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)

Tissue-type plasminogen activator (t-PA) is a fibrin-specific agent which has been used to treat acute myocardial infarction. In an attempt to clarify the determinants for its rapid clearance in vivo and high affinity for fibrin clots, we produced five variants containing amino acid substitutions in the finger domain, at amino acid residues 7-9, 10-14, 15-19, 28-33, and 37-42. All the variants had a prolonged half-life and a decreased affinity for fibrin of various degrees. The 37-42 variant demonstrated about a 6-fold longer half-life with a lower affinity for fibrin. Human plasma clot lysis assay estimated the fibrinolytic activity of the 37-42 variant to be 1.4-fold less effective than that of the wild-type rt-PA. In a rabbit jugular vein clot lysis model, doses of 1.0 and 0.15 mg/kg were required for about 70% lysis in the wild-type and 37-42 variant, respectively. Fibrinogen was degraded only when the wild-type rt-PA was administered at a dose of 1.0 mg/kg. These findings suggest that the 37-42 variant can be employed at a lower dosage and that it is a more fibrin-specific thrombolytic agent than the wild-type rt-PA.
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PMID:Recombinant variants of tissue-type plasminogen activator containing amino acid substitutions in the finger domain. 128 81

Plasma von Willebrand factor, plasminogen activator inhibitor activity and C-reactive protein were assessed as markers of coronary recanalisation in 30 patients with acute myocardial infarction receiving tissue-type plasminogen activator (t-PA). Blood samples were taken before t-PA (time 0), 4-hourly for 24 h and daily up to 72 h. A continuous electrocardiogram was recorded in the first 24 h. Coronary arteriography was performed 90 min and 24 h after the start of t-PA. Patients with a patent infarct artery (n = 17), compared to those with occluded artery (n = 13), showed a fall in von Willebrand factor from 0 to 24 h (p = 0.001), a greater fall in plasminogen activator inhibitor from 24 to 48 h (p = 0.04) and a fall in C-reactive protein from 48 to 72 h (p = 0.002). The accuracy of these indices compared favourably with time to peak plasma MB creatine kinase and > or = 50% resolution of maximal ST-deviation on the electrocardiogram. Thus, changes in plasma von Willebrand factor, plasminogen activator inhibitor and C-reactive protein during the first 3 days of myocardial infarction are indicative of thrombolytic efficacy. Their concordant behaviour may reflect a common regulatory mechanism.
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PMID:Von Willebrand factor, plasminogen activator inhibitor-1 and C-reactive protein are markers of thrombolytic efficacy in acute myocardial infarction. 128 82

This 6-month follow-up of the patients recruited into the GISSI-2 Study and the International Study substantially confirmed the in-hospital results. The aim was to compare the effectiveness and safety of alteplase (tPA) and streptokinase (SK), and of heparin and no heparin, in patients with acute myocardial infarction in an open multicentre randomized trial with a 2 x 2 factorial study design. Six-months' mortality rates were similar for patients randomized to tPA or SK (12.3% vs 11.7%, RR = 1.06, 95% CI 0.97-1.15) and for patients randomized to heparin or no heparin (11.9% vs 12.1%, RR = 0.98, 95% CI 0.90-1.07). Mortality rates were also similar between randomized treatments in the pre-defined subgroups: sex, age above and below 70 years, with and without previous myocardial infarction, Killip class at entry and randomization within 3 h or between 3 and 6 h from onset of symptoms. Reinfarction and cerebrovascular accidents were similar in all treatment groups. Adjusted analysis (Cox model) indicated that age and higher Killip class were the most important predictors of a poor prognosis. Previous myocardial infarction, female sex and longer delay from onset of symptoms were also indicators. Patients treated with SK plus heparin have a statistically significant better survival than the others, although the statistical significance of the remaining absolute difference disappears once the substantial proportion of patients dying in the first 12 h is excluded, when, by design, no heparin was given.
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PMID:Six-month survival in 20,891 patients with acute myocardial infarction randomized between alteplase and streptokinase with or without heparin. GISSI-2 and International Study Group. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto. 128 1

