Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Thrombotic obstruction of a mechanical cardiac valve prosthesis requires urgent therapy. We report on the treatment of prosthetic valve thrombosis with recombinant tissue plasminogen activator (rt-PA) in three children at the age of 4, 10 and 18 months, in whom a St. Jude Medical prosthesis had been placed at the atrioventricular valve level 2 to 6 weeks earlier. The initial rt-PA dose was 0.4 mg/kg given over 15 min and followed by a continuous daily infusion of 1.6 to 2.0 mg/kg. In addition the patients received heparin (200 U/kg/d). Thrombolytic therapy was administered for a range of 4 to 28 days. The therapy was successful in the first case. The second child had four recurrent events of prosthetic valve thrombosis and the thrombolytic therapy was successful three times. However, the prosthesis had to be finally replaced. In the third case the thrombolytic therapy was only partially successful due to an organized thrombus requiring prosthesis replacement.
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PMID:[Thrombolysis of prosthetic heart valve thrombosis using recombinant tissue plasminogen activator (rt-PA) in infancy and childhood]. 1131 78

Previous studies have shown that external ultrasound with low frequencies and high intensities can enhance thrombolytic drug-induced clot dissolution during in vitro experiments. In this series of studies, we evaluated the efficacy of peripheral and coronary thrombolysis in vivo in animals by using noninvasive transcutaneous ultrasound combined with thrombolytic drugs (streptokinase and tPA) and/or microbubbles agents (dodecafluoropentane [DDFP] and perfluorocarbon-exposed sonicated dextrose albumin [PESDA]). Thrombotic occlusions were induced in 74 rabbit iliofemoral arteries and 24 canine left anterior descending (LAD) coronary arteries in this in vivo study. By using the combination of transcutaneous ultrasound and streptokinase, the angiographic patency rate in rabbit iliofemoral arteries was higher (56%-100%) than with ultrasound (6%; P < or = 0.0036) and streptokinase alone (6%; P < or = 0.0012). Also, with transcutaneous ultrasound and microbubbles, the angiographic patency rates were 76%-100% as compared with ultrasound alone (0%, P < or = 0.0003) or microbubbles alone (9%, P < or = 0.0001). In the canine study of acute myocardial infarction, thrombolysis in myocardial infarction (TIMI) grade flow at 90 minutes in the tPA alone group was 0.92 +/- 1.4 as compared with 2.42 +/- 1.9 in the tPA plus transthoracic ultrasound group (P = 0.006). There was much improved reperfusion with tPA plus ultrasound as compared with tPA alone. In vivo animal studies demonstrate that noninvasive transcutaneous ultrasound can greatly enhance the effect of clot dissolution with thrombolytic drugs and/or microbubbles, and has the potential for clinical application as an adjunctive method to improve arterial thrombolysis.
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PMID:Noninvasive transcutaneous low frequency ultrasound enhances thrombolysis in peripheral and coronary arteries. 1132 8

Using tracings of (125)I-labeled fibrin(ogen) in rodents, we examined the hypothesis that platelets impede the lysis of pulmonary emboli. (125)I-Microemboli (ME, 3-10 micron diameter) lodged homogeneously throughout the lungs after intravenous injection in both rats and mice (60% of injected dose), caused no lethality, and underwent spontaneous dissolution (50 and 100% within 1 and 5 h, respectively). Although lung homogenates displayed the most intense fibrinolytic activity of all the major organs, dissolution of ME was much slower in isolated perfused lungs (IPL) than was observed in vivo. Addition of rat plasma to the perfusate facilitated ME dissolution in IPL to a greater extent than did addition of tissue-type plasminogen activator alone, suggesting that permeation of the clot by plasminogen is the rate-limited step in lysis. Platelet-containing ME injected in rats lysed much more slowly than did ME formed from fibrin alone. (125)I-Thrombi, formed in the pulmonary vasculature of mice in response to intravascular activation of platelets by injection of collagen and epinephrine, were essentially resistant to spontaneous dissolution. Moreover, injection of the antiplatelet glycoprotein IIb/IIIa antibody 7E3 F(ab')(2) facilitated spontaneous dissolution of pulmonary ME and augmented fibrinolysis by a marginally effective dose of Retavase (10 microg/kg) in rats. These studies show that platelets suppress pulmonary fibrinolysis. The mechanism(s) by which platelets stabilize ME and utility of platelet inhibitors to facilitate their dissolution deserves further study.
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PMID:Platelets inhibit the lysis of pulmonary microemboli. 1183 49

