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)

To delineate the role of plasmin inhibitors, especially the two molecular forms of alpha 2-antiplasmin (that is, the plasminogen-binding and the nonplasminogen-binding forms), in the control of systemic effects during thrombolytic therapy, the consumption of plasmin inhibitors and the degree of fibrinogen breakdown were studied in 35 patients with acute myocardial infarction treated with recombinant tissue-type plasminogen activator (rt-PA) or streptokinase. At a low degree of plasminogen activation (in six patients treated with rt-PA), plasminogen-binding alpha 2-antiplasmin was consumed first. At a higher degree of plasminogen activation (in 20 patients), plasminogen-binding alpha 2-antiplasmin became exhausted (less than 20%) and other plasmin inhibitors (that is, nonplasminogen-binding alpha 2-antiplasmin and alpha 2-macroglobulin) were consumed. After extensive plasminogen activation (in nine patients treated with streptokinase), plasminogen-binding alpha 2-antiplasmin consumption was complete and nonplasminogen-binding alpha 2-antiplasmin and alpha 2-macroglobulin were consumed to about 30% to 50% of the pretreatment level. No significant C1-inactivator consumption occurred, even at extreme degrees of plasminogen activation. Fibrinogen breakdown as a marker for systemic effects correlated strongly with consumption of plasminogen-binding alpha 2-antiplasmin. Fibrinogen breakdown did occur, but only when the amount of plasminogen-binding alpha 2-antiplasmin was decreased to less than 20% of the pretreatment level. The other plasmin inhibitors could not prevent fibrinogen breakdown. These results were confirmed by in vitro studies. It is concluded that plasminogen-binding alpha 2-antiplasmin is the most important inhibitor of plasmin in the circulation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Plasmin inhibitors in the prevention of systemic effects during thrombolytic therapy: specific role of the plasminogen-binding form of alpha 2-antiplasmin. 169 50

Patients with unstable angina pectoris (UAP; n = 20) and acute myocardial infarction (AMI; n = 34) were studied in the acute phase of ischaemic heart disease. We found significantly higher levels of thrombin-antithrombin-III (TAT) complexes, lower levels of systemic tissue plasminogen activator (t-PA) activity, and higher levels of plasminogen activator inhibitor (PAI) activity in the AMI patients compared to the UAP patients. In contrast to these specific changes, general acute phase reactants such as C-reactive protein, fibrinogen and von Willebrand factor did not differ significantly between the two groups. Studies of the relationship between coagulation (TAT-complexes) and fibrinolysis data revealed a significant positive correlation between plasma antigen concentrations of TAT-complexes and t-PA (P less than 0.02), and between TAT-complexes and PAI-I (P less than 0.002). These observations indicate a common pathophysiological mechanism underlying the changes in coagulation and fibrinolysis, suggesting that coagulation activity and t-PA-related fibrinolysis are interrelated processes in vivo, and probably take place at the level of the endothelial cell.
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PMID:Interrelationship between coagulant activity and tissue-type plasminogen activator (t-PA) system in acute ischaemic heart disease. Possible role of the endothelium. 170 58

Human tissue-type plasminogen activator (t-PA) is a glycoprotein used currently in thrombolytic therapy for patients with acute myocardial infarction. Due to its rapid rate of clearance from the circulation, continuous intravenous administration of approximately 100 mg over 3 h is recommended. We have previously characterized novel thrombolytic variant forms of t-PA which offer the potential of administration by bolus injection and reduced dosage due to their slower rates of clearance, relative to t-PA. This study was undertaken to quantitatively compare the pharmacokinetics, thrombolytic activity, and hemostatic effects of two of these variant forms, called delta FE1X and delta FE3X plasminogen activator (PA), with commercially available recombinant t-PA (Activase). These evaluations were performed in rabbits after bolus intravenous injection of the proteins. Following injection of 0.25 mg of protein/kg of body weight, the rates of clearance for delta FE3X and delta FE1X PA antigen were decreased approximately 9- and 18-fold, respectively, relative to Activase. Plasma plasminogen activator activity was also measured and the rates of clearance of delta FE3X and delta FE1X PA activity were similarly decreased by approximately 9- and 22-fold, respectively, relative to Activase. To quantitate thrombolytic activity we used the rabbit jugular vein thrombosis model and demonstrated that approximately 50% thrombolysis was achieved with delta FE1X and delta FE3X PA at approximately an 8.6- and 3-fold lower dose than Activase, respectively. No major differences in fibrinogen and alpha 2-antiplasmin depletion were observed among the agents at doses required to produce 50% thrombolysis, indicating similarities in fibrin specificities among these agents. These results demonstrate a reciprocal relationship between thrombolysis and rate of clearance for these thrombolytic proteins. The 8.6-fold increase in potency of delta FE1X PA relative to Activase supports the future clinical testing of this novel engineered protein as a thrombolytic agent.
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PMID:Protein engineering of novel plasminogen activators with increased thrombolytic potency in rabbits relative to activase. 170 73

