Alternative Thrombolytic Agent Research Articles

Reteplase versus Alteplase for Acute Ischemic Stroke

BackgroundAlteplase is the standard agent used in early reperfusion therapy, but alternative thrombolytic agents are needed. The efficacy and safety of reteplase as compared with alteplase in patients with acute ischemic stroke are unclear.MethodsWe randomly assigned patients with ischemic stroke within 4.5 hours after symptom onset in a 1:1 ratio to receive intravenous reteplase (a bolus of 18 mg followed 30 minutes later by a second bolus of 18 mg) or intravenous alteplase (0.9 mg per kilogram of body weight; maximum dose, 90 mg). The primary efficacy outcome was an excellent functional outcome, defined as a score of 0 or 1 on the modified Rankin scale (range, 0 [no neurologic deficit, no symptoms, or completely recovered] to 6 [death]) at 90 days. The primary safety outcome was symptomatic intracranial hemorrhage within 36 hours after symptom onset.ResultsA total of 707 patients were assigned to receive reteplase, and 705 were assigned to receive alteplase. An excellent functional outcome occurred in 79.5% of the patients in the reteplase group and in 70.4% of those in the alteplase group (risk ratio, 1.13; 95% confidence interval [CI], 1.05 to 1.21; P<0.001 for noninferiority and P=0.002 for superiority). Symptomatic intracranial hemorrhage within 36 hours after disease onset was observed in 17 of 700 patients (2.4%) in the reteplase group and in 14 of 699 (2.0%) of those in the alteplase group (risk ratio, 1.21; 95% CI, 0.54 to 2.75). The incidence of any intracranial hemorrhage at 90 days was higher with reteplase than with alteplase (7.7% vs. 4.9%; risk ratio, 1.59; 95% CI, 1.00 to 2.51), as was the incidence of adverse events (91.6% vs. 82.4%; risk ratio, 1.11; 95% CI, 1.03 to 1.20).ConclusionsAmong patients with ischemic stroke within 4.5 hours after symptom onset, reteplase was more likely to result in an excellent functional outcome than alteplase. (Funded by China Resources Angde Biotech Pharma and others; RAISE ClinicalTrials.gov number, NCT05295173.)

Tenecteplase Versus Alteplase in Acute Ischemic Stroke in Chinese Patients: Protocol for the ORIGINAL Study

Background Tenecteplase, a bioengineered variant of alteplase, is a new alternative thrombolytic agent. The ORIGINAL study aims to evaluate the efficacy and safety of tenecteplase versus standard care in Chinese patients with acute ischemic stroke within 4.5 hours of symptom onset. Methods This is a multicenter phase III study that employs a randomized (1:1), active‐controlled, parallel‐group, prospective, open‐label, blinded–end point design. Adult participants (aged ≥18 years) with acute ischemic stroke who are eligible for intravenous thrombolysis within 4.5 hours of symptom onset according to current guideline recommendations are recruited from ≈55 neurology clinics/stroke centers throughout China. Results The primary objective of the ORIGINAL study is to demonstrate the noninferiority of tenecteplase (0.25 mg/kg) to alteplase (0.9 mg/kg) on the basis of the proportion of patients who achieve a modified Rankin Scale score of 0 or 1 on day 90, that is, a favorable functional outcome. The prespecified noninferiority risk ratio margin is 0.937. Secondary end points include other functional outcomes and the following safety end points: adjudicated symptomatic intracerebral hemorrhage (up to 36 hours after the end of study drug administration) based on the European Cooperative Acute Stroke Study III definition; all‐cause death within 90 days; and the proportion of patients with a modified Rankin Scale score of 5 or 6 on day 90. Conclusions It is anticipated that the results of this study will contribute to the growing body of evidence for the noninferiority of tenecteplase to alteplase given within 4.5 hours of acute ischemic stroke symptom onset and support a new indication for tenecteplase in China. Clinical Trial Registration Information NCT04915729 ( https://clinicaltrials.gov/study/NCT04915729 )

Reteplase versus alteplase for acute ischaemic stroke within 4.5 hours (RAISE): rationale and design of a multicentre, prospective, randomised, open-label, blinded-endpoint, controlled phase 3 non-inferiority trial

Background and purposeReteplase is the third generation of alternative thrombolytic agent. We hypothesis that reteplase will be non-inferior to alteplase in achieving excellent functional outcome at 90 days among eligible...

