinary thromboxane and 6-keto-PGF1 alpha excretion, or on coagulation. Patients taking 1,200 mg aspirin a day had a lower haemoglobin and packed cell volume, lower resting fibrinopeptide A concentration and lower basal plasminogen activator activity than those on placebo. Response to venous occlusion was normal in all groups. The results suggest 300 mg and 1,200 mg aspirin have an equivalent platelet inhibitory effect but 1,200 mg aspirin causes greater gastro-intestinal blood loss.
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PMID:Coagulation, fibrinolytic and platelet function in patients on long-term therapy with aspirin 300 mg or 1,200 mg daily compared with placebo. 207 96

SK, t-PA or APSAC were incubated in human plasma (adjusted to 300,000 platelets/mm3), in vitro, for up to 90 minutes using concentrations which were equivalent to those achieved in the treatment of AMI patients. Aggregation was measured in response to ADP and collagen. SK inhibited platelet aggregation after a 60 minute incubation. t-PA was less inhibitory and significant effects were only achieved on extended incubation with a higher concentration of activator. APSAC markedly inhibited platelet aggregation in response to both ADP and collagen and the inhibition was achieved earlier than with SK. The difference in temporal response between APSAC and SK was not attributed to differences in systemic plasminogen activation. There was no influence of anti-SK antibody (IgG) on the platelet function response to APSAC or SK. Aspirin inhibited second phase aggregation induced by ADP but even in the presence of aspirin, the net inhibition of platelet aggregation was greater for APSAC than for SK. This marked effect of APSAC on platelet aggregation helps to explain the high initial patency and low re-occlusion rates seen when APSAC is administered to AMI patients.
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PMID:Comparison of the effects of streptokinase, t-PA and APSAC on human platelet aggregation in vitro in the absence and presence of aspirin. 212 20

In the course of studies on the regulation of plasminogen activator-mediated extracellular matrix degradation in muscle we found the presence of a factor, a cellular inhibitor of serine proteases having features similar to the serpin protease nexin I (PNI). This factor was present in the medium and at maximum concentration following fusion of skeletal muscle cells in culture. The ability of the PNI homologue in mouse muscle to inhibit ECM degradation by urokinase in myoblast medium was compared to that of human PNI purified from human fibroblasts. Stable (to SDS) 1:1 molar ratio complex formation between PNI and proteases, the proposed means by which these enzymes are regulated and removed, was also detected. Cell surface receptors for protease:PNI complexes, the specific binding sites for inactive complex internalization, were found on multinucleated myotubes, while little or no receptor activity was detected on myoblasts. These data suggest that developmental regulation of a) increased PNI proteolytic inhibitory activity expression and b) the appearance of protease:inhibitor complex receptors on muscle cell surfaces during myogenesis may constitute important regulatory features of muscle surface proteolytic activity. They complement previous studies of proteoglycan metabolism in muscle, which itself contains molecules capable of regulating the activity of myotube surface proteases.
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PMID:Plasminogen activators and their inhibitors in the neuromuscular system: II. Serpins and serpin: protease complex receptors increase during in vitro myogenesis. 216 58


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