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)

This study examines the cardioprotective effects of Na+/H+ exchange inhibition with BIIB-722 or ischemic preconditioning after occlusive thrombus formation and subsequent thrombolysis for reperfusion. Coronary artery thrombosis was induced by vessel wall electrolytic injury. Thrombotic occlusion was maintained for 60 or 90 min in 4 different groups: (1) control; (2) Na+/H+ exchange inhibitor, BIIB-722 (3 mg/kg) before occlusion; (3) BIIB-722 (0.75 mg/kg) before reperfusion; (4) ischemic preconditioning (4 x 5 min). Thrombolysis with intracoronary recombinant tissue plasminogen activator produced reperfusion in 6.3 +/- 1.4 min (average for 68 dogs). After restoration of blood flow, vessel patency was maintained for 4 h with the glycoprotein IIb/IIIa receptor antagonist, BIBU 52ZW. BIIB-722, administered before (26.9 +/- 3.6%) or after (22.0 +/- 2.3%) 60-min ischemia or preconditioning (18.4 +/- 2.8%), produced comparable and significant reductions in infarct size (percent of area at risk) compared to controls (47.2 +/- 2.0%). After 90 min of ischemia, BIIB-722 administered before occlusion (37.3 +/- 1.1%) and ischemic preconditioning (35.0 +/- 4.8%) provided significant cardioprotection compared to control (45.9 +/- 1.8%). BIIB-722 was not cardioprotective when administered during occlusion (48.0 +/- 2.4%). The results indicate that Na+/H+ exchange inhibition and preconditioning provide a comparable degree of cardioprotection against 60 min of regional ischemia. However, when the regional ischemic period is extended to 90 min, the degree of cardioprotection is markedly reduced. Further studies incorporating clinically relevant events such as thrombosis and thrombolysis are required before one can conclude that Na+/H+ exchange inhibition is effective against more prolonged myocardial ischemia.
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PMID:Effect of sodium/hydrogen exchange inhibition on myocardial infarct size after coronary artery thrombosis and thrombolysis. 1689 91

Hyperglycemia independently predicts poor outcome after acute ischemic stroke. CLOTBUST (Combined Lysis Of Thrombus in Brain ischemia using transcranial Ultrasound and Systemic tPA) demonstrated that ultrasound-augmented thrombolysis improves recanalization and 24-hour outcome in patients with acute ischemic stroke. We hypothesized that ultrasound would preferentially benefit hyperglycemic patients, and reviewed CLOTBUST with respect to admission glucose and good outcome. We found that ultrasound's benefit on 90-day outcome was primarily apparent at higher glucose levels, suggesting that ultrasound therapy may improve outcome following hyperglycemic stroke.
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PMID:Outcome in hyperglycemic stroke with ultrasound-augmented thrombolytic therapy. 1692 29

We report the life-saving administration of thrombolysis during cardiopulmonary resuscitation in a patient with recent intracerebral haemorrhage. A 53-year-old male with intracerebral haemorrhage was admitted to the intensive care unit. On the 24th day of treatment he suffered cardiac arrest with pulseless electrical activity. Transoesophageal echocardiography was performed during ongoing cardiopulmonary resuscitation. Thrombi in the right heart cavities with excessive right ventricular dysfunction confirmed the diagnosis of fulminant pulmonary embolism. Permanent restoration of a spontaneous rhythm was feasible only after administration of systemic thrombolysis with recombinant tissue plasminogen activator. Neurological examination and a computed tomogram of the brain did not show rebleeding. We conclude that under extreme circumstances absolute contraindications to thrombolysis should be weighed against the potential benefit.
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PMID:Successful resuscitation with thrombolysis of a patient suffering fulminant pulmonary embolism after recent intracerebral haemorrhage. 1708 12

Ultrasound (US) has emerged as a new tool to treat ischemic stroke. The potential advantage of US is decreased risk of systemic bleeding complications due to its site-specific effect. Moreover, external application is noninvasive and is readily available. Experimental studies showed that low intensity (<or=2W/cm2) US safely enhanced thrombolytic drug activity within a wide range of frequencies (0.04-3.4 MHz). In humans, transcranial sonothrombolysis with mid-kHz frequencies showed an unacceptably high rate of intracranial bleeding, while the use of 2MHz yielded promising results in The Combined Lysis of Thrombus in Brain Ischemia Using Transcranial Ultrasound and Systemic TPA (CLOTBUST) study. This study was a phase II randomized clinical trial that included patients with middle cerebral artery (MCA) occlusion within 3 h of stroke onset, who were treated with standard dose of tissue plasminogen activator (t-PA). Residual flow in MCA was monitored with 2MHz US in one group, and the rate of complete recanalization and dramatic clinical recovery significantly increased as compared to t-PA alone. This chapter further discusses diagnosis of an acute occlusion and recanalization using the thrombolysis in brain ischemia (TIBI) waveform flow grading scale, application of fast track insonation protocol, and administration of US. Also, the potential enhancement of sonothrombolysis with microbubbles is discussed.
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PMID:Acute stroke: therapeutic transcranial Doppler sonography. 1729 Jan 34

