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)

The Merci Retriever is a device used for mechanical clot extraction in cerebral arteries. It obtained US FDA clearance in August 2004 for recanalization of cerebral arteries in acute stroke. Previously, intravenous recombinant tissue plasminogen activator administered within 3 h from symptom onset was the only other FDA-approved treatment in acute stroke. Stroke from large brain artery occlusion, which has the highest morbidity and mortality rate, is inefficiently treated with intravenous recombinant tissue plasminogen activator and has a high likelihood of hemorrhagic complication. In the multicenter prospective Mechanical Embolus Removal in Cerebral Ischemia trial that led to FDA clearance, the Merci Retriever achieved 48% vessel recanalization when used within 8 h of stroke onset, and resulted in lower morbidity and mortality in revascularized patients. Clinical efficacy trials are needed to determine the place of this device in the treatment of stroke patients.
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PMID:Merci Retriever in acute stroke treatment. 1668 48

A decade after the US Food and Drug Administration (FDA) approved intravenous tissue plasminogen activator for treatment of acute ischemic stroke, the public health impact of this treatment on stroke outcome remains limited. The extremely small time window for treatment and very low recanalization rates in large artery strokes are its major shortcomings. Endovascular therapies for the treatment of acute stroke have rapidly evolved during this time period and may overcome these limitations. FDA approval of the Mechanical Embolus Removal in Cerebral Ischemia (MERCI) concentric retriever in August 2004 for the treatment of occluded brain arteries has spurred trials of newer devices for mechanical thrombolysis in acute stroke. At present, there are two major National Institutes of Health-sponsored randomized controlled trials testing endovascular treatments in acute stroke. In this article, we provide an experience-guided review of the current approach to the endovascular treatment of acute ischemic stroke and current evidence for various strategies. We first emphasize the key aspects of patient selection, including the increasingly central role of perfusion/diffusion imaging. The technical aspects of chemical, mechanical, ultrasound-based, and multimodal approaches are provided along with the authors' own experiences. Most of the endovascular modalities tested in clinical trials show recanalization rates in the range of 50% to 65%. However, no one modality is clearly superior. In practice, multimodal treatment strategy is often employed to achieve rapid recanalization of occluded cerebral vessels and minimize chances of hemorrhage. This may become the standard of care in the future.
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PMID:Acute endovascular stroke therapy. 1707 90

This review focuses on the several coagulation disorders (the so called hypercoagulable states) that are associated with cerebral venous thrombosis. Hypercoagulable states likely explain the high percentage of cases of cryptogenic cerebral infarction in young people. The most common of the hereditary defects appear to be deficiency of antithrombin III, protein C or protein S, activated protein C resistance and prothrombin 20211A mutation. In a large majority of cases activated protein C resistance is due to the presence of factor V Leiden. Antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibodies) represent an acquired disorder of coagulation. Rare defects include heparin cofactor II (HC II), plasminogen or tissue plasminogen activator deficiency (TPA), elevated plasminogen activator inhibitor-1 (PAI-1) and dysfibrinogenemia. Hyperhomocystinemia is responsible for both arterial and venous thrombosis. A work-up to identify one of the recognizable hypercoagulable states is indicated, especially in younger patients with stroke. Laboratory evaluation for hypercoagulable states may also often be indicated in those patients who do not have other obvious risk factors for their stroke. If from clinical history, family history and/or laboratory studies, a patient is felt to have a hypercoagulable state, the decision for long term chronic anticoagulation needs to be individualized. If a hereditary hypercoagulable state is found, it also may be appropriate to recommend screening of other family members.
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PMID:Haematologic disorders and cerebral venous thrombosis. 1718 75

A thrombolytic agent, recombinant tissue plasminogen activator (rt-PA), was recently approved in Japan for use on patients within 3 hrs of the onset of cerebral infarction. In order to salvage cerebral tissue after an ischemic insult, it is crucial to detect the ischemic lesion before it becomes irreversible and to detect the core and penumbra areas of the lesion for guidance in selecting the suitable therapy. In this symposium we discuss the detection of ischemic lesions using plain CT, perfusion CT, and MRI. In the section on plain CT, we present a typical case with early CT signs. In the section on perfusion CT, we report on the feasibility and limitation of the technique for the diagnosis of acute cerebral infarction. In the section on MRI, we study the usefulness of DWI for the early and highly reliable detection of ischemic stroke.
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PMID:[Early detection of ischemic lesions in the super-acute phase of ischemic cerebrovascular diseases by imaging]. 1743 94