Research progress on the fibrinolytic enzymes produced from traditional fermented foods.

Cardiovascular diseases (CVDs) are a global health problem and leading cause of death worldwide. Thrombus formation, one of the CVDs, is essentially the formation of fibrin clots. The existing thrombolytic agents have the disadvantages of high price, short half-life, and high bleeding risk; hence, there is an urgent need to find the alternative thrombolytic agents. In recent years, traditional fermented foods have been widely investigated for their outstanding effects in the prevention and treatment of thrombus formation. In this review, we have focused on fibrinolytic enzymes produced by microorganisms during the fermentation of traditional fermented foods and their potential use for treating CVDs. First, we discussed about the sources of fibrinolytic enzymes and microbial strains that produce those enzymes followed by the optimization of fermentation process, purification, and physicochemical properties of fibrinolytic enzymes. Finally, we have summarized the thrombolytic effects of fibrinolytic enzymes in humans and mice. Fibrinolytic enzymes produced by microorganisms during the fermentation of traditional fermented foods not only lyse thrombi but also acts as anti-atherosclerotic, anti-hyperlipidemia, and neuroprotection agents. Therefore, fibrinolytic enzymes from traditional fermented foods have great potential for the prevention and treatment of CVDs.

Serine metalloprotease with plasmin-like fibrinolytic activity of Serratia marcescens isolated from the Amazon basin

Research on new fibrinolytic agents has been oriented towards the discovery of microbial proteases with plasmin-like activity, as alternative thrombolytic agents for thrombosis treatment. This study reports the characterization of an extracellular serine metalloprotease of approximately 56 kDa, with fibrinolytic and fibrinogenolytic activity, isolated from a S. marcescens strain obtained from the Amazon (CBAM 519). The enzyme showed optimum activity at pH 9 and temperature of 37 °C. Activity was reduced in the presence of Na+, Cu2+ and Fe2+ ions, and increased with Mn2⁺. The enzyme did not show hemolytic activity, nor did it activate plasminogen, but it effectively hydrolyzed fibrin and fibrinogen, rapidly degrading all fibrinogen chains Aα, Bβ and γ. Therefore, fibrinolysis was promoted only by the direct route, with a fast acting, potent fibrinolytic activity. Based on this, we expect the enzyme to be a protease of the plasmin type that directly degrades fibrin. These characteristics demonstrate great potential for its application in the treatment of thrombosis.

Intravenous thrombolysis of ischemic stroke-Current status

Intravenous thrombolysis (IVT) treatment with alteplase (rtPA) is an essential part of the routine treatment of patients with ischemic stroke since its introduction in the late 1990s. Rapid treatment is of essential importance. For patients with an unclear time window, various mismatch concepts have been established to identify salvageable brain tissue prior to IVT. Numerous official contraindications for rtPA are not evidence-based; for example, current data from observational studies show that systemic thrombolytic treatment is possible even in patients receiving direct oral anticoagulant (DOAC) treatment. Tenecteplase (TNK) is an alternative thrombolytic agent with some pharmacologic advantages. The most recent guidelines indicate that TNK is particularly advantageous over rtPA in patients treated in combination with endovascular stroke therapy (EST). The combination of IVT and EST should primarily be performed in the 4.5‑h time window in patients without contraindications; in the later time window EST alone is conceivable if it can be performed without delay.

The End of Tissue-Type Plasminogen Activator's Reign?