We report chronic histopathological features in thrombi mechanically retrieved from five acute ischemic stroke patients with a median age of 68 years and a median pretreatment National Institutes of Health Stroke Scale score of 13. Early endothelialization occurred over and within the thrombus, and calcifications were seen, in addition to the usual acute laminar fibrin, intervening red blood cells, and neutrophils. The effectiveness of tissue plasminogen activator in clot dissolution might be affected by these features, if extensive. Thrombus composition could critically determine the success of chemical thrombolysis. Our results should stimulate the development of imaging modalities to determine thrombus composition.
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PMID:Calcification and endothelialization of thrombi in acute stroke. 1857 Feb 98

Warfarin therapy has served as the backbone of chronic anticoagulation therapy for decades to prevent thrombotic morbidity secondary to blood-biomaterial interfaces. Unfortunately, thrombotic and bleeding complications are observed despite maintenance of therapeutic international normalized ratio (INR) values. We proposed to define the effects of warfarin therapy on thrombus growth and disintegration following contact pathway protein or tissue factor (TF) initiation. Normal subject or patient plasma with INR values between 1.8 and 9.6 were exposed to TF or celite and tissue-type plasminogen activator (tPA). Thrombus growth/disintegration kinetics were determined by changes in resistance over time with the clot lifespan model (CSLM), a thrombelastographic-based methodology. Data were collected until clot lysis time was observed. Linear relationships of the difference between the CLSM parameter values obtained from paired celite and TF-activated samples and corresponding INR value were determined and reported as r. The time to clot initiation was progressively prolonged with increasing INR values in all samples, and speed of clot formation, clot strength, and time to onset of fibrinolysis decreased as INR increased. Throughout the range of INR values tested, contact activation resulted in faster growing, stronger, and longer lived thrombi when compared with matched TF-activated plasma samples. Only the time to maximum rate of lysis was correlated with INR (r=0.36, p=0.005). INR values have little correlation with the difference between contact protein and TF-activated coagulation/fibrinolysis.
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PMID:Clot lifespan model analysis of the effects of warfarin on thrombus growth and fibrinolysis: role of contact protein and tissue factor initiation. 1909 56

Two clinical trials have used ultrasound to improve tPA thrombolysis in patients with acute ischemic stroke. The Combined Lysis of Thrombus in Brain Ischemia Using Transcranial Ultrasound and Systemic tPA (CLOTBUST) trial reported accelerated recanalisation of the middle cerebral artery (MCA) in patients with symptoms of MCA infarction, which were monitored with 2-MHz transcranial Doppler. In CLOTBUST, there was no increased bleeding as evidenced by cranial computed tomography. The Transcranial Low-Frequency Ultrasound-Mediated Thrombolysis in Brain Ischemia (TRUMBI) trial, which employed magnetic resonance imaging (MRI) before and after tPA thrombolysis, was discontinued prematurely because of an increased number of secondary hemorrhages, possibly related to the use of low frequency 300-kHz ultrasound. The purpose of our work is to help identify possible mechanisms of intracerebral hemorrhage resulting from sonothrombolysis by applying a simulation tool that estimates the pressure levels in the human brain that are produced with different sonothrombolysis devices. A simulation software based on a finite difference time domain (FDTD) three-dimensional (3D) scheme was developed to predict acoustic pressures in the brain. This tool numerically models the wave propagation through the skull and reproduces both ultrasound protocols of CLOTBUST and TRUMBI for analysis of the distribution of acoustic pressure in the brain during stroke treatment. For the simulated TRUMBI trial, we analyzed both a "high" and "low" hypothesis according to published parameters (for high and low amplitude excitations). For these hypotheses, the mean peak rarefactional pressures in the brain were 0.26 +/- 0.2 MPa (high hypothesis) and 0.06 +/- 0.05 MPa (low hypothesis), with maximal local values as high as 1.2 MPa (high hypothesis) and 0.27 MPa (low hypothesis) for configurations modelled in this study. The peak rarefactional pressure was thus higher than the inertial acoustic cavitation threshold in the presence of a standing wave in large areas of the brain, even outside the targeted clot. For the simulated CLOTBUST trial, the maximum peak negative pressure was less than 0.07 MPa. This simulated pressure is below the threshold for both inertial and stable acoustic cavitation but likewise lower than any acoustic pressure that has been reported as sufficient for effective sonothrombolysis. Simulating the pressure field of ultrasound protocols for clinical trials of sonothrombolysis may help explain mechanisms of adverse effects. Such simulations could prove useful in the initial design and optimization of future protocols for this promising therapy of ischemic stroke.
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PMID:Simulation of intracranial acoustic fields in clinical trials of sonothrombolysis. 1939 56

