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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)

Major ischemic strokes secondary to proximal artery occlusions are responsible for significant morbidity and mortality. Owing to extensive clot burden, these strokes are poorly responsive to intravenous tissue plasminogen activator. The introduction of endovascular therapy, particularly mechanical devices, has resulted in markedly improved recanalization rates of large vessel occlusions. With increasing experience with the Penumbra Stroke System and the 054 reperfusion catheter, there has been further improvement in TIMI 2 and 3 revascularization rates with faster times to vessel opening. The aim of this technical review is to convey various tips and tricks learnt from this experience.
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PMID:The Penumbra Stroke System: a technical review. 2199 May 25

Despite considerable research that has contributed to a better understanding of the pathophysiology of stroke, translation of this knowledge into effective therapies has largely failed. The only effective treatment for ischemic stroke is rapid recanalization of an occluded vessel by dissolving the clot with tissue plasminogen activator (tPA). However, stroke adversely affects vascular function as well that can cause secondary brain injury and limit treatment that depends on a patent vasculature. In middle cerebral arteries (MCA), ischemia/reperfusion (I/R) cause loss of myogenic tone, vascular paralysis, and endothelial dysfunction that can lead to loss of autoregulation. In contrast, brain parenchymal arterioles retain considerable tone during I/R that likely contributes to expansion of the infarct into the penumbra. Microvascular dysregulation also occurs during ischemic stroke that causes edema and hemorrhage, exacerbating the primary insult. Ischemic injury of vasculature is progressive with longer duration of I/R. Early postischemic reperfusion has beneficial effects on stroke outcome but can impair vascular function and exacerbate ischemic injury after longer durations of I/R. This review focuses on current knowledge on the effects of I/R on the structure and function of different vascular segments in the brain and highlight some of the more promising targets for vascular protection.
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PMID:Vascular Protection Following Cerebral Ischemia and Reperfusion. 2210 80

In Japan, time window of IV-t-PA therapy for acute stroke is within 3 hours of stroke onset. Recently, ECASS III study revealed that time window of 3-4.5 hours of stroke onset is effective for acute stroke. Thus, now US, Australia, and many countries in Europe and Asia are available for time window of 4.5 hours. The extension of time window until 4.5 hours is expected in Japan. The target of treatment in acute stroke is penumbra. MRI can estimate the area of penumbra using perfusion MRI and diffusion MRI. IV-t-PA study using MRI was conducted in acute stroke patients with over 3-4.5 hours of onset, but did not reach satisfied results. We reported that M1 susceptibility vessel sign (SVS) on T(2)(*) can predict no early recanalization after t-PA infusion. Next, FLAIR can estimate the onset time of stroke in acute stroke patients within 24h of onset. Our study demonstrated that acute stroke patients with unknown onset time may be able to safely receive intravenous thrombolysis using FLAIR. Extension of time window and development of t-PA therapy using the MRI is expected in future.
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PMID:[The extension of time window until 4.5 hours and development of MRI in t-PA patients]. 2227 25

The molecular causality and response to stroke is complex. Yet, much of the literature examining the molecular response to stroke has focused on targeted pathways that have been well-characterized. Consequently, our understanding of stroke pathophysiology has made little progress by way of clinical therapeutics since tissue plasminogen activator was approved for treatment nearly a decade ago. The lack of clinical translation is in part due to neuron-focused studies, preclinical models of cerebral ischemia and the paradoxical nature of neuro-inflammation. With the evolution of the Stroke Therapy Academic Industry Roundtable criteria streamlining research efforts and broad availability of genomic technologies, the ability to decipher the molecular fingerprint of ischemic stroke is on the horizon. This review highlights preclinical microarray findings of the ischemic brain, discusses the transcriptome of cerebral preconditioning and emphasizes the importance of further characterizing the role of the neurovascular unit and peripheral white blood cells in mediating stroke damage and repair within the penumbra.
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PMID:The transcriptome of cerebral ischemia. 2238 15