Mechanical thrombectomy is a highly effective treatment for acute ischemic stroke caused by large-vessel occlusion in the anterior cerebral circulation, significantly increasing the likelihood of recovery to functional independence. Until recently, whether intravenous thrombolysis before mechanical thrombectomy provided additional benefits to patients with acute ischemic stroke-large-vessel occlusion remained unclear. Given that reperfusion is a key factor for clinical outcome in patients with acute ischemic stroke-large-vessel occlusion and the efficacy of both intravenous thrombolysis and mechanical thrombectomy is time-dependent, achieving complete reperfusion with a single pass should be the primary angiographic goal. However, it remains undetermined whether extending the procedure with additional endovascular attempts or local lytics administration safely leads to higher reperfusion grades and whether there are significant public health and cost implications. Here, we outline the current state of knowledge and research avenues that remain to be explored regarding the consistent therapeutic benefit of intravenous thrombolysis in anterior circulation strokes and the potential place of adjunctive intra-arterial lytics administration, including alternative thrombolytic agent place.

Off-Label Use of Tenecteplase for the Treatment of Acute Ischemic Stroke

Tenecteplase is being evaluated as an alternative thrombolytic agent for the treatment of acute ischemic stroke (AIS) within ongoing randomized clinical trials (RCTs). In addition, nonrandomized clinical experiences with off-label use of tenecteplase vs alteplase for AIS treatment are being published. To evaluate the available evidence on the safety and efficacy of intravenous tenecteplase compared with intravenous alteplase provided by nonrandomized studies. Eligible studies were identified by searching MEDLINE and Scopus databases. No language or other restrictions were imposed. The literature search was conducted on October 12, 2021. This meta-analysis used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was written according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) proposal. Nonrandomized studies (prospective or retrospective) comparing intravenous tenecteplase (at any dose) with intravenous alteplase in patients with AIS were included in the analysis. The crude odds ratios (ORs) and 95% CIs were calculated for the association of tenecteplase vs alteplase with the outcomes of interest and adjusted ORs were extracted if provided. Estimates using random-effects models were pooled. The primary outcome was the probability of good functional outcome (modified Rankin scale [mRS] score, 0-2) at 90 days. Six studies were identified including a total of 1820 patients (618 [34%] treated with tenecteplase). Patients receiving tenecteplase had higher odds of 3-month good functional outcome (crude odds ratio [OR], 1.22; 95% CI, 0.90-1.66; adjusted OR, 1.60, 95% CI, 1.08-2.37), successful recanalization (crude OR, 2.82; 95% CI, 1.12-7.10; adjusted OR, 2.38; 95% CI, 1.18-4.81), and early neurological improvement (crude OR, 4.88; 95% CI, 2.03-11.71; adjusted OR, 7.60; 95% CI, 1.97-29.41). No significant differences were detected in 3-month excellent functional outcome proportions (mRS score 0-1; crude OR, 1.53; 95% CI, 0.81-2.91; adjusted OR, 2.51; 95% CI, 0.66- 9.49), symptomatic intracranial hemorrhage (crude OR, 0.97; 95% CI, 0.44-2.16; adjusted OR, 1.16; 95% CI, 0.13-10.50), or parenchymal hematoma (crude OR, 1.20; 95% CI, 0.24-5.95). Evidence from nonrandomized studies suggests tenecteplase is as safe as alteplase and potentially associated with improved functional outcomes compared with alteplase. Based on these findings, enrollment in the ongoing RCTs appears to be appropriate.

Early Experience With Tenecteplase at a Comprehensive Stroke Center.

Purpose of ReviewTenecteplase has been studied and recommended as an alternative thrombolytic agent in patients with acute stroke. A brief review of clinical trials and guidelines pertinent to our clinical decision algorithm is described. This is followed by operational steps that were made to create and implement a clinical pathway based on available evidence in which tenecteplase is used in select patients with stroke at our comprehensive stroke center.Recent FindingsA number of patients have been treated at our center with IV tenecteplase. A case is presented to illustrate the successful implementation of this new process.SummaryDevelopment of our protocol is discussed in detail to enable other centers to create their own clinical pathways for thrombolytic treatment of acute ischemic stroke using tenecteplase.

