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Concept: Plasmin

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Background In patients with ischemic stroke, endovascular treatment results in a higher rate of recanalization of the affected cerebral artery than systemic intravenous thrombolytic therapy. However, comparison of the clinical efficacy of the two approaches is needed. Methods We randomly assigned 362 patients with acute ischemic stroke, within 4.5 hours after onset, to endovascular therapy (intraarterial thrombolysis with recombinant tissue plasminogen activator [t-PA], mechanical clot disruption or retrieval, or a combination of these approaches) or intravenous t-PA. Treatments were to be given as soon as possible after randomization. The primary outcome was survival free of disability (defined as a modified Rankin score of 0 or 1 on a scale of 0 to 6, with 0 indicating no symptoms, 1 no clinically significant disability despite symptoms, and 6 death) at 3 months. Results A total of 181 patients were assigned to receive endovascular therapy, and 181 intravenous t-PA. The median time from stroke onset to the start of treatment was 3.75 hours for endovascular therapy and 2.75 hours for intravenous t-PA (P<0.001). At 3 months, 55 patients in the endovascular-therapy group (30.4%) and 63 in the intravenous t-PA group (34.8%) were alive without disability (odds ratio adjusted for age, sex, stroke severity, and atrial fibrillation status at baseline, 0.71; 95% confidence interval, 0.44 to 1.14; P=0.16). Fatal or nonfatal symptomatic intracranial hemorrhage within 7 days occurred in 6% of the patients in each group, and there were no significant differences between groups in the rates of other serious adverse events or the case fatality rate. Conclusions The results of this trial in patients with acute ischemic stroke indicate that endovascular therapy is not superior to standard treatment with intravenous t-PA. (Funded by the Italian Medicines Agency, ClinicalTrials.gov number, NCT00640367 .).

Concepts: Clinical trial, Myocardial infarction, Stroke, Atrial fibrillation, Pulmonary embolism, Tissue plasminogen activator, Thrombolysis, Plasmin

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Background Endovascular therapy is increasingly used after the administration of intravenous tissue plasminogen activator (t-PA) for patients with moderate-to-severe acute ischemic stroke, but whether a combined approach is more effective than intravenous t-PA alone is uncertain. Methods We randomly assigned eligible patients who had received intravenous t-PA within 3 hours after symptom onset to receive additional endovascular therapy or intravenous t-PA alone, in a 2:1 ratio. The primary outcome measure was a modified Rankin scale score of 2 or less (indicating functional independence) at 90 days (scores range from 0 to 6, with higher scores indicating greater disability). Results The study was stopped early because of futility after 656 participants had undergone randomization (434 patients to endovascular therapy and 222 to intravenous t-PA alone). The proportion of participants with a modified Rankin score of 2 or less at 90 days did not differ significantly according to treatment (40.8% with endovascular therapy and 38.7% with intravenous t-PA; absolute adjusted difference, 1.5 percentage points; 95% confidence interval [CI], -6.1 to 9.1, with adjustment for the National Institutes of Health Stroke Scale [NIHSS] score [8-19, indicating moderately severe stroke, or ≥20, indicating severe stroke]), nor were there significant differences for the predefined subgroups of patients with an NIHSS score of 20 or higher (6.8 percentage points; 95% CI, -4.4 to 18.1) and those with a score of 19 or lower (-1.0 percentage point; 95% CI, -10.8 to 8.8). Findings in the endovascular-therapy and intravenous t-PA groups were similar for mortality at 90 days (19.1% and 21.6%, respectively; P=0.52) and the proportion of patients with symptomatic intracerebral hemorrhage within 30 hours after initiation of t-PA (6.2% and 5.9%, respectively; P=0.83). Conclusions The trial showed similar safety outcomes and no significant difference in functional independence with endovascular therapy after intravenous t-PA, as compared with intravenous t-PA alone. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00359424 .).