Stroke remains a major cause of death in the US and around the world. Despite major scientific advances in our understanding of stroke pathology, the only FDA-approved drug for ischemic stroke is tissue plasminogen activator (tPA). Moreover, the therapeutic window for tPA is confined to the acute phase of stroke, thereby greatly limiting its benefits to less than 3% of ischemic stroke patients. Many treatment strategies for stroke have targeted the subacute or chronic phase in an effort to abrogate the secondary cell death that ensues after the initial stroke insult. Here, we advance the hypothesis that blood vessel disruption, or aneurysm, in the brain is an exacerbating factor for stroke, especially in the evolution of the penumbra or peri-infarct area. A better understanding of aneurysm, specifically its dynamic onset and juxtaposition to the ischemic brain tissue should facilitate the development of novel strategies for attenuating the secondary cell death associated with stroke. To this end, we discuss the laboratory and clinical evidence implicating aneurysm formation in stroke and also provide insights on how stem cell therapy may prove efficacious in combating aneurysm and stroke.
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PMID:Cerebral aneurysm as an exacerbating factor in stroke pathology and a therapeutic target for neuroprotection. 2257 80

Multifocal cerebral venous sinus thrombosis (CVST) has a high mortality rate especially when patients present with stupor or coma. Medical treatment including anticoagulation raises concerns about the associated high risk of intracerebral hemorrhage. Treatment of multifocal CVST with mechanical thrombectomy devices and local tPA infusion have previously been reported. However, these devices may have technical limitations. Success of the new-generation aspiration thrombectomy device like the Penumbra system has been reported in few cases of isolated CVST without the use of chemical thrombolysis. We describe two cases in which mechanical thrombectomy were used in conjunction with intra-sinus tPA infusion. Both cases were complicated and failed initial anticoagulation. Penumbra 054 was used in both cases. The Penumbra 054 is a novel device that has a bigger lumen which provides compatibility with other microcatheters, if additional therapies are required. The larger internal diameter of this catheter also allows for stronger thrombo-aspiration, potentially effecting more rapid sinus recanalization. Both cases showed remarkable clinical recovery without any major complications. This is the first reported simultaneous use of the Penumbra system 054 along with tPA infusion. New devices such as the Penumbra system may offer additional therapeutic options in the treatment of multifocal CVST.
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PMID:Use of the Penumbra system 054 plus low dose thrombolytic infusion for multifocal venous sinus thrombosis. A report of two cases. 2295 71

Stroke is a major cause of mortality and morbidity, and thrombolysis has served as a catalyst for major changes in the management of acute ischaemic stroke. Intravenous alteplase (recombinant tissue plasminogen activator) is the only approved thrombolytic agent at present indicated for acute ischaemic stoke. While the licensed time window extends to 3h from symptom onset, recent data suggest that the trial window can be extended up to 4.5 h with overall benefit. Nonetheless, 'time is brain' and every effort must be made to reduce the time delay to thrombolysis. Intracranial haemorrhage is the major complication associated with thrombolysis, and key factors increasing risk of haemorrhage include increasing age, high blood pressure, diabetes and stroke severity. Currently, there is no direct evidence to support thrombolysis in patients >80 years of age, with a few case series indicating no overt harm. Identification of viable penumbra based on computed tomography/magnetic resonance imaging may allow future extension of the time window. Adjuvant transcranial Doppler ultrasound has the potential to improve reperfusion rates. While intra-arterial thrombolysis has been in vogue for a few decades, there is no clear advantage over intravenous thrombolysis. The evidence base for thrombolysis in specific situations (e.g. dissection, pregnancy) is inadequate, and individualized decisions are needed, with a clear indication to the patient/carer about the lack of direct evidence, and the risk-benefit balance. Patient-friendly information leaflets may facilitate the process of consent for thrombolysis. This article summarizes the recent advances in thrombolysis for acute ischaemic stroke. Key questions faced by clinicians during the decision-making process are answered based on the evidence available.
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PMID:Thrombolysis in acute ischaemic stroke: an update. 2325 46