Real-world comparative safety and efficacy of tenecteplase versus alteplase in acute ischemic stroke patients with large vessel occlusion.

Background and aims:Tenecteplase has recently emerged as an alternative thrombolytic agent in acute ischemic stroke (AIS) patients with large vessel occlusion (LVO), possibly superior in achieving early reperfusion compared with alteplase. We aimed to compare the safety and efficacy of intravenous tenecteplase with intravenous alteplase for AIS patients with LVO in everyday clinical practice settings.Methods:We prospectively evaluated patients with AIS due to LVO, treated with intravenous thrombolysis (IVT) with or without mechanical thrombectomy in two tertiary stroke centers. Patients were treated with standard-dose alteplase (0.9 mg/kg) or 0.25 mg/kg tenecteplase. Safety outcomes included prevalence of symptomatic intracranial hemorrhage (sICH) and mortality. Efficacy outcomes included averted thrombectomy, major neurological improvement at 24 h (defined as decrease in baseline NIHSS score of 8 points or greater) and functional status on discharge and on 3 months assessed by modified Rankin Scale (mRS).Results:Nineteen AIS patients with LVO received tenecteplase and 39 received alteplase. We observed a non-significant higher rate of averted thrombectomies (32% versus 18%, p = 0.243) and a non-significant higher rate of sICH (16% versus 5%, p = 0.201) in the tenecteplase group. The rate of 24 h major neurological improvement was higher in the tenecteplase group (64% versus 33%, p = 0.046) but this was marginally attenuated in multivariable analyses (adjusted OR 10.22, 95% CI: 0.73–142.98; p = 0.084). Discharge mRS, 3-months mRS, and 3-month functional independence (mRS scores of 0–2) did not differ (p > 0.2) between the two groups. The rates of 3-month mortality (11% versus 18%, p = 0.703) were similar in the two groups. No independent association between thrombolytic agent and safety or efficacy outcomes emerged in multivariable regression analyses.Conclusion:The present pilot observational study highlights that AIS patients with LVO treated with 0.25 mg/kg bolus administration of tenecteplase had increased likelihood to achieve early neurological improvement compared with AIS patients treated with alteplase, but this association was attenuated after adjustment for potential confounders. There were no significant differences in 3-month functional or safety outcomes between the two groups. This preliminary real-world observation requires independent confirmation in larger, multicenter studies.

Off-label use of intravenous thrombolysis for acute ischemic stroke: a critical appraisal of randomized and real-world evidence.

Intravenous thrombolysis (IVT) represents the only systemic reperfusion therapy able to reverse neurological deficit in patients with acute ischemic stroke (AIS). Despite its effectiveness in patients with or without large vessel occlusion, it can be offered only to a minority of them, because of the short therapeutic window and additional contraindications derived from stringent but arbitrary inclusion and exclusion criteria used in landmark randomized controlled clinical trials. Many absolute or relative contraindications lead to disparities between the official drug label and guidelines or expert recommendations. Based on recent advances in neuroimaging and evidence from cohort studies, off-label use of IVT is increasingly incorporated into the daily practice of many stroke centers. They relate to extension of therapeutic time windows, and expansion of indications in co-existing conditions originally listed in exclusion criteria, such as use of alternative thrombolytic agents, pre-treatment with antiplatelets, anticoagulants or low molecular weight heparins. In this narrative review, we summarize recent randomized and real-world data on the safety and efficacy of off-label use of IVT for AIS. We also make some practical recommendations to stroke physicians regarding the off-label use of thrombolytic agents in complex and uncommon presentations of AIS or other conditions mimicking acute cerebral ischemia. Finally, we provide guidance on the risks and benefits of IVT in numerous AIS subgroups, where equipoise exists and guidelines and treatment practices vary.

Tenecteplase for the treatment of acute ischemic stroke: A review of completed and ongoing randomized controlled trials.