Thrombolytic therapy for evolving acute myocardial infarction (AMI) reduces infarct size, preserves ventricular function, and reduces mortality. Intravenous streptokinase is commonly followed by approximately 50% patency of coronary arteries within 90 minutes and by reduction of mortality by 25%. Recombinant tissue plasminogen activator (rt-PA) is more potent for coronary arterial thrombolysis, producing both more rapid and more frequent recanalization (approximately 75% patency at 90 minutes) with a dose of 100 mg given over 3 hours. Side effects (mainly bleeding) associated with the use of streptokinase and rt-PA are not markedly different. That the higher efficacy of rt-PA would translate into a larger reduction of mortality is suggested by the results of several small trials but remains to be confirmed in well-designed comparative clinical trials. This question has not been adequately answered by the recent International rt-PA/streptokinase mortality trial and the International Study on Infarct Survival (ISIS-3) study, because of concerns with respect to the role of conjunctive intravenous heparin administration and the dose of rt-PA used in ISIS-3. All available thrombolytic agents still have significant shortcomings, including the need for large doses to be maximally efficient, a limited fibrin specificity, and a significant associated bleeding tendency. New developments toward improved efficacy and fibrin-specificity of thrombolytic agents include the use of mutants of rt-PA, chimeric rt-PA or single chain urokinase plasminogen activator molecules, and antibody-targeted thrombolytic agents. Some of these artificial plasminogen activators have a 5- to 10-fold increased potency (thrombolytic activity per unit dose), but whether they are safe enough to be clinically useful remains to be established. The conjunctive use of anticoagulants and antiplatelet agents with thrombolytic agents increases their efficacy to an extent that monotherapy with a plasminogen activator alone is no longer tenable. Heparin and aspirin are only moderately efficient for acceleration of lysis and prevention of reocclusion, but are relatively safe. More selective thrombin inhibitors and antiplatelet agents are more potent, but their safety remains to be confirmed. Continued investigation in this area will provide new insights and promote progress toward the development of the ideal thrombolytic therapy, characterized by maximized stable coronary arterial thrombolysis with minimal bleeding.
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PMID:Designing thrombolytic agents: focus on safety and efficacy. 172 81

Ventricular arrhythmias during thrombolysis for acute myocardial infarction and their relation to coronary artery patency were examined. Twenty-four-hour Holter monitoring was begun 3.1 +/- 0.2 hours after onset of pain in 40 patients (age 54 +/- 1.6 years; anterior infarction 42.5%) treated with streptokinase (42.5%) or recombinant tissue-type plasminogen activator (57.5%) (delay from pain 3.3 +/- 0.2 hours). A Marquette 8000 computer was used for Holter analysis. The infarct-related artery was considered as patent (72.5%) or non-patent (27.5%) according to coronary angiography (delay from pain 26.7 +/- 2.5 hours; 60% less than 24 hours). Ventricular arrhythmias were present in all patients. Tolerance was good (1 cardioversion for ventricular fibrillation). The incidence of accelerated idioventricular rhythm was not different between patients with a patent and nonpatent artery (90 vs 82%), nor for ventricular tachycardia (VT) (83 vs 73%). Coronary artery patency was associated with a 14-, 13- and 32-fold increase of ventricular premature complexes, VT and accelerated idioventricular rhythms, respectively. The increased incidence of sustained VT (patent 38%; nonpatent 0%; p less than 0.05) and early (before the first 6 hours) accelerated idioventricular rhythm (patent 76%; nonpatent 18%; p less than 0.01) associated with artery patency suggests that these arrhythmias may be noninvasive diagnostic criteria for reperfusion (sensitivity 38 vs 76%, and specificity 100 vs 82%). A positive correlation was found between the frequency of ventricular premature complexes and VT, and peak creatine kinase.
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PMID:Holter recording of ventricular arrhythmias during intravenous thrombolysis for acute myocardial infarction. 173 50

Whereas in vitro studies showed that plasmin may induce both inhibition and activation of platelets, in vivo and ex vivo investigations suggested that thrombolytic agents are responsible for platelet stimulation. To gain further information on this topic, ex vivo platelet function was studied in 24 subjects with acute myocardial infarction treated with streptokinase or recombinant tissue-type plasminogen activator (rt-PA). Ten patients with acute myocardial infarction who did not receive thrombolytic treatment were also investigated. The data shows that at the end of thrombolytic infusion, the maximal extent of platelet aggregation and adenosine triphosphate release was reduced in treated patients compared with that in untreated ones. In subjects treated with streptokinase, the defect in platelet aggregation derived from both cellular and plasmatic defects. Plasmatic beta-thromboglobulin concentration was significantly reduced after streptokinase, but unchanged after rt-PA. Three days after thrombolytic treatment, platelet aggregation of patients receiving streptokinase or rt-PA was not significantly different from that of untreated subjects. A similar defect in platelet function was obtained in vitro, incubating normal platelet-rich plasma with pharmacologic concentrations of streptokinase. Again, platelet function defect derived from both cellular and plasmatic damages. It cannot be excluded that platelet activation occurs in patients with acute myocardial infarction during the very early phases of thrombolytic treatment. However, it is suggested that a transient defect in platelet function follows both streptokinase and rt-PA infusion.
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PMID:Platelet function after in vivo and in vitro treatment with thrombolytic agents. 138 58