Concepts: Stroke, Modified Rankin Scale, Disability, Tissue plasminogen activator, Thrombolysis, Plasmin, Barthel scale, Rehabilitation medicine

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Background Among patients with acute ischemic stroke due to occlusions in the proximal anterior intracranial circulation, less than 40% regain functional independence when treated with intravenous tissue plasminogen activator (t-PA) alone. Thrombectomy with the use of a stent retriever, in addition to intravenous t-PA, increases reperfusion rates and may improve long-term functional outcome. Methods We randomly assigned eligible patients with stroke who were receiving or had received intravenous t-PA to continue with t-PA alone (control group) or to undergo endovascular thrombectomy with the use of a stent retriever within 6 hours after symptom onset (intervention group). Patients had confirmed occlusions in the proximal anterior intracranial circulation and an absence of large ischemic-core lesions. The primary outcome was the severity of global disability at 90 days, as assessed by means of the modified Rankin scale (with scores ranging from 0 [no symptoms] to 6 [death]). Results The study was stopped early because of efficacy. At 39 centers, 196 patients underwent randomization (98 patients in each group). In the intervention group, the median time from qualifying imaging to groin puncture was 57 minutes, and the rate of substantial reperfusion at the end of the procedure was 88%. Thrombectomy with the stent retriever plus intravenous t-PA reduced disability at 90 days over the entire range of scores on the modified Rankin scale (P<0.001). The rate of functional independence (modified Rankin scale score, 0 to 2) was higher in the intervention group than in the control group (60% vs. 35%, P<0.001). There were no significant between-group differences in 90-day mortality (9% vs. 12%, P=0.50) or symptomatic intracranial hemorrhage (0% vs. 3%, P=0.12). Conclusions In patients receiving intravenous t-PA for acute ischemic stroke due to occlusions in the proximal anterior intracranial circulation, thrombectomy with a stent retriever within 6 hours after onset improved functional outcomes at 90 days. (Funded by Covidien; SWIFT PRIME ClinicalTrials.gov number, NCT01657461 .).

Concepts: Stroke, Modified Rankin Scale, Disability, Tissue plasminogen activator, Thrombolysis, Plasmin

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Multiple sclerosis is among the most common causes of neurological disability in young adults. Here we provide the preclinical proof of concept of the benefit of a novel strategy of treatment for multiple sclerosis targeting neuroendothelial N-methyl-D-aspartate glutamate receptors. We designed a monoclonal antibody against N-methyl-D-aspartate receptors, which targets a regulatory site of the GluN1 subunit of N-methyl-D-aspartate receptor sensitive to the protease tissue plasminogen activator. This antibody reverted the effect of tissue plasminogen activator on N-methyl-D-aspartate receptor function without affecting basal N-methyl-D-aspartate receptor activity (n = 21, P < 0.01). This antibody bound N-methyl-D-aspartate receptors on the luminal surface of neurovascular endothelium in human tissues and in mouse, at the vicinity of tight junctions of the blood-spinal cord barrier. Noteworthy, it reduced human leucocyte transmigration in an in vitro model of the blood-brain barrier (n = 12, P < 0.05). When injected during the effector phase of MOG-induced experimental autoimmune encephalomyelitis (n = 24), it blocked the progression of neurological impairments, reducing cumulative clinical score (P < 0.001) and mean peak score (P < 0.001). This effect was observed in wild-type animals but not in tissue plasminogen activator knock-out animals (n = 10). This therapeutic effect was associated to a preservation of the blood-spinal cord barrier (n = 6, P < 0.001), leading to reduced leucocyte infiltration (n = 6, P < 0.001). Overall, this study unveils a critical function of endothelial N-methyl-D-aspartate receptor in multiple sclerosis, and highlights the therapeutic potential of strategies targeting the protease-regulated site of N-methyl-D-aspartate receptor.

Concepts: Immune system, Protein, Multiple sclerosis, Neurology, NMDA receptor, Tissue plasminogen activator, Plasmin, Ligand-gated ion channel

