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)

The use of fibrinolytic agents in acute ischemic stroke has received increasing attention due to the completion of several prospective studies examining the efficacy and safety of these drugs in this clinical setting. Experience with plasminogen activators indicates that recanalization of carotid and vertebrobasilar territory occlusion is feasible within 4-6 hours of symptom onset. The optimal plasminogen activator, its dose-rate and delivery system, however, is not known. The phase III trial of the European Cooperative Acute Stroke Study (ECASS) suggests potential modest benefit in outcome, although recombinant tissue plasminogen activator (rt-PA) had an increased risk of hemorrhage attributable to those patients with early CT-scan signs of ischemia. Complete cervical internal carotid artery occlusions by in situ thrombosis appear more resistant to thrombolysis than occlusions of the stem and major branches of the middle cerebral artery. The issue of hemorrhagic transformation is unsettled. It seams to be increased by delayed intervention on the one hand, but it is not different from that observed in placebo patients in phase I/II series.
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PMID:Thrombolysis in acute stroke. 871 49

Therapy for stroke is undergoing major changes. Many of the changes parallel the advances made in the therapy for myocardial infarction. Acute intervention with cytoprotective and thrombolytic agents is undergoing active investigation. Cytoprotective therapy includes drugs that act to prevent cell death during ischemia and reperfusion. These agents include calpain inhibitors, voltage-sensitive calcium- and sodium-channel antagonists, receptor-mediated calcium-channel antagonists [including N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) antagonists], glutamate-synthesis inhibitors, glutamate-release antagonists, gamma-aminobenzoic acid (GABA) antagonists, 5-HT (serotonin) receptor agonists, gangliosides, antioxidants, growth factors, antiapoptotic agents, and antiadhesion molecules. Thrombolysis is effective in myocardial infarction. Thrombolysis is undergoing evaluation in stroke with streptokinase, anisoylated plasminogen streptokinase activator complex (APSAC), tissue plasminogen activator (t-PA; including recombinant t-PA), urokinase, and single-chain urokinase (scu-PA). Both systemic and selective administration are being evaluated. Preventive therapy with both antiplatelet and anticoagulant drugs sheds new light on how best to stratify patients in terms of a risk-benefit ratio. Continuing public education will be essential as stroke therapy advances.
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PMID:Medical therapy for ischemic stroke. 877 66

To characterize the vasospastic angina patients with exercise-induced ischemia, we measured hemostasis (platelet factor 4; PF4, fibrinopeptide A; FPA) and fibrinolytic parameters (tissue plasminogen activator antigen; t-PA, free plasminogen activator inhibitor-1 antigen; free PAI-1) in 15 normal subjects and 33 vasospastic angina patients without significant coronary artery stenosis (less than 50% stenosis). All of the vasospastic angina patients began to feel chest pain within 3 months before diagnostic coronary angiography. Blood samples were obtained from all of the study patients at 8:30-9:30 am before exercise 201Tl emission computed tomography. Vasospastic angina patients were divided into 2 groups; 15 patients with exercise-induced ischemia (group 1) and 18 patients without exercise-induced ischemia (group 2). On coronary angiography, the severity of coronary artery stenosis at the site of spasm in group 1 (34 +/- 5%) was greater than that in group 2 (18 +/- 3%). Plasma FPA and PF 4 levels in group 1 were also significantly higher than those in normal subjects and group 2. Plasma t-PA and free PAI-1 levels in group 1 were significantly higher than those in normal subjects and group 2. Plasma levels of free PAI-1 group 2 were also significantly higher than those in normal subjects. The present study demonstrated that all of the patients with vasospastic angina had impaired fibrinolysis, and these patients with exercise-induced ischemia showed enhanced platelet activation, an enhanced coagulation system, and advanced atherosclerotic lesions. These results suggest that vasospastic angina with exercise-induced ischemia puts patients at increased risk for thrombus formation.
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PMID:Characteristics of vasospastic angina with exercised-induced ischemia--analysis of parameters of hemostasis and fibrinolysis. 880 21

Thrombin activity is increased in the setting of acute myocardial infarction (AMI) and has been shown to increase further after the administration of thrombolytic therapy for acute infarction. This increase in thrombin activity may play an important role in the 15% to 25% rate of failure to achieve initial reperfusion and in the 5% to 15% rate of early reocclusion after initially successful thrombolysis. To investigate potential mechanisms of thrombin formation in vivo, to understand better the balance of coagulation and fibrinolysis during treatment with recombinant tissue-type plasminogen activator (rt-PA), and to investigate the role of hemostatic markers as predictors of clinical events, we measured 3 markers of procoagulant activity: fibrinopeptide A (FPA), thrombin-antithrombin III complexes (TAT), and prothrombin fragment 1.2 (F1.2), and a marker of fibrinogenolytic activity (B beta 1-42) in patients enrolled in the Thrombolysis in Myocardial Infarction (TIMI)-5 study. This trial was a randomized, dose-ranging, pilot trial of hirudin versus heparin as adjunctive antithrombotic therapy with rt-PA administered to patients with AMI. Correlation of markers at 1 hour with clinical outcomes revealed that increased FPA and TAT levels were associated with increased mortality and TIMI grades 0, 1, or 2 flow at 90 minutes; increased F1.2 levels were associated with TIMI grade 0 or 1 flow at 90 minutes; and increased levels of all 3 procoagulant markers were associated with hemorrhagic events. Late (12 to 24 hours) increases in F1.2, TAT, and B beta 1-42 may be predictive of recurrent ischemia. These results suggest that selected markers of procoagulant and fibrinogenolytic activity may be useful in predicting clinical outcomes in patients treated with thrombolytic therapy for AMI.
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PMID:Usefulness of fibrinogenolytic and procoagulant markers during thrombolytic therapy in predicting clinical outcomes in acute myocardial infarction. TIMI-5 Investigators. Thrombolysis in Myocardial Infarction. 880 32