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

Sustained infarct artery patency is an important determinant of survival in patients with acute myocardial infarction. We studied 61 patients with acute myocardial infarction who received intravenous recombinant tissue-type plasminogen activator, aspirin or heparin within 6 hours of symptom onset, to determine if infarct artery patency after intravenous thrombolytic therapy influences myocardial electrical stability as measured by the prevalence of spontaneous ventricular ectopy or late potential activity. Infarct artery patency was determined by angiographic evaluation 2.5 +/- 3 days after infarction. Forty-eight patients (79%) had a patent infarct-related artery and 13 (21%) patients had an occluded vessel. The mean number of ventricular premature complexes (VPCs)/hour (p less than 0.01) and the prevalence of late potentials (54 vs 19%; p less than 0.03) were significantly higher in patients with an occluded versus patent-infarct related vessel. Although VPC frequency and late potentials were not influenced by the time to thrombolytic treatment, patients with a patent infarct-related artery had a lower prevalence of late potentials regardless of whether treatment was initiated less than or equal to 2 hours (25% patent vs 50% occluded; p = not significant) or 2 to 6 hours (16% patent vs 55% occluded; p greater than 0.03) after symptom onset. Thus, successful thrombolysis decreases the frequency of ventricular ectopic activity and late potentials in the early postinfarction phase. The reduction in both markers of electrical instability may help explain why the prognosis after successful thrombolysis is improved after acute myocardial infarction.
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PMID:Importance of myocardial infarct artery patency on the prevalence of ventricular arrhythmia and late potentials after thrombolysis in acute myocardial infarction. 174 20

Underlying the use of thrombolytic therapy is the hypothesis that reestablishment and maintenance of coronary blood flow (coronary patency) are the primary mechanisms of therapeutic benefit in patients with acute myocardial infarction. Early achievement and maintenance of adequate coronary blood flow (patency) in the infarct-related artery are the primary goals of thrombolytic therapy. One third of patients may achieve spontaneous patency within a few days following acute myocardial infarction. When antithrombotic therapy (i.e., heparin) is administered, this rate increases to greater than 50%, but patency is achieved only gradually and mortality reductions comparable to thrombolytic therapy are not achieved. After administration of a thrombolytic agent, early (90-minute) patency rates are greater with alteplase or anistreplase than with streptokinase. However, patency rates for alteplase decline by 10-30% if intravenous heparin is not given concurrently. When patency is assessed greater than 24 hours following thrombolytic therapy, no significant difference exists among the agents. A single angiographic observation of the artery at 90 minutes, although useful, may be inadequate to distinguish among the beneficial clinical effects of different thrombolytic regimens. The overall reperfusion or patency profile is probably a better basis for assessing relative benefits. Intravenous thrombolytic regimens that are increasingly effective in rapidly achieving and maintaining coronary patency are now available and in further development.
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PMID:Overview of patency as an end point of thrombolytic therapy. 174 46

Based on apparent higher recanalization rates of the infarct-related artery, preferential use of thrombolytic agents with high clot specificity has been proposed for treating patients with acute myocardial infarction. In the Thrombolysis in Myocardial infarction (TIMI-I) and European Cooperative Group studies, higher reperfusion rates were observed with alteplase compared with streptokinase, causing many to assume that the former would achieve a greater reduction in early hospital mortality. However, the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI-2) and its associated International Study Group failed to show any differences in 15-day mortality between these agents in more than 20,000 patients. This apparent lack of correlation between reperfusion rates and early mortality may be explained in part when one considers that recanalization or patency rates measured at a given point in time, such as 90 minutes after onset of therapy, fail to define the subsequent vessel status. Early reocclusion is the major reason for this and is a major limitation to the clinical efficacy of thrombolytic drugs. Following recanalization, residual fibrin-bound thrombin adherent to the site of arterial injury from plaque rupture strongly promotes rethrombosis. Although antiplatelet and antithrombin agents such as aspirin and heparin help to decrease rethrombosis, these agents are far from ideal. Thrombolytic agents that produce a significantly prolonged systemic thrombolytic state, such as streptokinase and anistreplase, are likely to result in less rethrombosis. Therefore, a systemic fibrinolytic state would appear to be an advantage rather than a disadvantage, particularly because the incidence of intracerebral hemorrhage does not appear to be greater with their use compared with agents producing less systemic fibrinolysis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Thrombolysis, anticoagulation, and reocclusion. 174 47


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