Local Cerebral Recombinant Tissue Plasminogen Activator Concentrations During Acute Stroke.
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ABSTRACT:
SUBMITTER: Essig F
PROVIDER: S-EPMC7941250 | biostudies-literature | 2021 May
REPOSITORIES: biostudies-literature
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Local Cerebral Recombinant Tissue Plasminogen Activator Concentrations During Acute Stroke.
Essig Fabian F Kollikowski Alexander M AM Müllges Wolfgang W Stoll Guido G Haeusler Karl Georg KG Schuhmann Michael K MK Pham Mirko M
JAMA neurology 20210501 5
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Project description:Background and aimsThrombolytic therapy is widely used to treat acute ischemic stroke (AIS) patients. As intracerebral hemorrhage is a life-threatening complication of this therapy, monitoring the fibrinolytic and coagulation systems is imperative. However, existing studies on plasmin inhibitor complex (PIC) and thrombin-antithrombin III complex (TAT) mostly apply the enzyme-linked immunosorbent assay (ELISA) method. The aim of this study is to establish the baseline of thrombolytic treatment for AIS patients; to monitor the fibrinolytic and coagulation system following alteplase administration; to ascertain the proper time point to predict intracerebral hemorrhage.MethodsThe method used to assess a patient's intravascular situation, namely chemiluminescence, was used to quantitatively assess the PIC, TAT, and thrombomodulin (TM). Immuno-turbidimetric was used to assess the concentration of D-dimer, fibrin/fibrinogen degradation products (FDP), and the Von Willebrand factor (vWF). The Clauss clotting method was used to assay the activated partial thromboplastin time (APTT), prothrombin time (PT) and FIB.ResultsPIC increased to its peak concentration at 3 hours post intravenous (IV) alteplase infusion and decreased by nearly 50% every 3 hours thereafter. After 24 hours, PIC returned to its normal range, while D-dimer and FDP decreased 3 hours later compared to PIC. PT and APTT exhibited no obvious change during the 24-hour period. TM also exhibited no changes during the treatment.ConclusionPIC decreased 3 hours earlier than D-dimer and FDP. The combined test of PIC, D-dimer, and fibrinogen can be used to monitor the fibrinolytic system after the IV alteplase infusion. The use of IV alteplase had no impact on the endothelium. Creating a patient's individual data curve could assist in the prediction of hemorrhagic transformation (HT) and a stroke occurring.
| S-EPMC7752160 | biostudies-literature
Project description:Background and purposePlasmin is a direct-acting thrombolytic with a better safety profile than recombinant tissue-type plasminogen activator (rtPA) in animal models. With the application of retrieval devices for managing acute ischemic stroke, extracted thromboemboli are available for ex vivo examination. We ask whether such thrombi are amenable to plasmin thrombolysis and whether such activity is different with rtPA.MethodsThromboembolic fragments (total 29) were retrieved from the intracranial carotid artery system of 15 patients with acute ischemic stroke and randomly assigned to ex vivo thrombolysis with plasmin or rtPA. After an initial 2-hour exposure, residual material was exposed to the other agent for an additional 2 hours. Thrombolysis was quantified by change in thrombus area and released d-dimer.ResultsPlasmin induced significant ex vivo thrombolysis of cerebral arterial thromboemboli, decreasing area by 45.9% ± 29.4% and 69.2% ± 52.5% and inducing median D-dimer release of 108,180 μg/L (range, 16,780 to 668,050 μg/L) and 16,905 μg/L (range, 240 to 403 085 μg/L) during the first and second 2-hour incubation periods, respectively. These changes were not different from those obtained with rtPA, which decreased area by 34.7% ± 57.8% (P=0.63) and by 68.4% ± 26.9% (P=0.97) and induced median D-dimer release of 151,990 μg/L (range, 9870 to 338,350 μg/L; P=0.51) and 34,520 μg/L (range 3794 to 325,400 μg/L; P=0.19) during the first and second 2-hour incubations.ConclusionsRetrieved human cerebral thromboemboli were amenable to ex vivo lysis by plasmin, the rate and degree of which was not different than that achieved with rtPA.