Reperfusion therapy for acute stroke has evolved from the initial use of intravenous tissue plasminogen activator (tPA) within 3 hours of symptom onset to more recent guideline-recommended use up to 4.5 hours. In addition, endovascular therapy is increasingly utilized for stroke treatment and is typically initiated up to 8 hours after onset. Recent studies demonstrate that imaging of the ischemic penumbra with diffusion/perfusion magnetic resonance imaging (MRI) can identify subgroups of patients who are likely to improve following successful reperfusion (Target Mismatch profile) and others who are at increased risk for hemorrhage and poor clinical outcomes (Malignant profile). New data indicate that stent retriever devices provide better recanalization efficacy and clinical outcomes than the previously available mechanical thrombectomy devices. Going forward, we believe that the use of penumbral imaging with validated MRI techniques, as well as the currently less well-validated computed tomography (CT) perfusion approach, will maximize benefit and reduce the risk of adverse events and poor outcomes when used both early after stroke onset and at later time points. New trials that feature diffusion/perfusion MRI or CT perfusion-based patient selection for treatment with intravenous tPA and or endovascular therapies versus nonreperfused control groups are planned or in progress. We predict that these trials will confirm the hypothesis that penumbral imaging can enhance patient selection and extend the therapeutic time window for acute ischemic stroke.
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PMID:Advanced imaging to extend the therapeutic time window of acute ischemic stroke. 2337 23

Despite advances in the diagnosis and treatment of acute ischaemic stroke in the past two decades, stroke has remained the third cause of mortality and the single leading cause of disability worldwide. The immediate goal of acute ischaemic stroke therapy is to salvage the ischaemic penumbra through recanalisation of the occluded cerebral blood vessel. This is currently achieved through thrombolytics, which are pharmacological agents that can break up a clot blocking the flow of blood. To date, the only approved thrombolytic for treatment of acute ischaemic stroke is recombinant tissue plasminogen activator (alteplase, rt-PA), however, alteplase is substantially underused because of concerns regarding adverse bleeding risk. This limitation has fuelled the search for other thrombolytic agents, which display greater fibrin dependence and selectivity, but lack detrimental effects within the central nervous system. Development of alternative fibrinolytic agents that might be easier and safer to administer could lead to wider acceptance and use of thrombolytic therapy for stroke. Although other thrombolytic agents (e.g. streptokinase) have failed to show benefit over alteplase, there is still on-going research in search of alternative agents with higher target specificity and better safety profile. The potential thrombolytic agents with trials in progress include desmoteplase, tenecteplase, reteplase, plasmin and microplasmin. This review summarises current therapies with thrombolytics (e.g. alteplase and urokinase), their limitations and side effects, and also discusses ongoing clinical studies with the various potential emerging thrombolytic agents.
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PMID:Thrombolytic agents for acute ischaemic stroke treatment: the past, present and future. 2339 31

The Massachusetts General Hospital Neuroradiology Division employed an experience and evidence based approach to develop a neuroimaging algorithm to best select patients with severe ischemic strokes caused by anterior circulation occlusions (ACOs) for intravenous tissue plasminogen activator and endovascular treatment. Methods found to be of value included the National Institutes of Health Stroke Scale (NIHSS), non-contrast CT, CT angiography (CTA) and diffusion MRI. Perfusion imaging by CT and MRI were found to be unnecessary for safe and effective triage of patients with severe ACOs. An algorithm was adopted that includes: non-contrast CT to identify hemorrhage and large hypodensity followed by CTA to identify the ACO; diffusion MRI to estimate the core infarct; and NIHSS in conjunction with diffusion data to estimate the clinical penumbra.
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PMID:The Massachusetts General Hospital acute stroke imaging algorithm: an experience and evidence based approach. 2349 40


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