Alteplase has been the mainstay of thrombolytic treatment since the National Institutes of Neurological Disorders and Stroke trial was published in 1995. Over recent years, several trials have investigated alternative thrombolytic agents. Tenecteplase, a genetically engineered mutant tissue plasminogen activator, has a longer half-life, allowing single intravenous bolus administration without infusion, is more fibrin specific, produces less systemic depletion of circulating fibrinogen, and is more resistant to plasminogen activator inhibitor compared to alteplase. Tenecteplase is established as the first-line intravenous thrombolytic drug for myocardial infarction, where it has been shown to achieve comparable reperfusion with reduced risk of systemic bleeding in comparison to alteplase. We review the literature on tenecteplase for the treatment of acute ischemic stroke, with a focus on the major completed and ongoing trials. Overall, tenecteplase shows promise for treatment of acute ischemic stroke, both in populations currently eligible for alteplase and also in groups not currently treated with thrombolysis.

Tenecteplase versus Alteplase for the Management of Acute Ischemic Stroke in a Low-income Country-Nepal: Cost, Efficacy, and Safety.

Intravenous alteplase is the only approved treatment for acute ischemic stroke. Tenecteplase, a genetically engineered, mutant tissue plasminogen activator, is an alternative thrombolytic agent. The economic feasibility of stroke treatment has been a matter of huge debate and discussion thus far. The use of thrombolytics for the management of ischemic stroke has recently begun in Nepal. In low-income countries like Nepal, where the per capita income falls at just $691.7 and 25.2% of the population are under the poverty line, stroke patients cannot meet treatment expenses. Tenecteplase is easily available (for the management of acute coronary syndrome) in tertiary-level hospitals of Nepal and the price quote of tenecteplase ($450) is half the price of alteplase ($1000). In emergency cases, sometimes, the cost of alteplase can be greater than the patient can afford and they can't undergo thrombolysis even after arriving on time. However, evidence exists that supports the use of other alternatives (tenecteplase), which are also effective in the management of acute ischemic stroke. In this article, we examined current evidence for the efficacy and safety of tenecteplase when compared to alteplase. This review will make neurologists in Nepal familiar with the efficacy and safety of tenecteplase in comparison with alteplase since it is common for patients to not be able to afford the expensive alteplase, which makes guideline-based practice impossible some times.

Fibrinolytic activity and dose-dependent effect of incubating human blood clots in caffeic acid phenethyl ester: in vitro assays.

Background. Caffeic acid phenethyl ester (CAPE) has been reported to possess time-dependent fibrinolytic activity by in vitro assay. This study is aimed at investigating fibrinolytic dose-dependent activity of CAPE using in vitro assays. Methods. Standardized human whole blood (WB) clots were incubated in either blank controls or different concentrations of CAPE (3.75, 7.50, 15.00, 22.50, and 30.00 mM). After 3 hours, D-dimer (DD) levels and WB clot weights were measured for each concentration. Thromboelastography (TEG) parameters were recorded following CAPE incubation, and fibrin morphology was examined under a confocal microscope. Results. Overall, mean DD (μg/mL) levels were significantly different across samples incubated with different CAPE concentrations, and the median pre- and postincubation WB clot weights (grams) were significantly decreased for each CAPE concentration. Fibrin removal was observed microscopically and indicated dose-dependent effects. Based on the TEG test, the Ly30 fibrinolytic parameter was significantly different between samples incubated with two different CAPE concentrations (15.0 and 22.50 mM). The 50% effective dose (ED50) of CAPE (based on DD) was 1.99 mg/mL. Conclusions. This study suggests that CAPE possesses fibrinolytic activity following in vitro incubation and that it has dose-dependent activities. Therefore, further investigation into CAPE as a potential alternative thrombolytic agent should be conducted.

Vessel occlusion, penumbra, and reperfusion - translating theory to practice.