We analyzed the 395 patients randomized into the Primary Angioplasty in Myocardial Infarction (PAMI) trial to receive tissue plasminogen activator (tPA) or to undergo primary percutaneous transluminal coronary angioplasty (PTCA) for acute myocardial infarction (AMI). Of these, 168 were current smokers and 128 had never smoked. Univariate analyses of baseline characteristics and outcome, including death, recurrent AMI, and recurrent ischemia, were done by chi-square analysis. Multivariate stratified analysis was then performed controlling for age and gender, which were found to be confounders of outcome. The combined in-hospital outcomes of death, recurrent AMI, and recurrent ischemia were similar for smokers and nonsmokers (p = 0.12). When stratified according to treatment modality, non-smokers treated with PTCA had a lower frequency of death and nonfatal recurrent AMI (7% vs 18%; p = 0.05), in-hospital ischemia (11% vs 33%; p = 0.004), or the combined event (13% vs 40%; p = 0.001). At 6 months, nonsmokers treated with PTCA continued to have a lower incidence of death or nonfatal recurrent AMI (11% vs 24%; p = 0.07) compared with tPA. Conversely, in smokers, the treatment strategy did not significantly affect hospital outcomes: recurrent ischemia (12% vs 23%; p = 0.07), death and recurrent AMI (6% vs 8%; p = 0.55), or the combined event (15% vs 25%; p = 0.12). The statistical significance of these associations was maintained when multivariate analysis controlling for age and gender was used. Thus, nonsmokers presenting with AMI had a significantly better outcome when treated with primary angioplasty; these differences were not seen in smokers.
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PMID:Effect of reperfusion modality on outcome in nonsmokers and smokers with acute myocardial infarction (a Primary Angioplasty in Myocardial Infarction [PAMI] substudy). PAMI Investigators. 880 33

Cerebral ischemia is caused by reduced blood supply at the microcirculatory level. In the microvessels, the main elements of the reperfusion injury following brain ischemia are the transformation of endothelial cell-surface from anticoagulant to procoagulant property, leukocyte adhesion, sludge or clot formation. There is a paucity of information on how hemostatic factors, cytokines, lipoprotein(a) (Lp(a)) and endothelin-1 (ET-1), being responsible for ischemic/reperfusion injury, interact with human brain microvessel endothelium (HBEC). There are no data furthermore about the expression of complement proteins of HBEC influenced by cytokines or fibrinolytic factors. Previously we established optimal conditions for culturing HBEC. Cell contraction induced by thrombin, plasmin, miniplasmin was recorded. The reassembly of F-actin was observed after thrombin treatment. ICAM-1 upregulation was measured following TNF-alpha, IL-1-alpha and thrombin incubation. Plasmin and miniplasmin downregulated the ICAM-1 in our cell culture system. Lp(a) modulated the thromboresistant cell-surface by reduction of t-PA and u-PA, but PAI-1 remained unchanged. Lp(a) modulated the ET-1 production by early increasing and late decreasing, in a bimodal manner. The increased secretion of ET-1 by cytokines (TNF-alpha, IL-1-alpha) was reduced in the presence of Lp(a). Gradual increase of complement proteins (factor H, factor B, C4) was induced by cytokines. Plasmin and miniplasmin augmented a rapid increase of C4. Some factors of complex relationship between regulators and modulators of endothelial adhesion molecules have been demonstrated in a human cell culture system prepared from brain microvessel endothelium. A unified concept of sequential events of ischemia/reperfusion in the brain has not yet developed.
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PMID:Human brain microvessel endothelial cell culture as a model system to study vascular factors of ischemic brain. 889 62

