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)

We developed a fibrin-rich thrombotic focal cerebral ischemic model with reproducible and predictable infarct volume in rats. In male Wistar rats (n = 77), a thrombus was induced at the origin of the middle cerebral artery (MCA) by injection of thrombin via an intraluminal catheter placed in the intracranial segment of the internal carotid artery (ICA). Thrombus induction and consequent ischemic cell damage were examined by histopathological analysis and neurological deficit scoring, and by measuring changes in cerebral blood flow (CBF) using laser-Doppler flowmetery (LDF), perfusion-weighted imaging (PWI), and by diffusion weighted imaging (DWI). Histopathology revealed that a fibrin-rich thrombus localized to the origin of the right MCA. Regional cerebral blood flow (rCBF) in the right parietal cortex was reduced by 34-58% of preinjection levels after injection of thrombin in rats administered 30 U of thrombin (n = 10). Magnetic resonance imaging (MRI) showed a reduction in CBF and a hyperintensity DWI encompassing the territory supplied by the right MCA. The infarct volume in rats administered 80 U of thrombin was 31.29 +/- 12.9% of the contralateral hemisphere at 24 h (n = 13), and 34.7 +/- 16.4% of the contralateral hemisphere at 168 h (n = 6). Rats administered 30 U of thrombin exhibited a hemispheric infarct volume of 34.0 +/- 14.5% (n = 9) at 24 h and 29.7 +/- 13.9% (n = 8) at 168 h. In addition, thrombotic rats (n = 3) treated with recombinant tissue plasminogen activator (rt-PA) (10 mg/kg) 2 h after thrombosis showed that CBF rapidly returned towards preischemic values as measured by PWI. This model of thrombotic ischemia is relevant to thromboembolic stroke in humans and may be useful in documenting the safety and efficacy of thrombolytic intervention as well as for investigating therapies complementary to antithrombotic therapy.
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PMID:A new rat model of thrombotic focal cerebral ischemia. 904 Apr 91

Thrombotic complications constitute an important risk in transplant recipients, in whom a hypercoagulable state and hypofibrinolysis have been associated with immunosuppressive treatment, especially with cyclosporine. In no case have clotting and fibrinolytic abnormalities been correlated with steroid immunosuppression, even though steroids were always administered. Previous studies found a relationship between hypercorticism and hypofibrinolysis both in Cushing's disease and after renal transplantation. The aim of this investigation was to compare fibrinolytic potential using the venous occlusion test in two similar groups of heart transplant patients treated with or without steroids. Euglobulin lysis time, tissue-type plasminogen activator and plasminogen activator inhibitor-1 (PAI-1) activities, and antigens were determined before and after the venous occlusion test. A reduced fibrinolytic potential (significant prolongation of lysis time) due to a significant increase in PAI-1 activity and antigen levels was found in heart transplant patients treated with steroids, as compared with patients without steroid treatment and control subjects. The prevalence of reduced fibrinolytic potential was 69.2% (18 cases) in the steroid-treated group and 34.8% (8 cases) in the non-steroid-treated group. In every case, the impaired fibrinolytic potential was due to high basal PAI-1 levels. Our results are compatible with the presence of a hypofibrinolytic state secondary to long-term steroid treatment. In heart transplant recipients, steroid-induced hypofibrinolysis may constitute a further risk factor for thrombotic disease.
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PMID:Impairment of fibrinolytic potential in long-term steroid treatment after heart transplantation. 941 68