We observed the changes of molecular markers for hemostatic activation in a patient with acute pulmonary embolism treated with 2 x 10(7) unit tissue plasminogen activator (t-PA). Blood samples were obtained before, just after, at 30 min, 1, 2, 6, and 24 hours after the infusion. Molecular markers included thrombin-antithrombin III complex (TAT), plasminogen-alpha 2 plasmin inhibitor complex (PIC), and thrombomodulin (TM). Marked elevation of TAT was observed from immediately after the t-PA infusion to 6 hours after, although it had been observed for only 1 hour in our previous report on the cases of acute myocardial infarction. PIC level was significantly increased during t-PA infusion but returned to almost baseline value 6 hours after the end of t-PA infusion. This finding was almost the same as the one previously reported concerning acute myocardial infarction cases. TM level increased throughout the evaluation, and remained so, even on the 7th day after t-PA infusion. Our present data revealed a clear difference between the reactive TAT increases after t-PA therapy in acute myocardial infarction cases and in acute pulmonary embolism cases. Our present data also revealed a prolonged elevation of TM during the acute period of pulmonary embolism. It is therefore necessary to keep an eye on the changes of molecular markers for hemostatic activation after t-PA therapy in acute pulmonary embolism.
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PMID:[The changes in molecular markers for hemostatic activation after t-PA therapy in case of pulmonary embolism]. 131 73

Atherosclerosis is probably caused by multiple interacting factors such as disturbed lipid metabolism; endothelial cell damage, leading to platelet aggregation and monocyte invasion with the release of mitogenic factors; and disorders of fibrin balance, leading to persisting fibrin deposits. Deficient fibrinolysis may (1) predispose to fibrin deposition and contribute to the pathogenesis of atherosclerosis and (2) contribute to occlusive thrombus formation on fissured plaque, provoking atherothrombosis. Prospective epidemiologic studies have so far not provided definitive evidence that deficient fibrinolysis constitutes a significant risk factor for the development of atherosclerosis. Two recent findings, however, strongly suggest a contribution: (1) Increased lipoprotein(a) levels that reduce tissue-type plasminogen activator (t-PA)-mediated clot lysis are a clear risk factor for atherosclerosis; and (2) increased plasminogen activator inhibitor-1 (PAI-1) levels in patients with disturbed glucose tolerance predispose to an accelerated development of atherosclerotic disease. However, deficient fibrinolysis constitutes a risk factor for the development of thrombotic complications (acute myocardial infarction) in patients with coronary artery disease. The potential role of deficient fibrinolysis in the pathogenesis of atherosclerosis and of atherothrombosis suggests that drugs normalizing deficient endogenous fibrinolysis by either reducing PAI-1 synthesis or by stimulating endogenous t-PA synthesis may be of clinical value. Although regulation of the gene expression of PAI-1 and t-PA is presently under active investigation, no potent specific and safe agents to downregulate PAI-1 or to upregulate t-PA have as yet been identified. Retinoic acid appears to be a specific inducer of t-PA synthesis in human endothelial cells in culture and may constitute a model for the development of drugs that stimulate endogenous t-PA synthesis.
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PMID:On the role of coagulation and fibrinolysis in atherosclerosis. 134 93

Tissue-type plasminogen activator produced by recombinant DNA technology, has been established as an important thrombolytic agent in the treatment of acute myocardial infarction. New approaches to increase the effectiveness of this agent, including rapid high dose administration are being investigated. Several novel protein engineered variant forms of plasminogen activators have been produced that have increased thrombolytic potency in animal models and offer the potential of a more effective lower dose agent than can be administered clinically as a single bolus intravenous injection.
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PMID:Thrombolytic therapy with tissue-type plasminogen activator: new modes and novel variant plasminogen activators. 136 62

Pharmacokinetics and fibrin specificity of alteplase (recombinant tissue-type plasminogen activator) were determined in 10 patients with acute myocardial infarction undergoing an accelerated infusion regimen during the alteplase/anistreplase patency study (TAPS). Fifteen milligrams of alteplase was administered as an intravenous bolus injection, followed by infusions of 50 mg over 30 min and 35 mg over a further 60 min. Mean steady state plasma concentrations of alteplase during the initial 30 min were 3.2 +/- 0.84 micrograms/ml, measured immunochemically, and 2.1 +/- 0.23 micrograms/ml, measured using a functional activity assay. These values were 45% and 51% higher, respectively, than those during the standard infusion schedule (p less than 0.01). However, the predominant plasma half-life determined by model fitting based on either assay (3.3 to 3.5 min) was unaltered compared with the standard regimen. Maximal concentrations of fibrin and fibrinogen degradation products were 5.1 +/- 2.2 and 1.9 +/- 1.1 micrograms/ml, respectively. Plasminogen decreased to 70% and alpha 2-antiplasmin to 35% of values before infusion. The results indicate that 1) improved coronary patency rates during "front-loaded" infusions can be rationalized in terms of higher plasma concentrations of both free and immunoreactive alteplase, 2) kinetic variables are comparable with those of other dosing strategies, and 3) fibrin specificity is not diminished relative to that of the standard infusion regimen.
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PMID:Pharmacokinetics and fibrin specificity of alteplase during accelerated infusions in acute myocardial infarction. 155 98