The causes of perioperative ischemia and myocardial infarction (MI) in coronary artery bypass graft (CABG) patients are almost certainly multifactorial, although not well understood. Ultimately, outcome after CABG is dependent on myocardial preservation and prevention of further myocardial ischemia. The largest number of ST-T-wave events come immediately after protamine is given, suggesting that re-establishment of coagulation function after cardiopulmonary bypass (CPB) may be an important event. CPB induces an inflammatory state that involves platelet-endothelial-cell interactions and vasospastic responses that result in low flow states in the coronary vasculature. The fibrinolytic system is activated during CPB, with raised tissue plasminogen activator (tPA) levels and related falls in plasminogen activator inhibitor (PAI-1). PAI-1 levels rise during the postoperative period. There is a huge variability in human response. However, the patients with the highest tPA surge are not the same patients who have the highest PAI surge. It could be postulated that patients with high PAI-1 levels are at highest risk for early ischemia. New data just being evaluated from the Multicenter Study of Perioperative Ischemia (McSPI) Research Groups' database in San Francisco may support the hypothesis that coagulation influences perioperative ischemia. The study of approximately 2,400 patients undergoing CABG surgery at 24 major institutions in the United States revealed that intensive care unit (ICU) entry hematocrit was significantly related to the risk for postoperative MI. Patients entering the ICU with hematocrits below 24% had the lowest MI rate (3.7%), whereas those with hematocrits greater than 34% had the highest rate (8.1%). Patients with ICU entry hematocrits below 18% had a zero incidence of perioperative MI. One possible explanation for these findings is that platelets are involved. As red cells stream down vessels, they marginate the smaller formed elements of the blood. As hematocrit is increased, the number of platelets moved to the outer sides of the vessels increases. Therefore, the number of endothelial-platelet interactions would increase over time with higher hematocrits.
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PMID:Ischemia--a coagulation problem? 893 82

A 2300-g pre-term neonate with severe hyaline membrane disease experienced right forearm and hand ischemia following a brachial arterial line insertion. Limb salvage was achieved through combined microsurgical exploration and thrombectomy of the brachial and radial arteries, with postoperative regional infusion of tissue plasminogen activator (TPA) through the distal radial artery for 48 hr, to dissolve a thrombus within the small vessels of the hand. This report advocates combined surgical and regional thrombolytic therapy with tissue plasminogen activator as management for neonatal arterial thrombosis and limb ischemia.
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PMID:Microvascular and thrombolytic revascularization of an arm in a 32-week-gestation neonate: case report and review of the literature. 895 Nov 22

Microvascular anastomoses are at risk of thrombosis, especially when repairing avulsed or crushed tissues, or when ischemia time is prolonged. When all surgical techniques to avoid thrombosis of the microanastomoses fail, thrombolytic agents may play a role in dissolving the thrombus and preventing rethrombosis. The authors present a case in which recombinant tissue plasminogen activator (rt-PA) was locally infused to salvage thrombosed venous microanastomoses after replantation of an amputated forearm. They also review the effects of different thrombolytic agents, and emphasize the benefits of rt-PA and its promising role in microsurgery.
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PMID:Local intravenous thrombolysis with recombinant tissue plasminogen activator for salvage of forearm replantation. 895 Nov 23

Although heart attack is caused by occlusion of a major coronary artery, some patients have occlusion without heart attack because these patients have sufficient collateral circulation to provide an alternate pathway for blood supply to the myocardium at ischemic risk. The growth of new capillary vessels (angiogenesis) and enlargement of preexisting vessels play an important role in the collateral development. We evaluated the hypothesis that extracellular matrix metalloproteinase (MMP) expression is altered in coronary collateral arteries (0.5-1 mm o.d.) isolated from canine hearts 2-4 months after surgical placement of an ameroid occluder around the proximal left circumflex artery (n = 4), during the development of collateral vessels and restructuring new vessels. Histologic studies (hematoxylin and eosin, trichrome, and van Gieson stains) indicated cellular proliferation and increased collagen and elastin content in collateral vessels compared with comparable-sized unoccluded arterial segments of the left anterior descending (LAD) artery. In situ MMP activity of collateral vessels, measured using denatured collagen in the gel matrix, indicated an increase in total MMP activity in the intima of collateral vessels compared with normal LAD vessels. To further identify the type of MMP, tissue homogenates were prepared from collateral and LAD vessels and analyzed by SDS-PAGE zymography. The results suggest induction of gelatinase A and gelatinase B expression in collateral vessels compared with normal LAD tissue, when identical amounts of total protein were loaded onto each lane in the gel. Based on plasminogen-casein zymography, we observed the tissue plasminogen activator level to be increased in collateral vessels. On the basis of immunoblot and mRNA (Northern blot) analyses, we determined that the MMP-1 level was induced in collateral vessels 2 and 4 months after ameroid occlusion. In contrast with MMP-1, the level of TIMP-1 (tissue inhibitor of metelloproteinases) was decreased significantly (p < 0.001) in collateral compared with LAD vessels, suggesting a role for arterial TIMP in anti-angiogenic activity. Collectively, these results suggest that chronic occlusion of a major coronary artery induces upregulation of vascular remodeling mechanisms subserving collateral development. Increased MMP-2 activity in collaterals may be associated with decreased levels of tissue inhibitor of metalloproteinases and fibrous tissue remodeling following angiogenic and (or) adaptive responses of the myocardium to chronic ischemia.
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PMID:Temporal expression of extracellular matrix metalloproteinases and tissue plasminogen activator in the development of collateral vessels in the canine model of coronary occlusion. 896 Mar 89


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