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Background: Trauma is a global disease with over 2.5 million deaths annually from haemorrhage and coagulopathy. Overt hyperfibrinolysis is rare in trauma and associated with massive fatal injuries. Paradoxically, clinical trials suggest a much broader indication for antifibrinolytics. Objective: To determine the incidence and magnitude of fibrinolytic activation in trauma patients and its relationship to clot lysis as measured by thromboelastometry. Methods: Prospective cohort study of 303 consecutive trauma patients admitted between January 2007 and June 2009. Blood was drawn on arrival for thromboelastometry (TEM) and coagulation assays. Follow-up was until hospital discharge or death. TEM hyperfibrinolysis was defined as maximum clot lysis (ML) >15%. Fibrinolytic Activation (FA) measured by plasmin-antiplasmin complex (PAP) and D-dimer levels. Data were collected on demographics, mechanism, severity of injury and baseline vital signs. Outcome Measure(s): 28-day mortality. Secondary: 28-day ventilator-free days and 24-hour transfusion requirement. Results: Only 5% of patients had severe fibrinolysis on TEM, but 57% of patients had evidence of ‘moderate’ fibrinolysis with PAP levels elevated over twice normal (>1500μg/L) without lysis on TEM. TEM only detected clot lysis when PAP levels were increased 30 times normal (p<0.001) and antiplasmin levels were less than 75% of normal. Patients with FA had increased 28-day mortality compared with no FA (12% vs 1%, p<0.001), fewer ventilator-free days and longer hospital stay. Conclusions: FA occurs in the majority of trauma patients and the magnitude of FA correlates with poor clinical outcome. This was not detected by conventional thromboelastometry, an insensitive measure of endogenous fibrinolytic activity. © 2012 International Society on Thrombosis and Haemostasis.

Concepts: Coagulation, Pulmonary embolism, Fibrin, Fibrinolysis, Thrombus, Plasmin, Alpha 2-antiplasmin, Thromboelastometry

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Intravenous thrombolysis remains the mainstay treatment for acute ischemic stroke. One of the most feared complications of the treatment is thrombolysis-related symptomatic intracerebral hemorrhage (sICH), which occurs in nearly 6% of patients and carries close to 50% mortality. The treatment options for sICH are based on small case series and expert opinion, and the efficacy of recommended treatments is not well known.

Concepts: Stroke, Thrombosis, Pulmonary embolism, Cerebral hemorrhage, Tissue plasminogen activator, Thrombolysis, Plasmin

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BACKGROUND: Lacunar infarcts constitute up to 25% of all ischaemic strokes. As acute intracranial vascular imaging has become widely available with computed tomographic angiography, thrombolysis of lacunar strokes has become contentious because an intracranial vascular lesion cannot be visualized. We studied the effect of thrombolysis on lacunar strokes compared to other clinical ischaemic stroke sub-types. METHODS: Ischaemic stroke patients from phase 3 of the Registry of the Canadian Stroke Network data (July 2003-March 2008) were included. Lacunar stroke was defined as a lacunar syndrome supported by computed tomography brain showing a subcortical hypodense lesion with a diameter <20 mm. Clinical syndromes were used to define other stroke sub-types. The outcomes were mortality at 90 days, modified Rankin Scale score 0-2 at discharge, occurrence of intracranial haemorrhage as a complication of stroke in-hospital, and discharge disposition to home. RESULTS: A total of 11 503 patients of ischaemic stroke were included from the Registry of the Canadian Stroke Network 3 between July 2003 and March 2008. Lacunar strokes formed 19·1% of the total strokes. The total number of patients who received tissue plasminogen activator was 1630 (14·2%). A significant association was found between tissue plasminogen activator treatment and outcomes after controlling Oxfordshire Community Stroke Project types - for modified Rankin Scale at discharge and discharge to home, but not for mortality. A thrombolysis-by-Oxfordshire Community Stroke Project stroke sub-type interaction was observed due to lack of benefit among the posterior circulation stroke sub-types. Patients with lacunar strokes, partial anterior circulation stroke, and total anterior circulation strokes all benefited approximately equally from thrombolysis. CONCLUSIONS: Thrombolysis is associated with clinically improved outcome among patients with lacunar stroke syndromes.

Concepts: Blood, Stroke, Pulmonary embolism, Modified Rankin Scale, Tissue plasminogen activator, Thrombolysis, Plasmin, Lacunar stroke