The etiologic role of thrombotic and fibrinolytic disorders in Perthes' disease has not been determined. A case control study was conducted to determine whether thrombotic and fibrinolytic disorders are associated with Perthes' disease. Twenty-six patients with Perthes' disease were matched with 26 control patients for gender, age (2-year range), and time of presentation (1-year range). Thrombotic disorders were investigated for protein C activity, protein S activity, antithrombin III, anticardiolipin antibody immunoglobulins G and M, and lupus anticoagulant. Fibrinolytic disorders were investigated for tissue-plasminogen activator, plasminogen activator inhibitor-1, plasminogen activator inhibitor-1 to tissue plasminogen activator ratio, lipoprotein (a), and plasminogen. The activity of protein C, which suppresses factor Va and leads to an increase of coagulant activity when decreased, was increased in patients. There were no significant differences in the levels of other factors between the patients and controls. No evidence was found to prove a relationship between Perthes' disease and thrombotic or fibrinolytic disorders in the patients in the current study.
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PMID:Role of thrombotic and fibrinolytic disorders in the etiology of Perthes' disease. 1201 5

Thrombus formation and degradation is partly due to a complex interplay between tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1). There is accumulating evidence that plasma levels of t-PA and PAI-1 may be influenced by an interaction between the fibrinolytic and renin-angiotensin systems. The goal of this study was to conduct an exploratory data analysis to determine whether there is evidence that the relationship (i.e. correlation) between plasma t-PA and PAI-1 is influenced by interactive effects of the angiotensin converting enzyme (ACE) insertion/deletion (I/D) and plasminogen activator inhibitor 1 (PAI-1) 4G/5G polymorphisms in a sample of 50 unrelated African Americans and 117 unrelated Caucasians. In a single-locus analysis, no evidence for heterogeneity of plasma t-PA and PAI-1 correlations among either ACE I/D or PAI-1 4G/5G genotypes was detected. However, using the combinatorial partitioning method for exploratory data analysis, we identified evidence that is suggestive of heterogeneity of plasma t-PA and PAI-1 correlations among multilocus ACE I/D and PAI-1 4G/5G genotypes in African American females, Caucasian females, Caucasian males, but not African American males. From these results, we propose as a working hypothesis that the correlation between plasma t-PA and PAI-1 may be dependent on epistatic effects of the ACE I/D and PAI-1 4G/5G polymorphisms. This study supports the idea that interactions between the fibrinolytic and renin-angiotensin systems play an important role in the genetic architecture of plasma t-PA and PAI-1.
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PMID:The relationship between plasma t-PA and PAI-1 levels is dependent on epistatic effects of the ACE I/D and PAI-1 4G/5G polymorphisms. 1212 88

The authors evaluated the therapeutic efficacy of tacrolimus (FK506), administered alone or in combination with recombinant tissue plasminogen activator (t-PA), on brain infarction following thrombotic middle cerebral artery (MCA) occlusion. Thrombotic occlusion of the MCA was induced by a photochemical reaction between rose bengal and green light in Sprague-Dawley rats, and the volume of ischemic brain damage was determined 24 hours later. Intravenous administration of tacrolimus or t-PA dose-dependently reduced the volume of ischemic brain infarction, whether administered immediately or 1 hour after MCA occlusion. When tacrolimus or t-PA was administered 2 hours after MCA occlusion, each drug showed a tendency to reduce ischemic brain damage. However, combined treatment with both drugs resulted in a significant reduction in ischemic brain damage. On administration 3 hours after MCA occlusion, tacrolimus alone showed no effect, and t-PA tended to worsen ischemic brain damage. However, the combined treatment with both drugs not only ameliorated the worsening trend seen with t-PA alone, but also tended to reduce ischemic brain damage. In conclusion, tacrolimus, used in combination with t-PA, augmented therapeutic efficacy on brain damage associated with focal ischemia and extended the therapeutic time window compared to single-drug treatments.
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PMID:A combined treatment with tacrolimus (FK506) and recombinant tissue plasminogen activator for thrombotic focal cerebral ischemia in rats: increased neuroprotective efficacy and extended therapeutic time window. 1236 59

Thrombus formation after rupture of an atherosclerotic plaque plays a crucial role in coronary artery disease (CAD). A decreased endogenous fibrinolytic system and prothrombotic factors are supposed to influence coronary thrombosis. It was our aim to investigate the predictive value of tissue plasminogen activator (t-PA) antigen, von Willebrand Factor, Lipoprotein (a) and anti-cardiolipin antibodies for major adverse coronary events in patients with stable CAD in a prospective cohort study of more than 10 years. We observed 141 patients with angiographically proven CAD for a median follow-up period of 13 years. t-PA antigen was the only marker predicting coronary events (logistic regression, p = 0.044) with a poor prognosis for patients in the 5th quintile with an odds ratio of 7.3 (compared to the 1st quintile). The odds ratio even increased to 10.0 for coronary events associated with the "natural course" of CAD excluding events due to restenosis. t-PA antigen had a slightly higher prognostic power (ROC curve; AUC = 0.69) than fasting glucose (AUC = 0.68) and cholesterol (AUC = 0.67). Triglycerides influenced plasma levels of t-PA antigen (regression, p < 0.001). The predictive value of t-PA antigen remained significant after adjustment for inflammation (logistic regression, p = 0.013) and extent of CAD (p = 0.045) but disappeared adjusting for insulin resistance (p = 0.12). In conclusion t-PA antigen predicted coronary events during a very long-term follow-up with a comparable prognostic power to established cardiovascular risk factors. Markers of insulin resistance influenced t-PA antigen and its predictive value.
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PMID:Circulating t-PA antigen predicts major adverse coronary events in patients with stable coronary artery disease--a 13-year follow-up. 1288 83