Thrombotic risk factors may be important in determining cardiovascular outcome in patients with symptomatic peripheral arterial disease. A cohort study with a 6-year follow-up period was established to determine the relationships between haemostatic and rheological factors and incident ischaemic heart disease (IHD) and stroke events in patients with peripheral arterial disease. A consecutive series of 607 patients with intermittent claudication was examined between 1989 and 1990 at the Peripheral Vascular Clinic, Royal Infirmary of Edinburgh. Main outcome measures were combined fatal and non-fatal stroke, non-fatal myocardial infarction (MI), coronary death and total coronary events. A total of 210 patients died during follow-up. 203 patients did not experience a vascular event or deterioration of limb ischaemia. Median levels of fibrinogen, von Willebrand factor (VWF), tissue plasminogen activator (t-PA) antigen, fibrin D-dimer and whole blood viscosity were significantly higher in those who experienced an event compared with those who did not. After adjusting for age and sex, fibrin D-dimer was significantly associated with risk of non-fatal myocardial infarction (RR 1.50, 95% CI 1.09-2.06, P < or = 0.01). Both fibrinogen and fibrin D-dimer were associated with risk of total coronary events (P < or = 0.05). The risk of stroke was related to baseline levels of t-PA antigen (RR 1.87, 95% CI 1.04-3.34, P < or = 0.05) and whole blood viscosity (RR 1.33, 95% CI 1.07-1.65, P < or = 0.01). All the relationships became weaker and statistically non-significant after further adjustment for cigarette smoking, systolic blood pressure, glucose and baseline IHD. The associations of these factors to IHD and stroke may therefore be partly related to cardiovascular risk factors, but are likely to be important in the pathogenesis of future atherothrombotic events in subjects with peripheral arterial disease.
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PMID:Haemostatic factors and prediction of ischaemic heart disease and stroke in claudicants. 953 45

Thrombotic obstruction of mechanical prosthetic valves is a frequently encountered cause of prosthetic valve dysfunction, which can result in stenosis and regurgitation. We present a case of thrombotic obstruction of a bileaflet mechanical aortic valve prosthesis that resulted in severe stenosis and regurgitation. Considering the known risk factors associated with both surgical and thrombolytic treatments, a decision was made to use tissue plasminogen activator therapy to relieve the burden of the thrombotic valvular obstruction. In this case review, we use continuous wave Doppler to demonstrate recovery of normal valve function despite suboptimal two-dimensional imaging.
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PMID:Evaluation of a bileaflet aortic valve prosthesis before and after thrombolytic tissue plasminogen activator therapy by continuous wave Doppler ultrasound. 961 20

We describe the cases of two premature infants carrying a central venous line who developed on the fourth day of life a catheter related intracardiac thrombus. Although they were clinically asymptomatic we opted for thrombolytic treatment considering the potential risks of this situation. Treatment with recombinant tissue plasminogen activator (rt-PA) was performed for one day in the first case and for three days in the second one, in association with fresh frozen plasma. Thrombus dissolution occurred in both patients and no adverse effects were noted. In our experience tissue plasminogen activator was a therapy acceptably safe and effective inducing clot lysis in very low birthweight neonates into critical situations.
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PMID:Successful use of tissue plasminogen activator (t-PA) in catheter-related intracardiac thrombi of two premature infants. 968 66

The role of fibrinolytic system components in thrombus formation and removal in vivo was investigated in groups of six mice deficient in urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA), or plasminogen activator inhibitor-1 (PAI-1) (u-PA-/-, t-PA-/- or PAI-1-/-, respectively) or of their wild type controls (u-PA+/+, t-PA+/+ or PAI-1+/+). Thrombus was induced in the murine carotid artery by endothelial injury using the photochemical reaction between rose bengal and green light (540 nm). Blood flow was continuously monitored for 90 min on day 0 and for 20 min on days 1, 2 and 3. The times to occlusion after the initiation of endothelial injury in u-PA+/+, t-PA+/+ or PAI-1+/+ mice were 9.4+/-1.3, 9.8+/-1.1 or 9.7+/-1.6 min, respectively. u-PA-/- and t-PA-/- mice were indistinguishable from controls, whereas that of PAI-1-/- mice were significantly prolonged (1 8.4+/-3.7 min). Occlusion persisted for the initial 90 min observation period in 10 of 18 wild type mice and was followed by cyclic reflow and reocclusion in the remaining 8 mice. At day 1, persistent occlusion was observed in 1 wild type mouse, 8 mice had cyclic reflow and reocclusion and 9 mice had persistent reflow. At day 2, all injured arteries had persistent reflow. Persistent occlusion for 90 min on day 0 was observed in 3 u-PA-/-, in all t-PA-/- mice at day 1 and in 2 of the t-PA-/-mice at day 2 (p <0.01 versus wild type mice). Persistent patency was observed in all PAI-1-/- mice at day 1 and in 5 of the 6 u-PA-/- mice at day 2 (both p <0.05 versus wild type mice). In conclusion, t-PA increases the rate of clot lysis after endothelial injury, PAI-1 reduces the time to occlusion and delays clot lysis, whereas u-PA has little effect on thrombus formation and spontaneous lysis.
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PMID:Differential role of components of the fibrinolytic system in the formation and removal of thrombus induced by endothelial injury. 1023 47

