Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.68 (tissue plasminogen activator)
 11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To elucidate interactions responsible for inhibition of aggregation of platelets in platelet-rich plasma (PRP) harvested from whole blood preincubated with t-PA, experiments were performed with PRP and washed platelets under diverse conditions of preincubation. Both ADP and collagen induced aggregation were inhibited in PRP unless aprotinin had been added to the preincubated whole blood concomitantly with t-PA. However, in washed platelets prepared after the same exposure aggregation was intact. When washed platelets were supplemented with fibrinogen degradation products (FDPs) in concentrations simulating those in whole blood preincubated with t-PA, aggregation induced with either ADP or collagen was inhibited. Thus, the inhibition in PRP depended on generation of FDPs by activated plasminogen. The functional integrity of surface glycoprotein (GP) IIb/IIIa receptors in washed platelets was documented by autoradiography after SDS-PAGE of surface labeled GPs and by fibrinogen binding despite preincubation of the whole blood or washed platelets themselves with t-PA and plasminogen as long as exogenous calcium (greater than or equal to 0.1 microM) was present. In contrast, when calcium was absent, the platelet GP IIb/IIIa receptor was rendered susceptible to degradation by plasmin, and aggregation was inhibited by preincubation at 37 degrees C even if aprotinin was present when aggregation was being assayed. These observations reconcile disparate results in the literature from studies in vivo and in vitro by demonstrating that inhibition of aggregation of platelets in PRP and in whole blood reflects indirect effects of plasminogen activation rather than direct effects of t-PA or plasmin on the platelets themselves.
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PMID:The nature of interactions between tissue-type plasminogen activator and platelets. 214 66

Platelet activation is markedly increased during coronary thrombolysis and limits the response to thrombolytic therapy. A possible mediator of platelet activation in this setting is thromboxane (TX) A2, a potent platelet agonist formed in greatly increased amounts during coronary thrombolysis in man. To address this hypothesis, we examined the role of TXA2 in modulating the response to intravenous tissue-type plasminogen activator (t-PA) in a chronic canine model of coronary thrombosis. Reperfusion occurred in 60 +/- 5 minutes and was complicated by spontaneous reocclusion. The times to reperfusion and reocclusion were platelet-dependent. Consistent with a role for TXA2 in this process, TXA2 biosynthesis, determined a excretion of its enzymatic metabolite, 2,3-dinor-TXB2, was markedly increased during coronary thrombolysis. Furthermore, inhibition of TXA2 by aspirin, given alone or in combination with a TXA2/prostaglandin endoperoxide receptor antagonist, accelerated reperfusion and partly inhibited cyclic flow variations during reperfusion. The delay in reperfusion and reocclusion induced by TXA2 appeared to be mediated by platelet aggregation since the F(ab')2 fragment of 7E3, a monoclonal antibody to the platelet GPIIb/IIIa, also accelerated reperfusion and prevented reocclusion without altering TXA2 biosynthesis. These finding suggest that platelet aggregation limits the response to coronary thrombolysis and that platelet activation in this setting is partly TXA2-dependent.
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PMID:Increased thromboxane biosynthesis during coronary thrombolysis. Evidence that platelet activation and thromboxane A2 modulate the response to tissue-type plasminogen activator in vivo. 250 Feb 70

F(ab')2 fragments of a murine monoclonal anti-platelet GPIIb/IIIa antibody (7E3) are a potent platelet aggregation inhibitor, which in a canine coronary artery thrombosis model accelerate lysis with recombinant tissue-type plasminogen activator (rt-PA) and prevent reocclusion (7). In the present study, we have investigated the potential value of platelet aggregation inhibition as adjunctive therapy to lysis of venous thrombi, by measuring the thrombolytic potency of 7E3-F(ab')2 and rt-PA used alone or in combination, in dogs with a 125I-fibrin labeled femoral vein thrombus. The dose-response of thrombolysis with rt-PA infused over 4 hours was linear: doses of 0.075 mg/kg, 0.15 mg/kg and 0.3 mg/kg produced 37 +/- 3, 57 +/- 11 and 83 +/- 4% lysis respectively, against a background value of 20 +/- 2%. With F(ab')2 fragments of 7E3 given as a bolus of 1.2 mg/kg, which saturated 70% of the platelet GPIIb/IIIa receptors and prolonged the bleeding to more than 30 min, lysis was not significantly increased over background. Combination of 0.3 or 0.6 mg/kg of 7E3-F(ab')2 with either 0.03 or 0.06 mg/kg of rt-PA did not produce more lysis than obtained with a comparable dose of rt-PA alone. No significant changes in plasma fibrinogen or alpha 2-antiplasmin were observed with either agent alone or with the combination. It is concluded that extensive inhibition of platelet aggregation does not potentiate the thrombolytic effect of rt-PA in this venous thrombosis model.
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PMID:Absence of potentiation with murine antiplatelet GPIIb/IIIa antibody of thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) in a canine venous thrombosis model. 250 92