| S-EPMC3217902 | biostudies-literature
Project description:Introduction:Currently, the most available treatment for acute ischemic stroke (AIS) is thrombolytic therapy with recombinant tissue plasminogen activator (r-TPA). A challenge in r-TPA therapy is the prediction of recovery in each case. Objective:The aim was to find a possible relationship between the cerebral oximetry indexes and the clinical outcome of r-TPA therapy to assess the cerebral oximetry as a non-invasive monitoring agent for therapy. Methods:The inclusion criteria were all patients with AIS who received r-TPA. The neurologic status was evaluated based on the national institutes of health stroke scale (NIHSS) score at arrival, and after a period of 24 hours. In addition, the levels of brain oxygenation in both hemispheres were measured before and continuously over the first 24 hours after r-TPA injection, using an oximetric sensor in the frontal lobes. The clinical success was defined as a 4-point improvement from the baseline NIHSS. Results:Total 44 patients with the mean age of 58.2 ± 2.18 years were enrolled, of whom 68.18% were male. Twenty-eight patients remained clinically unimproved and 16 patients were improved. A significant difference was found in the mean surface area under the brain oximetric curve in the 24 hour, in the affected hemisphere in the improved group, compared to the unimproved group (P = 0.007). There was a significant difference between the mean increase in brain oxygenation within 24 hours in the improved and unimproved groups (P = 0.002). Conclusion:It is likely that, The cerebral oximetry could contribute to predict the likelihood of r-TPA prognosis in patients with AIS.
| S-EPMC6955029 | biostudies-literature
Project description:To determine the expression of circulating miRNAs in AIS patients with thrombolysis and without thrombolysis. Grant ID: 81100882 Grant title: The relation between transcription of miR-497 and neurons apoptosis after ischemic stroke Funding source: Chinese National Natural Science Foundation Grantee First Name: Zhen Grantee Last Name:Deng
2017-02-23 | GSE95204 | GEO
Project description:Background and purposeWe conducted a randomized exploratory study to assess safety and the probability of a favorable outcome with adjunctive argatroban, a direct thrombin-inhibitor, administered to recombinant tissue-type plasminogen activator (r-tPA)-treated ischemic stroke patients.MethodsPatients treated with standard-dose r-tPA, not receiving endovascular therapy, were randomized to receive no argatroban or argatroban (100 μg/kg bolus) followed by infusion of either 1 (low dose) or 3 μg/kg per minute (high dose) for 48 hours. Safety was incidence of symptomatic intracerebral hemorrhage. Probability of clinical benefit (modified Rankin Scale score 0-1 at 90 days) was estimated using a conservative Bayesian Poisson model (neutral prior probability centered at relative risk, 1.0 and 95% prior intervals, 0.33-3.0).ResultsNinety patients were randomized: 29 to r-tPA alone, 30 to r-tPA+low-dose argatroban, and 31 to r-tPA+high-dose argatroban. Rates of symptomatic intracerebral hemorrhage were similar among control, low-dose, and high-dose arms: 3/29 (10%), 4/30 (13%), and 2/31 (7%), respectively. At 90 days, 6 (21%) r-tPA alone, 9 (30%) low-dose, and 10 (32%) high-dose patients were with modified Rankin Scale score 0 to 1. The relative risks (95% credible interval) for modified Rankin Scale score 0 to 1 with low, high, and either low or high dose argatroban were 1.17 (0.57-2.37), 1.27 (0.63-2.53), and 1.34 (0.68-2.76), respectively. The probability that adjunctive argatroban was superior to r-tPA alone was 67%, 74%, and 79% for low, high, and low or high dose, respectively.ConclusionsIn patients treated with r-tPA, adjunctive argatroban was not associated with increased risk of symptomatic intracerebral hemorrhage and provides evidence that a definitive effectiveness trial is indicated.Clinical trial registrationURL: http://www.clinicaltrials.gov. Unique Identifier: NCT01464788.