The effect of recombinant microplasmin (micro-plasmin) on acute cerebral infarction was evaluated in rats, and compared with recombinant tissue plasminogen activator (rt-PA). After the model of middle cerebral artery occlusion (MCAO) was established by autologous blood clots, different doses of micro-plasmin (2.5, 5, and 10 mg x kg(-1)) were administered into the thrombus intra-arterial. Twelve hours after administration of micro-plasmin, the neurological deficit score of rats was recorded and the infarct volumes were determined. Bleeding time (BT), fibrin degradation product (FDP) concentration in serum and thrombin time (TT), prothrombin time (PT) and fibrinogen (FIB) concentration in plasma were tested after administration. Intra-arterial administration of micro-plasmin could reduce significantly neurological deficit score and infarct volumes in MCAO rats. FDP concentration increased significantly as compared with model group. There were no significant differences in TT, PT and BT. FIB concentration reduced markedly as compared with model group, but had no significant difference as compared with sham group. The results suggest that micro-plasmin is effective in treatment of rat acute cerebral infarction, and has no significant influence on fibrinolytic system and blood clotting system, indicating that micro-plasmin may be useful for treatment of acute cerebral infarction, and not lead to hemorrhage. Micro-plasmin seems to be distinguished from clinical used rt-PA by its no hemorrhage effect.
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PMID:[Effect of recombinant microplasmin on acute cerebral infarction in rats]. 1833 39

Stroke is the second most common cause of death and major cause of disability worldwide. Because of the ageing population, the burden will increase greatly during the next 20 years, especially in developing countries. Advances have occurred in the prevention and treatment of stroke during the past decade. For patients with acute stroke, management in a stroke care unit, intravenous tissue plasminogen activator within 3 h or aspirin within 48 h of stroke onset, and decompressive surgery for supratentorial malignant hemispheric cerebral infarction are interventions of proven benefit; several other interventions are being assessed. Proven secondary prevention strategies are warfarin for patients with atrial fibrillation, endarterectomy for symptomatic carotid stenosis, antiplatelet agents, and cholesterol reduction. The most important intervention is the management of patients in stroke care units because these provide a framework within which further study might be undertaken. These advances have exposed a worldwide shortage of stroke health-care workers, especially in developing countries.
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PMID:Stroke. 1880 27

Thrombolysis with tissue plasminogen activator increases the risk of brain hemorrhage after ischemic stoke. However, the relationship between the duration of ischemia and the risk of hemorrhagic transformation is still unclear. In the present study, we used a rat model of thrombolysis with tissue plasminogen activator after different periods of middle cerebral artery occlusion and we analyzed the effect of the duration of ischemia on the rate of hemorrhagic transformation, the extent of cerebral infarction and the degree of neurological impairment. Most of the rats reperfused before 3 h of ischemia did not develop intracerebral hemorrhages, while 90% of the rats occluded for more than 3 h developed cerebral hemorrhages ranging from benign hemorrhagic infarctions to severe parenchymal hemorrhages. After 6-hour occlusion, the proportion of parenchymal hemorrhages, as seen in 50% of the animals, was significantly augmented compared to the 11 to 13% of parenchymal hemorrhages observed in animals occluded for less than 6 h. Meanwhile, the quantity of hemoglobin measured in the brain parenchyma of animals showing hemorrhagic infarctions was doubled (0.19 mg/hemisphere in rats reperfused after 6 h of ischemia compared to 0.08 mg/hemisphere in rats reperfused earlier). Neurological outcome did also worsen with the duration of ischemia. However, the amplitude of cerebral infarction was not statistically different in animals subjected to short or longer time of ischemia. In addition, the risk of hemorrhagic transformation and the degree of neurological impairment were not statistically different between animals occluded for less than 3 h and animals permanently occluded. Our data clearly demonstrate a progression in the risk and gravity of hemorrhagic transformation that parallels the increase in the duration of transient cerebral ischemia. The results suggest a relationship, which is independent on the duration of ischemia, between neurological deficit and hemorrhagic transformation and confirm the expected but still debated principle that early recanalization of an occluded artery reduces the hemorrhagic risk after thrombolysis with tissue plasminogen activator.
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PMID:Effect of the duration of middle cerebral artery occlusion on the risk of hemorrhagic transformation after tissue plasminogen activator injection in rats. 1883 59