The purpose of this article is to report four patients with massive pulmonary embolism treated with percutaneous catheter and guidewire fragmentation and local administration of recombinant tissue plasminogen activator (r-TPA). Four patients with massive pulmonary embolism initially underwent pulmonary angiography. Thrombus fragmentation was performed with both standard angiographic guidewires and catheters followed by local infusion of 41-200 mg of r-TPA. Pulmonary angiography was repeated after treatment. All patients survived with improvement in their clinical status and eventual discharge from hospital. Angiography in all patients post treatment demonstrated improvement in pulmonary perfusion (mean Miller score before treatment 22.5; mean Miller score after treatment 5.75). No patient had a significant complication. Mechanical fragmentation of the thrombus followed by local infusion of r-TPA was an effective treatment for massive pulmonary embolism in these four patients with no significant complications.
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PMID:Percutaneous catheter and guidewire fragmentation with local administration of recombinant tissue plasminogen activator as a treatment for massive pulmonary embolism. 1037

Thrombus formation at the site of atherosclerotic lesions, especially on a ruptured plaque, plays a central role in the "atherothrombosis" hypothesis. An activation of the hemostasis and a disturbed fibrinolysis are known. These alterations are especially marked in patients with acute coronary syndromes. In stable coronary artery disease, fibrinogen is elevated. Furthermore, minor alterations of the contact phase factor VII and consecutively of the thrombin system are detectable depending on the study population. Thrombin generation and activation become marked in patients with unstable angina pectoris or acute myocardial infarction. Possible reasons for this activation are an activation of the contact phase factor XII system and the release of tissue factor both from the ruptured plaque and from stimulated monocytes. The fibrinolytic system is markedly altered already in patients with stable coronary heart disease. Increased levels of tissue-type plasminogen activator and of urokinase-type plasminogen activator/receptor are measurable in atheromas. Tissue-type plasminogen activator mass concentration is systemically elevated already at early stages of atherosclerosis. Especially in patients with increased risk for acute coronary syndromes, the plasminogen activator inhibitor activity is significantly increased. Furthermore, a hypercoagulative state with increased d-dimer levels and plasmin-antiplasmin complexes can be measured. The alterations of hemostasis and especially of fibrinolysis are detectable for prolonged time period and persist much longer than the clinical symptoms of the patients. The increased plasminogen activator inhibitor activity is associated with the metabolic syndrome and constitutes an (in part genetically determined) disturbance in patients with stable or unstable coronary heart disease. However, the large intra- und interobserver as well as diurnal variability of this marker limits its use as a routine measure for risk stratification in patients. Alterations of the hemostasis and disturbances of fibrinolysis are detectable during the chronic as well as the acute phase of atherosclerosis. These changes are best documented for coronary heart disease, whereas less data are available for other manifestations of atherosclerosis. The use of newly developed molecular markers for single reaction steps of pathways instead of global functional tests and of new molecular biological methods did considerably improve the detailed knowledge on the pathomechanisms of the development of atherosclerosis, making the development of targeted therapies, e.g., against receptors possible. Future studies will investigate the quantitative impact of the various activated pathways (cause or reaction) and the effects of interventions on these pathomechanisms in patients with acute coronary syndromes. Studies will have to focus especially on the meaning of polymorphisms, early changes in the development of atherosclerosis and interactions with inflammatory processes.
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PMID:[Blood coagulation and fibrinolysis in arteriosclerosis]. 1041 53