The composition of an evolving arterial thrombus may be a determinant of how effectively pharmacologic agents prevent reocclusion after initially successful thrombolysis. In this study, reoccluding platelet- or fibrin-rich thrombi as delineated by scanning electron microscopy were produced selectively in the femoral arteries of dogs with the use of electrically induced vascular injury or implantation of copper wire, respectively. Initial thrombolysis after intravenous infusion of tissue-type plasminogen activator (1 mg/kg over 30 minutes) was less frequent in the preparation producing platelet-rich thrombi than in that producing fibrin-rich thrombi (lysis in 19 of 24 versus 18 of 18, p = 0.06). In dogs with initial arterial recanalization, intravenous infusion of arginine-glycine-aspartate-O-methyltyrosine amide (RGDY), which competes with fibrinogen for binding to platelet glycoprotein IIb/IIIa receptors, prevented reocclusion caused by recurrence of platelet-rich thrombi in six of six dogs within 90 minutes; reocclusion occurred in five of seven saline-infused control dogs (p = 0.02). RGDY was only partially effective in preventing reocclusion caused by recurrence of fibrin-rich thrombi (reocclusion in three of six versus five of six controls, p = 0.54). Similar results were obtained with aspirin in both preparations. At least 98% of platelet aggregation induced ex vivo by collagen was inhibited by either RGDY or aspirin. In contrast with aspirin, however, platelet function returned to normal within 1 hour after discontinuation of RGDY. Thus, the relative proportions of platelets or fibrin incorporated into thrombi influence the efficacy of both tissue-type plasminogen activator for inducing thrombolysis and antiplatelet agents for preventing reocclusion. RGDY is a potent, short-acting inhibitor of platelet aggregation that effectively prevents reocclusion under conditions in which platelet deposition predominates.
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PMID:Prevention of reoccluding platelet-rich thrombi in canine femoral arteries with a novel peptide antagonist of platelet glycoprotein IIb/IIIa receptors. 259 49

Localized thrombosis was produced in the left anterior descending (LAD) coronary artery of open chest dogs by constricting a segment so as to produce greater than 90% stenosis (reducing blood flow to 40 +/- 10% of baseline), and placing a thrombus in the segment immediately proximal to the stenosis by inducing endothelial cell injury and instilling a mixture of blood and thrombin. Intravenous infusion of recombinant tissue-type plasminogen activator (rt-PA) at a rate of 15-30 micrograms/kg per min for 30 or 60 min in eight dogs induced coronary artery reperfusion within 23 +/- 7 min (mean +/- SD), but reocclusion occurred despite heparin anticoagulation in all but one of these dogs within 7 +/- 5 min. Intravenous injection of 0.8 mg/kg of the F(ab')2 fragment of a monoclonal antibody (7E3) directed against the platelet GPIIb/IIIa receptor, prevented reocclusion in 10/10 dogs during an observation period of 2 h (P less than 0.001 vs. rt-PA alone). The antibody abolished ADP-induced platelet aggregation and markedly prolonged the bleeding time. Intravenous aspirin or dipyridamole prevented reocclusion for 1 h or more in only 2/7 and 1/6 dogs, respectively. We conclude that the monoclonal antibody is very effective in preventing reocclusion after successful thrombolysis of occluded coronary arteries with rt-PA.
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PMID:Monoclonal antibody against the platelet glycoprotein (GP) IIb/IIIa receptor prevents coronary artery reocclusion after reperfusion with recombinant tissue-type plasminogen activator in dogs. 283 48