| S-EPMC5499711 | biostudies-literature
Project description:BackgroundRecombinant tissue plasminogen activator (rt-PA, alteplase) improved functional outcome in patients treated soon after acute ischaemic stroke in randomised trials, but licensing is restrictive and use varies widely. The IST-3 trial adds substantial new data. We therefore assessed all the evidence from randomised trials for rt-PA in acute ischaemic stroke in an updated systematic review and meta-analysis.MethodsWe searched for randomised trials of intravenous rt-PA versus control given within 6 h of onset of acute ischaemic stroke up to March 30, 2012. We estimated summary odds ratios (ORs) and 95% CI in the primary analysis for prespecified outcomes within 7 days and at the final follow-up of all patients treated up to 6 h after stroke.FindingsIn up to 12 trials (7012 patients), rt-PA given within 6 h of stroke significantly increased the odds of being alive and independent (modified Rankin Scale, mRS 0-2) at final follow-up (1611/3483 [46·3%] vs 1434/3404 [42·1%], OR 1·17, 95% CI 1·06-1·29; p=0·001), absolute increase of 42 (19-66) per 1000 people treated, and favourable outcome (mRS 0-1) absolute increase of 55 (95% CI 33-77) per 1000. The benefit of rt-PA was greatest in patients treated within 3 h (mRS 0-2, 365/896 [40·7%] vs 280/883 [31·7%], 1·53, 1·26-1·86, p<0·0001), absolute benefit of 90 (46-135) per 1000 people treated, and mRS 0-1 (283/896 [31·6%] vs 202/883 [22·9%], 1·61, 1·30-1·90; p<0·0001), absolute benefit 87 (46-128) per 1000 treated. Numbers of deaths within 7 days were increased (250/2807 [8·9%] vs 174/2728 [6·4%], 1·44, 1·18-1·76; p=0·0003), but by final follow-up the excess was no longer significant (679/3548 [19·1%] vs 640/3464 [18·5%], 1·06, 0·94-1·20; p=0·33). Symptomatic intracranial haemorrhage (272/3548 [7·7%] vs 63/3463 [1·8%], 3·72, 2·98-4·64; p<0·0001) accounted for most of the early excess deaths. Patients older than 80 years achieved similar benefit to those aged 80 years or younger, particularly when treated early.InterpretationThe evidence indicates that intravenous rt-PA increased the proportion of patients who were alive with favourable outcome and alive and independent at final follow-up. The data strengthen previous evidence to treat patients as early as possible after acute ischaemic stroke, although some patients might benefit up to 6 h after stroke.FundingUK Medical Research Council, Stroke Association, University of Edinburgh, National Health Service Health Technology Assessment Programme, Swedish Heart-Lung Fund, AFA Insurances Stockholm (Arbetsmarknadens Partners Forsakringsbolag), Karolinska Institute, Marianne and Marcus Wallenberg Foundation, Research Council of Norway, Oslo University Hospital.
| S-EPMC3386494 | biostudies-literature
Project description:IntroductionStudies have demonstrated that intravenous recombinant tissue plasminogen activator (IV rtPA) is a cost-effective treatment for acute ischemic stroke. Age-specific cost effectiveness has not been well examined. This study estimated age-specific incremental cost-effectiveness ratios (ICERs) of IV rtPA treatment versus no IV rtPA.MethodsA Markov model was developed to examine the economic impact of IV rtPA over a 20-year time horizon on four age groups (18-44, 45-64, 65-80, and ≥81 years) from the U.S. healthcare sector perspective. The model used health outcomes from a national stroke registry adjusted by parameters from previous literature and current hospitalization costs in 2013 U.S. dollars. Long-term annual costs and quality-adjusted life years (QALYs) in the years after a stroke were discounted at 3% per year. Incremental costs, incremental QALYs, and ICERs were estimated and sensitivity analyses were conducted between 2015 and 2017.ResultsUse of IV rtPA gained 0.55 QALYs and cost $3,941 more than no IV rtPA for stroke patients aged ≥18 years over a 20-year time horizon. IV rtPA was a dominant strategy compared to no IV rtPA for patients aged 18-44 and 45-64 years. For patients aged 65-80 years, IV rtPA gained 0.44 QALYs and cost $4,872 more than no IV rtPA (ICER=$11,132/QALY). For patients aged ≥81 years, ICER was estimated at $48,676/QALY.ConclusionsIV rtPA saved costs and improved health outcomes for patients aged 18-64 years and was cost effective for those aged ≥65 years. These findings support the use of IV rtPA.
| S-EPMC5819005 | biostudies-literature
Project description:There's no evidence demonstrating the association between noncoding RNAs levels before IV recombinant tissue plasminogen activator (rtPA) administration and the outcomes of acute ischemic stroke (AIS). 145 AIS patients received rtPA treatment were recruited at the stroke center from 2018 to 2019, and 103 patients were included in this study. A panel of noncoding RNAs (miRNA-23a, miRNA-193a, miRNA-128, miRNA-99a, miRNA-let-7a, miRNA-494, miRNA-424, and lncRNA H19) were measured in the circulating neutrophils of AIS patients before rtPA treatment. Endpoints included excellent outcome (modified Rankin Scale score [mRS] 0-1) or poor outcome (mRS > 1) at 3 months and symptomatic intracerebral hemorrhage (sICH) after rtPA treatment. Among the eight noncoding RNAs detected in circulating neutrophils of the 103 participants, miRNA-23a levels were associated with the stroke severity on admission and symptom progression at 24 h after rtPA treatment. A noncoding RNA score composed of miRNA-23a, miRNA-99a, and lncRNA H19 was screened to predict the functional outcome at 3 months and the incidence of sICH after rtPA treatment. In the logistic regression analysis, the noncoding RNA score ≥ -0.336 (OR = 2.862 [1.029-7.958], p = 0.044) was an independent predictor of the poor outcome at 3 months after adjustment of clinical variables, the addition of the noncoding RNA score to the clinical model improved the discrimination (IDI% = 4.68 [0.65-8.71], p = 0.020), as well as the net reclassification (NRI% = 33.04 [0.54-71.49], p = 0.016). The noncoding RNA score ≥ -0.336 (OR = 5.250 [1.096-25.135], p = 0.038) was also independently predicted the sICH, the addition of the noncoding RNA score to the clinical variables improved discrimination and reclassification as well. The noncoding RNA score was also associated with the infarct volume and symptom improvement at 7 days after rtPA treatment. In conclusion, a higher neutrophilic noncoding RNA score provides predictive value to identify AIS patients with worse outcomes after rtPA treatment. miRNA-23a, miRNA-99a, and lncRNA H19 are worth further investigation for their effects in thrombolysis after AIS.