In the past 10 years, thrombolytics have become standard therapy for acute myocardial infarction. Although the ability of streptokinase to lyse clot was first recognised in the 1930s, thrombolytic therapy was not used to treat acute myocardial infarction until the early 1980s, when the importance of thrombosis in the pathogenesis of acute infarction was fully recognised. In addition to streptokinase and urokinase, recombinant human tissue plasminogen activator (tPA) and anistreplase were developed and widely used in the 1980s. Saruplase (prourokinase) and BM-06022 (recombinant plasminogen activator) have also undergone human clinical studies. All of these agents are effective at achieving clot lysis and coronary patency. Large, randomised clinical trials have demonstrated that thrombolytic therapy reduces mortality in patients with ST elevation treated within the first 6 to 12 hours of acute infarction, with an approximately 0.5% risk of intracranial haemorrhage. Recent data have more clearly identified which patients benefit from thrombolytic therapy. Efforts have been made to improve the speed of reperfusion, decrease reocclusion, simplify administration and reduce adverse effects. The characteristics of fibrin specificity and more rapid clot lysis with tissue plasminogen activator have not yet been translated into overall clinical benefit compared with the less expensive streptokinase. The lack of close association of improved early patency and improved global left ventricular function with improved survival challenges the very paradigm which led to the use of thrombolytic therapy for acute myocardial infarction. The need for development of additional methods for evaluation of new thrombolytic agents is evident.
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PMID:Thrombolytic therapy for acute myocardial infarction. A review . 138 31

A 29-year-old man with congenital protein C deficiency and acute myocardial infarction is reported. Four hours after the onset of chest pain, he was treated intravenously with tissue-type plasminogen activator. Subsequent coronary angiography revealed only slight stenosis of the left anterior descending coronary artery without any atherosclerosis. The propositus, his brother, and his mother, showed low levels of both protein C activity and antigen, while plasma thrombomodulin levels were normal. His grandfather had died from acute myocardial infarction at 38 years of age. We investigated several other risk factors for arterial thrombosis, including factor VII, fibrinogen, heparin cofactor II, lipoprotein (a), and anticardiolipin antibodies. No other haemostatic abnormalities apart from factor VII hyperactivity were detected in this family. To study the effects of protein C and factor VII on procoagulant activity, prothrombin time was measured after the addition of activated protein C and factor VII to protein C-deficient plasma. The prothrombin time ratio decreased along with an increase in the factor VII level. It also decreased with a decrease in the activated protein C level. These findings indicated that the procoagulant activity of factor VII was enhanced by low protein C levels, suggesting that concomitant factor VII hyperactivity may cause acute myocardial infarction in patients with protein C deficiency.
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PMID:Congenital protein C deficiency and myocardial infarction:concomitant factor VII hyperactivity may play a role in the onset of arterial thrombosis. 144 May 17

While it is no longer possible to imagine the treatment of an acute transmural myocardial infarction without the use of thrombolytic agents, some discussion still exists as to the choice of the thrombolytic agent. Our study concerns a group of 160 patients with an acute transmural myocardial infarction, 60 of whom were treated with anistreplase, 52 with streptokinase and 48 with alteplase. Statistically, the administration of anistreplase was associated with a significantly higher frequency of ventricular arrhythmias in comparison to the other thrombolytic agents, whereas after subsequent coronary angiography, the anistreplase group revealed a significantly lower number of completely occluded coronary arteries. The data from this study demonstrate that anistreplase is a very valuable thrombolytic agent. It may even be more effective than streptokinase and alteplase in the treatment of acute myocardial infarction when the patency of the coronary arteries 1 month after the acute coronary event is considered the primary endpoint.
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PMID:Are the various thrombolytic agents equally effective in the treatment of acute transmural myocardial infarction? 145 46


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