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Purpose To study the relationship between functional independence and time to reperfusion in the Solitaire with the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke (SWIFT PRIME) trial in patients with disabling acute ischemic stroke who underwent endovascular therapy plus intravenous tissue plasminogen activator (tPA) administration versus tPA administration alone and to investigate variables that affect time spent during discrete steps. Materials and Methods Data were analyzed from the SWIFT PRIME trial, a global, multicenter, prospective study in which outcomes were compared in patients treated with intravenous tPA alone or in combination with the Solitaire device (Covidien, Irvine, Calif). Between December 2012 and November 2014, 196 patients were enrolled. The relation between time from (a) symptom onset to reperfusion and (b) imaging to reperfusion and clinical outcome was analyzed, along with patient and health system characteristics that affect discrete steps in patient workflow. Multivariable logistic regression was used to assess relationships between time and outcome; negative binomial regression was used to evaluate effects on workflow. The institutional review board at each site approved the trial. Patients provided written informed consent, or, at select sites, there was an exception from having to acquire explicit informed consent in emergency circumstances. Results In the stent retriever arm of the study, symptom onset to reperfusion time of 150 minutes led to 91% estimated probability of functional independence, which decreased by 10% over the next hour and by 20% with every subsequent hour of delay. Time from arrival at the emergency department to arterial access was 90 minutes (interquartile range, 69-120 minutes), and time to reperfusion was 129 minutes (interquartile range, 108-169 minutes). Patients who initially arrived at a referring facility had longer symptom onset to groin puncture times compared with patients who presented directly to the endovascular-capable center (275 vs 179.5 minutes, P < .001). Conclusion Fast reperfusion leads to improved functional outcome among patients with acute stroke treated with stent retrievers. Detailed attention to workflow with iterative feedback and aggressive time goals may have contributed to efficient workflow environments. (©) RSNA, 2016 Online supplemental material is available for this article.

Concepts: Regression analysis, Clinical trial, Patient, Informed consent, Stroke, Clinical research, Tissue plasminogen activator, Plasmin

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Herinase, a new bi-functional fibrinolytic metalloprotease, was purified from a medicinal and edible mushroom Hericium erinaceum. The enzyme was monomeric with a molecular mass of 51 kDa. Analysis of fibrin zymography showed an active band with a similar molecular mass. The N-terminal sequence of herinase VPSSFRTTITDAQLRG was highly distinguished from known fibrinolytic enzymes. Moreover, the enzyme activity was strongly inhibited by EDTA and EGTA, indicating that herinase is a metalloprotease. Herinase exhibited high specificity for the substrate t-PA followed by plasmin. The K m and V max values for H-D-Ile-Pro-Arg-PNA were found to be 4.7 mg and 26.7 U/ml respectively. Similarly, fibrin plate assays revealed that it was able to degrade fibrin clot directly and also able to activate plasminogen. Herinase provoked a rapid degradation of fibrin and fibrinogen α chains and slower degradation of γ chains. It had no activity on the β chains of fibrin and fibrinogen. This result suggests that herinase could possibly contain higher amount of α-fibrinogenase. The activity of herinase was stimulated by metal ions such as Ca(2+), Mg(2+), and Mn(2+), but inhibited by Cu(2+), Fe(2+), and Zn(2+). Herinase exhibited maximum activity at 30 °C and pH 7.0. These results demonstrate that herinase could be a novel fibrinolytic enzyme.

Concepts: Protein, Enzyme, Fibrin, Fibrinolysis, Protease, Plasmin, Edible mushroom, Hericium erinaceus

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OBJECTIVE:To present a case of nebulized tissue plasminogen activator (t-PA) treatment for symptomatic plastic bronchitis in a pediatric patient years after a Fontan procedure.CASE SUMMARY:A 13-year-old boy with a history of corrected congenital heart disease was admitted to the pediatric intensive care unit after 2 weeks of worsening respiratory distress. A chest radiograph and subsequent bronchoscopy revealed extensive mucus plugging due to plastic bronchitis. Casts reaccumulated quickly after manual removal of the mucus and a regimen of aerosolized t-PA was initiated to break down the casts and prevent further cast formation over the 17-day hospital course. The treatment was successful and the patient was discharged home without evidence of bronchial casts.DISCUSSION:Plastic bronchitis is a potentially devastating condition in which pulmonary infiltrates line the bronchial tree, forming casts and prohibiting effective oxygen exchange. There are few effective treatment options for this condition. The use of aerosolized t-PA for the treatment of plastic bronchitis has been reported to be safe and effective in 4 cases but no consistent regimen, dose, or duration of treatment has been established.CONCLUSIONS:t-PA can be nebulized and inhaled for successful inhibition of bronchial cast formation. More information to determine the most effective dose and duration of therapy is needed to effectively improve the lives of people with plastic bronchitis.

Concepts: Asthma, Lung, Heart, Respiratory system, Mucus, Tissue plasminogen activator, Plasmin