Thrombotic risk in hyperlipidemic women and its response to lipid therapy is unknown. We prospectively studied 28 men and 29 women with high low-density lipoprotein (LDL) cholesterol during 6 months of therapy with pravastatin. Women had significantly higher high-density lipoprotein (HDL) cholesterol (54.2 +/- 1.7 vs 39.5 +/- 2.2 mg/dl, p <0.01), lower prevalence of coronary artery disease (41% vs 67%, p = 0.04), and otherwise similar baseline characteristics compared with men. Both genders achieved a 33% reduction in LDL at 6 weeks (188 +/- 6 to 133 +/- 5 mg/dl) and maintained similar LDL levels throughout the study. Systemic hemostatic markers and thrombus formation under dynamic flow conditions were evaluated at baseline, and at 3 and 6 months of follow-up. Prothrombin fragment F1.2, a marker of thrombin generation, was higher in women versus men at baseline (2.4 +/- 0.2 vs 1.4 +/- 0.3 nmol/L, p = 0.02). The levels decreased in women to 2.0 +/- 0.3 nmol/L at 3 months and to 1.6 +/- 0.2 nmol/L at 6 months (p <0.045, analysis of variance), whereas it remained unchanged in men. Plasminogen activator inhibitor-I significantly decreased at 3 and 6 months of follow-up: by 12.6% and 18.7%, respectively, in women, and by 18.8% and 23.5%, respectively, in men. Similarly, tissue plasminogen activator decreased significantly by 7.4% in women and 11.8% in men at 6 months compared with baseline. Fibrinogen showed an increase in both genders at follow-up. Thrombus formation was similar at baseline between the 2 genders, and decreased at 3 and 6 months compared with baseline by 12.5% and 29.5% in women, and by 18.6% and 19.4% in men (p <0.04 at 6 months vs baseline in both men and women). Other markers, including C-reactive protein, fibrinopeptide A, D-dimer, and factor VIIa, did not differ between genders and did not change with therapy. Thus, despite higher HDL, and lower incidence of coronary disease, women with high LDL had a comparable thrombotic and/or fibrinolytic profile to men and even evidence of increased thrombin generation at baseline. Blood thrombogenicity was reduced with pravastatin in both genders; in addition, thrombin generation was gradually reduced in women to a level similar to that of men by 6 months of follow-up.
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PMID:Gender differences in blood thrombogenicity in hyperlipidemic patients and response to pravastatin. 1049 31

Thrombus formation is a key component of the pathogenesis of restenosis after arterial balloon injury. The purpose of this study was to determine whether intimal hyperplasia could be attenuated by infusion of recombinant tissue plasminogen activator (tPA). Forty-two Kurosawa and Kusanagi hypercholesterolemic rabbits were divided into tPA (n = 20) and control (n = 22) groups, the former receiving 7 days of continuous tPA infusion (0.6 mg/kg/day) via ear veins. The walls of the common iliac arteries were injured using 2.5-mm balloon catheters and then examined histologically 7, 14, 21, and 28 days later. Cell proliferation was assessed by immunohistochemical analysis of proliferating cell nuclear antigen (PCNA), and transforming growth factor (TGF)-beta immunohistochemistry was carried out to estimate cell proliferation and differentiation. It was observed that 28 days after balloon injury, intimal cross-sectional areas in the tPA group were significantly smaller than in controls (0.11 +/- 0.03 mm2 vs. 0.57 +/- 0.08 mm2, p < 0.01), as were ratios of the cross-sectional areas of the intima and media (0.21 +/- 0.07 vs. 1.06 +/- 0.18, p < 0.05). In addition, the numbers of PCNA-positive medial cells were significantly lower (0.06 +/- 0.01 vs. 0.36 +/- 0.08, p < 0.05) and TGF-beta-positive vessel wall areas were significantly smaller in tPA-treated animals 7 days after balloon injury (0.47 +/- 0.28% vs. 4.55 +/- 1.44%, p < 0.05). Thus infusion of tPA after arterial balloon injury appears to decrease medial cell proliferation and suppress intimal hyperplasia.
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PMID:Suppression of cell proliferation by tissue plasminogen activator during the early phase after balloon injury minimizes intimal hyperplasia in hypercholesterolemic rabbits. 1120 98


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