Carbon monoxide, derived from carbon monoxide-releasing molecules, has been recently demonstrated to enhance the velocity of formation and strength of plasma thrombi. We tested the hypothesis that carbon monoxide-releasing molecule-2 would modulate fibrinolysis of plasma thrombi. Normal plasma was exposed to 0, 25, 50, 100 or 200 micromol/l carbon monoxide-releasing molecule-2, with coagulation activated with tissue factor and fibrinolysis initiated with tissue-type plasminogen activator. Additional experiments utilized factor XIII, plasminogen activator inhibitor-1, thrombin activatable fibrinolysis inhibitor or alpha2-antiplasmin-deficient plasmas. Thrombus growth/disintegration kinetics was monitored with thrombelastography. Carbon monoxide-releasing molecule-2, in a concentration-dependent fashion, increased the velocity of thrombus formation and strength, and markedly attenuated fibrinolysis in normal plasma. In factor XIII-deficient plasma, carbon monoxide-releasing molecule-2 mediated effects on thrombus growth/disintegration kinetics were similar to that seen with normal plasma; however, carbon monoxide-releasing molecule-2 had a less marked effect on thrombus growth/disintegration in both plasminogen activator inhibitor-1 and thrombin activatable fibrinolysis inhibitor-deficient plasma, with even less carbon monoxide-releasing molecule-2-mediated effects noted in alpha2-antiplasmin-deficient plasma. Carbon monoxide-releasing molecule-2 attenuated fibrinolysis by enhancing the velocity of clot growth and strength while augmenting the effects of plasminogen activator inhibitor-1, thrombin activatable fibrinolysis inhibitor and alpha2-antiplasmin. These findings serve as the rationale for further investigations to determine if carbon monoxide-releasing molecules could be utilized as hemostatic agents.
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PMID:Carbon monoxide-releasing molecule-2 decreases fibrinolysis in human plasma. 1958

Carbon monoxide derived from a carbon monoxide-releasing molecule [tricarbonyldichlororuthenium (II) dimer; CORM-2] has been recently demonstrated to diminish tissue-type plasminogen activator (tPA)-mediated fibrinolysis of plasma thrombi via enhancement of alpha2-antiplasmin-plasmin interactions. The goal of this study was to confirm this mechanism by comparing tPA-mediated fibrinolysis with fibrin-independent, alpha2-antiplasmin-resistant streptokinase-mediated fibrinolysis in CORM-2 exposed plasma. Normal plasma was exposed to 0 or 100 micromol/l CORM-2, with coagulation activated with tissue factor and fibrinolysis initiated with 100 U/ml tPA or 50 U/ml streptokinase. Thrombus growth/disintegration kinetics were monitored with thrombelastography until clot lysis time occurred. Unlike tPA-lysed clots, streptokinase-exposed thrombi demonstrated no significant CORM-2-mediated prolongation of clot growth time or clot lysis time. In contrast, streptokinase-mediated lysis did not significantly change the CORM-2-mediated percentage increase in the maximum rate of clot growth or maximum rate of clot lysis compared with tPA-exposed thrombi. CORM-2 likely attenuates fibrinolysis by a fibrin-dependent/alpha2-antiplasmin-dependent mechanism. Additional molecular investigation (e.g., mass spectroscopy) is planned to further elucidate how CORM-2 modifies fibrinogen/fibrin.
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PMID:The antifibrinolytic effects of carbon monoxide-releasing molecule-2 are fibrin and alpha2-antiplasmin dependent. 2068 24

Reperfusion therapy for myocardial infarction is limited by significant re-occlusion rates and less-than-optimal myocardial tissue perfusion. It was the objective of this study to assess and compare the effect of ticagrelor, the first reversibly binding oral P2Y12 receptor antagonist, with that of clopidogrel, in conjunction with thrombolytic therapy, on platelet aggregation, thrombus formation, and myocardial perfusion in a canine model. Thrombus formation was induced by electrolytic injury and blood flow was measured with a Doppler ultrasonic flowmeter. All animals received tissue plasminogen activator (tPA) (1 mg/kg over 20 min); 10 animals received clopidogrel (10 mg/kg IV bolus over 5 min), 10 animals received ticagrelor initiated with a 1-min bolus (75 microg/kg/min), followed by continuous infusion (10 microg/kg/min) for 2 h, and 10 animals received IV saline. Re-occlusion rate and cyclic flow variation decreased with ticagrelor compared to saline groups (p<0.05). Adenosine phosphate (ADP)-induced platelet aggregation decreased with ticagrelor (1.9% +/- 2.67) and clopidogrel (1.11% +/- 2.0) vs. saline (26.3% +/- 23.5, p<0.05) at the end of adjunctive therapy. Bleeding time increased in the clopidogrel compared to the ticagrelor group (p=0.01). Infarct size was reduced with ticagrelor compared to the clopidogrel and saline groups (p<0.05). Blood flow remained significantly below baseline values at 20 min after tPA administration in the saline and clopidogrel groups but not in the ticagrelor group. In conclusion, in a dog coronary thrombosis model, ticagrelor blocks ADP-induced platelet activation and aggregation; prevents platelet-mediated thrombosis; prolongs reperfusion time and reduces re-occlusion and cyclic flow variation; and significantly decreases infarct size and rapidly restores myocardial tissue perfusion.
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PMID:Adjunctive treatment with ticagrelor, but not clopidogrel, added to tPA enables sustained coronary artery recanalisation with recovery of myocardium perfusion in a canine coronary thrombosis model. 2069 85


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