A 63-year-old man was admitted because of sudden transient consciousness disturbance and left-side hemiparesis 110 minutes after the onset. Typical symptoms of aortic dissection, such as chest pain, back pain, neck pain, laterality of blood pressure or hypotension were not found. Brain magnetic resonance imaging (MRI) showed multiple acute brain infarction of the right middle cerebral artery territory. Carotid duplex ultrasonography demonstrated a subintimal dissection with a false channel of the right common carotid artery (CCA) and the right internal carotid artery (ICA). Thoracoabdominal computed tomographic (CT) scan demonstrated the false lumen in ascending and descending thoracic aorta. Cervical CT scan showed a dissection with a false channel of the right CCA. Intravenous administration of recombinant tissue plasminogen activator (rt-PA) is a contraindicant therapy in patients of brain infarction with aortic dissection. Thus our patient showed thoracic aortic dissection with extension of the dissection toward the right internal carotid artery. And the patient complained of neither the pain in the chest, the back nor the neck. So we emphasize the necessity of carotid duplex ultrasonography examination before intravenous administration of rt-PA in the treatment of the cerebral infarction, regardless of having chest pain, back pain, neck pain or not.
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PMID:[A case of brain infarction and thoracic aortic dissection without chest nor back pain diagnosed by carotid duplex ultrasonography]. 1934 75

We found a heterozygous dysfibrinogenemia caused by the substitution of BbetaGly15Cys and designated it fibrinogen Hamamatsu II (H-II). Although the propositus suffered an infarction of the medulla oblongata, other thrombotic risk factors, paradoxical cerebral infarction, and arterial dissection were not found. To determine whether the delayed lysis of fibrin clots or not in the context of the BbetaGly15Cys substitution, we examined the clot lysis and plasmin generation of propositus' fibrinogen. Fibrinogen was purified from the propositus' and normal control plasma by immunoaffinity chromatography and was used for the following experiments: sodium dodecyl sulfate-polyacrylamide gel electrophoresis, fibrin polymerization, scanning electron microscopic observation of fibrin clot and fibers, clot lysis, and tissue-type plasminogen activator-mediated plasminogen activation. The H-II plasma fibrinogen showed the presence of albumin-binding variant forms, a dimeric molecule of variant fibrinogen, and impairment of lateral aggregation during fibrin polymerization. The H-II fibrin clot showed lower density of bundles and thinner diameters of fibers than in the normal fibrin clot. In the clot lysis experiments with overlaid plasmin, H-II fibrin showed a similar lysis period and lysis rate to the normal control. Moreover, plasmin generation from a mixture of thrombin, tissue-type plasminogen activator, plasminogen, and H-II fibrinogen also showed a similar rate to normal fibrinogen. Although the propositus suffered an infarction, the present study did not observe delayed clot lysis, that is, the clot was not resistant to plasmin degradation. Therefore, we did not clarify an association between the BbetaGly15Cys dysfibrinogenemia and arterial thrombosis.
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PMID:Analysis of plasmin generation and clot lysis of plasma fibrinogen purified from a heterozygous dysfibrinogenemia, BbetaGly15Cys (Hamamatsu II). 1980 4

Thrombolytic serine proteases not only initiate fibrinolysis, but also are up-regulated in vascular disease and acute inflammatory responses. Although the serine protease inhibitor (serpin) plasminogen activator inhibitor-1 (PAI-1) is considered a main regulator of thrombolysis, PAI-1 is also associated with vascular inflammation. The role of other serpins that target thrombolytic proteases, PAI-2, PAI-3, and neuroserpin (NSP), in vascular inflammation is, however, less well defined. NSP is a mammalian serpin that, similar to PAI-1, inhibits urokinase- and tissue-type plasminogen activators (uPA and tPA, respectively) and has been most closely associated with the nervous system, with a demonstrated protective role after cerebral infarction in mouse models. However, the role of NSP in systemic arterial inflammation and plaque growth is not known. Serp-1 is a myxoma viral serpin that also inhibits tPA and uPA, as well as additionally inhibiting plasmin and factor Xa (fXa). Serp-1 has proven highly potent anti-inflammatory and anti-atherogenic activity. Here we assess the effects of NSP treatment on plaque growth and T-helper (Th) lymphocyte activity in a mouse aortic allograft transplant model, with comparison to Serp-1. NSP and Serp-1 both significantly reduced plaque growth and T-cell invasion. T-bet (a Th1 differentiation marker) was significantly reduced in transplanted aorta with associated reductions in Th1 and Th17, but not Th2, in splenocytes. NSP had additional Th modifying activity in non-transplanted mice. In summary, this is the first report that NSP possesses anti-inflammatory activity in systemic arteries, modifying Th cell responses and significantly reducing plaque growth in mouse aortic allografts.
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PMID:Neuroserpin, a thrombolytic serine protease inhibitor (serpin), blocks transplant vasculopathy with associated modification of T-helper cell subsets. 2013 65


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