| S-EPMC9582270 | biostudies-literature
Project description:Early reperfusion of occluded arteries via recombinant tissue plasminogen activator (rtPA) administration is considered to be an effective strategy for the treatment of acute ischemic stroke. However, delayed administration of rtPA may cause severe hemorrhagic transformation (HT) and undesirable neurological outcomes. The current study aims to establish a canine HT model using rtPA administration and to investigate the potential mechanisms underlying HT. Following anesthesia, two autologous clots were injected into the middle cerebral artery (MCA) to induce ischemic stroke. To induce reperfusion, rtPA (2 mg/kg) was administrated intravenously 4.5 h after the establishment of stroke. The occurrence of HT was determined by computed tomography (CT) and by pathological assessment. Transmission electron microscopy was utilized to assess blood-brain barrier (BBB) damage. The expression of matrix metalloprotein 9 (MMP-9) was analyzed by enzyme linked immunosorbent assay (ELISA), immunofluorescence (IF), and western blot. Administration of rtPA 4.5 h after stroke induced reperfusion in 73.9% of the canines, caused evident HT, and did not improve neurological outcomes compared to canines that did not receive rtPA. There was a significant increase in expression of MMP-9 after rtPA administration, accompanied by BBB disruption. We have established a canine HT model that closely mimics human HT by using rtPA administration after the induction of middle cerebral artery occlusion (MCAO) with autologous clots. Our data suggest that a potential mechanism underlying rtPA-caused HT may be related to BBB dysfunction induced by an increase in MMP-9 expression.
| S-EPMC6603151 | biostudies-literature
Project description:Background and purposeIn a previous study, 0.3 and 0.45 mg/kg of intravenous recombinant tissue plasminogen activator (rt-PA) were safe when combined with eptifibatide 75 mcg/kg bolus and a 2-hour infusion (0.75 mcg/kg per minute). The Combined Approach to Lysis Utilizing Eptifibatide and rt-PA in Acute Ischemic Stroke-Enhanced Regimen (CLEAR-ER) trial sought to determine the safety of a higher-dose regimen and to establish evidence for a phase III trial.MethodsCLEAR-ER was a multicenter, double-blind, randomized safety study. Ischemic stroke patients were randomized to 0.6 mg/kg rt-PA plus eptifibatide (135 mcg/kg bolus and a 2-hour infusion at 0.75 mcg/kg per minute) versus standard rt-PA (0.9 mg/kg). The primary safety end point was the incidence of symptomatic intracranial hemorrhage within 36 hours. The primary efficacy outcome measure was the modified Rankin Scale (mRS) score ≤1 or return to baseline mRS at 90 days. Analysis of the safety and efficacy outcomes was done with multiple logistic regression.ResultsOf 126 subjects, 101 received combination therapy, and 25 received standard rt-PA. Two (2%) patients in the combination group and 3 (12%) in the standard group had symptomatic intracranial hemorrhage (odds ratio, 0.15; 95% confidence interval, 0.01-1.40; P=0.053). At 90 days, 49.5% of the combination group had mRS ≤1 or return to baseline mRS versus 36.0% in the standard group (odds ratio, 1.74; 95% confidence interval, 0.70-4.31; P=0.23). After adjusting for age, baseline National Institutes of Health Stroke Scale, time to intravenous rt-PA, and baseline mRS, the odds ratio was 1.38 (95% confidence interval, 0.51-3.76; P=0.52).ConclusionsThe combined regimen of intravenous rt-PA and eptifibatide studied in this trial was safe and provides evidence that a phase III trial is warranted to determine efficacy of the regimen.Clinical trial registration urlhttp://www.clinicaltrials.gov. Unique identifier: NCT00894803.
| S-EPMC3970761 | biostudies-literature