Poor recovery after systemic tissue plasminogen activator (tPA) therapy could result from the initial severity of ischemic insult and slow and incomplete thrombolysis. Persisting arterial occlusions can be identified at bedside using portable diagnostic ultrasound by detecting residual flow signals around the thrombus (thrombolysis in brain ischemia [TIBI] flow grades). A narrow pulsed ultrasound beam can be steadily aimed at the thrombus/residual flow interface, exposing more thrombus surface and structures to tPA, and tPA activity can be enhanced with 2 MHz transcranial Doppler (TCD). A randomized, multicenter, clinical trial called CLOTBUST (Combined Lysis of Thrombus in Brain ischemia using transcranial Ultrasound and Systemic tPA) trial showed a 49% rate of complete recanalization or dramatic clinical recovery from stroke within 2 hours after tPA bolus when tPA infusion was continuously monitored with TCD, compared with 30% among patients who received tPA without ultrasound monitoring (P=0.03, number needed to treat, 5). Early complete recanalization was sustained at 2 hours by 38% of monitored patients compared with 12.7% controls. The CLOTBUST Trial showed a trend toward sustaining complete recovery at 3 months (41.5% versus 28%, modified Rankin Scale scores 0 to 1), subject for a pivotal phase III trial. Ultrasound is an inexpensive, noninvasive, real-time monitoring tool to identify nonresponders to systemic tPA and select patients with persisting occlusions for intraarterial interventions. Early brain perfusion augmentation, complete recanalization, and dramatic clinical recovery are feasible goals for ultrasound-enhanced thrombolysis.
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PMID:Ultrasound identification and lysis of clots. 1537 1

Thrombus formation within hemodialysis catheters contributes to inadequate dialysis and adverse patient outcomes. A thrombolytic agent may be required to restore patency and improve blood flow. This study evaluates the efficacy of instilling low dose (1 mg/ml) t-PA in catheter lumens to restore patency in malfunctioning catheters. t-PA was utilized to treat suspected catheter thrombus over a four-month period. Seventeen patients with 21 catheters (12 temporary, 9 permanent) received 40 doses of t-PA. Catheter function was restored in 39 of 40 cases (97.5%). Significant improvement in blood flow was confirmed by paired t-test (p < 0.001). Sustained improvement in blood flow was confirmed by ANOVA (p < 0.001). The mean primary patency of all catheters was 29.7 days (SD = 27.0 days). No adverse patient effects were noted. These results demonstrate that t-PA can safely and effectively restore blood flow and extend patency in hemodialysis catheters.
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PMID:Tissue plasminogen activator (t-PA) efficacy in the restoration of hemodialysis catheter function. 1571 85

Thrombotic complications in pediatrics are more common today due to our ability to treat complicated diseases. In pediatric patients where thrombolytic therapy is indicated, the lack of evidence-based medicine forces practitioners to extrapolate dose recommendations for recombinant tissue plasminogen activator (rt-PA) from adult studies. This often results in a high rate of major complications. Low-dose rt-PA is an option that is effective and safe. The authors describe a child with septic thrombus of the superior vena cava who was successfully treated with low-dose, peripherally administered rt-PA, and review the efficacy and safety of standard- versus low-dose rt-PA in children. A Medline search was completed for the use of standard- and low-dose rt-PA in children with thromboembolic disease. Five studies large enough to present efficacy and safety data on standard- and/or low-dose t-PA use in children and neonates were analyzed. Two studies using low-dose rt-PA reported efficacy rates equal to or greater than those reported for standard-dose regimens. Rates of major complications were approximately 5% for low-dose regimens and up to 40% for standard-dose ones. Low-dose, peripherally administered rt-PA is safe and may be as effective as standard-dose rt-PA. A randomized controlled trial should be done to confirm this assumption.
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PMID:Superior vena cava thrombus treated with low-dose, peripherally administered recombinant tissue plasminogen activator in a child: case report and review of the literature. 1634 66


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