The effects of bolus injections of recombinant single-chain tissue-type plasminogen activator (rt-PA) and of F(ab')2 fragments of a murine monoclonal antibody (7E3) against the human platelet GPIIb/IIIa receptor [7E3-F(ab')2] on coronary arterial thrombolysis and reocclusion was studied in a canine preparation of coronary artery thrombosis superimposed on high-grade stenosis. Bolus intravenous injections of rt-PA at a dose of 0.45 mg/kg, repeated at 15 min intervals until reperfusion occurred (maximum of four injections) caused reperfusion in five of seven dogs within 100 min (33 +/- 15 min, mean +/- SD). Reperfusion was rapidly followed (generally within 10 min) by reocclusion and then by periods of cyclical reflow and reocclusion. A single intravenous injection of 7E3-F(ab')2 alone at 0.8 mg/kg caused reperfusion within 100 min in two of six dogs (19 and 37 min) without subsequent reocclusion. Single bolus injections of different amounts (0.1 to 0.8 mg/kg) of 7E3-F(ab')2 were then combined with bolus injections of 0.45 mg/kg of rt-PA. Stable reperfusion without reocclusion was accomplished with 0.8 or 0.6 mg/kg 7E3-F(ab')2 and a single injection of 0.45 mg/kg rt-PA within 6 +/- 3 min (n = 6, p less than .01) and 8 +/- 5 min (n = 5, p less than .02), respectively. None of these animals suffered reocclusion of the coronary artery. Lower doses (0.1 to 0.2 mg/kg) of 7E3-F(ab')2 did not significantly shorten the time to reperfusion and did not prevent reocclusion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Rapid and sustained coronary artery recanalization with combined bolus injection of recombinant tissue-type plasminogen activator and monoclonal antiplatelet GPIIb/IIIa antibody in a canine preparation. 312 74

The effects of Ro 44-9883, a new specific antagonist of platelet glycoprotein IIb-IIIa receptor, on thrombus formation and reocclusion after thrombolysis induced by tissue-type plasminogen activator (t-PA) were compared with those of vapiprost, a thromboxane (TX) A2 receptor antagonist, using a photochemically-induced thrombosis model in the guinea-pig femoral artery. Pretreatment with Ro 44-9883 (5, 10 and 20 micrograms/kg/min, i.v.) prolonged the time required to occlude the artery in a dose-dependent manner. Ro 44-9883 at 10 and 20 micrograms/kg/min significantly inhibited ex vivo platelet aggregation in whole blood induced by collagen, ADP or U46619. Vapiprost 0.3 mg/kg inhibited thrombus formation and platelet aggregation induced by collagen or U46619, to the same extent as Ro 44-9883 at the higher doses. In the thrombolysis study, Ro 44-9883 at the higher doses given as comedication with t-PA reduced the time to achieve reperfusion and increased the vascular patency after successful reperfusion. Vapiprost also significantly reduced the time to reperfusion and prevented reocclusion. However, the vascular patency after thrombolysis by t-PA with vapiprost was significantly increased compared with Ro 44-9883. Ro 44-9883 inhibited platelet aggregation, but did not prevent TXA2 formation in platelets. Thus, vascular contraction mediated by platelet-derived TXA2 may be responsible for lower efficacy of Ro 44-9883 against reocclusion compared with vapiprost. These results indicate that not only platelet aggregation but also vasoconstriction may contribute to reocclusion after t-PA-induced thrombolysis in the guinea-pig.
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PMID:Comparison of antithrombotic effects of GPIIb-IIIa receptor antagonist and TXA2 receptor antagonist in the guinea-pig thrombosis model: possible role of TXA2 in reocclusion after thrombolysis. 749 79

We examined the efficacy of the monoclonal antibody (MoAb) 7E3 F(ab')2 fragment, an inhibitor of the platelet glycoprotein (GP)IIb/IIIa receptor, to prevent coronary artery rethrombosis after successful thrombolysis with rt-PA. The circumflex coronary artery of anesthetized dogs was instrumented with a flow probe, an electrode, and a stenosis. After recovery from the surgical procedure, the animals were reanesthetized on post-operative day 9, and vessel wall injury was induced with current applied to the intimal surface of the circumflex coronary artery. The resulting occlusive thrombus was aged for 30 min, and recombinant tissue plasminogen activator (rt-PA) was administered. The animals were allocated to receive either placebo or a single dose of 7E3 [0.8 mg/kg intravenous (i.v.) bolus] as the sole adjunctive agent. Ex vivo platelet function and coronary artery blood flow velocity were recorded on each of 5 consecutive days. Reocclusion and mortality were reduced significantly in animals treated with 7E3 as compared with the placebo-treated group. Significant inhibition of ex vivo platelet aggregation persisted for 48 h after a single injection of 7E3. The MoAb 7E3 F(ab')2 fragment is effective as the sole adjunctive agent with rt-PA for prevention of rethrombosis. The present study is unique in that it examined the efficacy of GPIIb/IIIa inhibition in an experimental model for an extended time, demonstrating the duration of antiplatelet therapy required to prevent rethrombosis after thrombolysis.
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PMID:Prevention of rethrombosis after coronary thrombolysis in a chronic canine model. I. Adjunctive therapy with monoclonal antibody 7E3 F(ab')2 fragment. 751 47

Despite their widespread use in patients with acute myocardial infarction, all currently available thrombolytic agents suffer from a number of significant limitations, including resistance to reperfusion, the occurrence of acute coronary reocclusion, and bleeding complications. Several lines of research towards improvement of thrombolytic therapy are being explored, including strategies to enhance the fibrinolytic potency of plasminogen activators and to improve conjunctive antiplatelet or antithrombotic agents. Mutants and variants of plasminogen activators, chimeric plasminogen activators, and conjugates of plasminogen activators with monoclonal antibodies have been constructed, and plasminogen activators from animal or bacterial origin have been evaluated. Some of these new thrombolytic agents have shown promise in animal models of venous or arterial thrombosis and in pilot studies in patients with acute myocardial infarction. Such molecules include mutants of tissue-type plasminogen activator (t-PA) with prolonged half-life and/or resistance to protease inhibitors and staphylokinase. Antiplatelet strategies include the use of platelet glycoprotein IIb/IIIa receptor blocking agents, of thromboxane synthase inhibitors and endoperoxide receptor antagonists. Antithrombotic strategies include the use of selective inhibitors of thrombin, tissue factor or factor Xa. The efficiency and safety of these new agents in man will have to be carefully evaluated.
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PMID:New thrombolytic agents and strategies. 754 72

The antiaggregatory and antithrombotic actions of MK-0383, a low molecular weight, nonpeptide antagonist of the platelet glycoprotein IIb/IIIa, were evaluated in a variety of canine models. Inhibition of ex vivo platelet aggregation responses to ADP and collagen were observed after the acute sequential i.v. administrations of 10 to 500 micrograms/kg or 360-min continuous i.v. infusions of 1 to 10 micrograms/kg/min of MK-0383. Hemostatic function normalized within 30 (platelet response to collagen, template bleeding times) to 90 min (platelet response and sensitivity to ADP) after the termination of 360-min i.v. MK-0383 infusions, suggesting no protracted, direct effects on platelet function. With acute sequential i.v. administrations of MK-0383, platelet response to ADP was abolished without significant extension of bleeding time. In a model of platelet-dependent cyclic flow reductions in injured, stenosed left circumflex coronary artery, the bolus i.v. administrations of 300 and 1000 micrograms/kg of MK-0383 totally abolished cyclic flow reductions for periods of 18 +/- 1 and 37 +/- 5 min, respectively. In a model of electrically induced left circumflex coronary artery occlusive thrombosis, 10 micrograms/kg/min i.v. of MK-0383 initiated 15 min before electrical injury prevented occlusive thrombosis in three of six preparations despite continued electrical stimulation of the vessel for 300 min, delayed occlusion in three of six preparations (160.3 +/- 5.5 min) and reduced thrombus mass (5.1 +/- 1.3 mg), compared to the development of occlusive thrombosis in six of six saline-treated preparations (50.5 +/- 8.7 min; 19.1 +/- 3.0 mg). When administered as an adjunct to thrombolytic agents in the presence of background heparin for lysis of electrically induced left circumflex coronary artery occlusive thrombus, 10 micrograms/kg/min i.v. of MK-0383 initiated 15 min before tissue-type plasminogen activator or streptokinase increased the incidence of (tissue-type plasminogen activator: eight of nine MK-0383 vs. three of eight saline; streptokinase: eight of eight MK-0383 vs. two of eight saline) and accelerated reperfusion, and reduced the incidence of acute thrombotic reocclusion during continued MK-0383 infusion. These findings indicate significant antithrombotic potential for MK-0383 alone or as an adjunct to thrombolytic therapy in the treatment of coronary artery ischemic syndromes.
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PMID:Nonpeptide glycoprotein IIb/IIIa inhibitors. 5. Antithrombotic effects of MK-0383. 781 34


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