The management of ischemic stroke is at a critical juncture. Administration of intravenous tPA is currently restricted to within 4.5 h from stroke onset with several trials in longer time windows proving neutral (1, 2). Revascularization success with tPA in major vessel occlusion is widely recognized as suboptimal (3). Alternative thrombolytic agents with theoretical efficacy advantages such as tenecteplase and desmoteplase are yet to show benefit in phase 3 trials. The promise of endovascular therapy has also yet to translate into positive randomized trials (4–6), although a new generation of devices is currently being studied. While it is possible that these therapeutic approaches are simply ineffective, the heterogeneity of stroke pathophysiology is likely to be contributing to the neutral results we often observe. Imaging selection has been proposed as a means of reducing heterogeneity by identifying patients with the potential to benefit from revascularization and therefore enhancing the probability of success in trials of new therapies. However, whether it is sufficient to demonstrate an occluded artery as the target or to also require evidence of salvageable downstream tissue has been debated. The recent announcement of neutral results in DIAS 3 (7), a trial that compared desmoteplase versus placebo 3–9 h after stroke onset in patients with vessel occlusion, without reference to downstream tissue status other than what was visible on non-contrast CT, will no doubt further stimulate this discussion. It is, therefore, salient to consider the current methods to identify salvageable ischemic penumbra and the potential value of commonly used surrogates for clinical outcome, chiefly reperfusion, recanalization, and infarct growth.

Thrombolysis in the Developing World: Is There a Role for Streptokinase?

Intravenous thrombolysis with tissue plasminogen activator is the only proven acute therapy for ischemic stroke. This therapy has not been translated into clinical practice in the developing world primarily due to economic constraints. Streptokinase, a lower cost alternative thrombolytic agent, is widely available in developing countries where it is utilized to treat patients with acute coronary syndromes. Although this drug has previously been found to be ineffective in ischemic stroke, the lack of benefit may have been related to a number of factors related to trial design rather than the drug itself. Specific features of prior trial designs that may have adversely affected outcomes include a prolonged treatment window, inclusion of patients with established infarction on computed tomography scan, failure to treat excessive arterial pressures, a fixed dose of streptokinase, and concomitant use of antithrombotic medications. Given the lack of therapeutic alternatives in developing countries, a new trial of streptokinase in acute stroke, utilizing stricter inclusion criteria similar to those in more recent thrombolytic studies, appears warranted.

New and old: notable drug developments for clinical practice

Which drug to use and when for a particular condition is frequently a complex issue relating to individual patient characteristics and circumstance. However, it seems that it was only relatively recently that this quandary was a luxury more commonly associated with non-neurological diseases. However, the last 30 years has seen the exponential development of therapeutic interventions for neurological disease together with increasing and possibly excessive use of trial-related acronyms. Given current requirements for complex trial construction and meeting of regulatory demands, the development of a novel proven therapeutic intervention in area of need is no mean task and commonly followed by a prolonged period where indications are refined and then a more pragmatic analysis of treatment algorithms ensues. In Journal Club, this month we examine results for a new oral treatment for relapsing multiple sclerosis (MS) in the form of a placebo-controlled trial of laquinimod. It is perhaps a statement of advances made in MS treatments to date that this trial may finally herald the end of the placebo arm in controlled trials in relapsing MS. The results of this trial by contemporary standards, while demonstrating some limited effectiveness, might be considered disappointing. In turn, this then begs the question as to where the place of laquinimod might be in the expanding arsenal of treatments for relapsing disease. Secondly, we look at a head-to-head trial of intravenous alteplase and a potential alternative thrombolytic agent for acute ischaemic stroke. Finally, we review the latest output from the SANAD (Standard and New Antiepileptic Drug) trial, which examines prognostic factors for time to treatment failure across a wide range of standard antiepileptic drug interventions for focal epilepsy.

How to make better use of thrombolytic therapy in acute ischemic stroke

Around 15 years have now elapsed since thrombolysis was first shown to be effective for treating acute ischemic stroke, but therapeutic uptake has been modest. As outlined in this Review, research efforts are being directed towards rectifying this situation in a number of ways. First, strategies to enhance thrombolytic efficacy are being tested; these include intravenous and intra-arterial bridging protocols, sonothrombolysis, and the use of alternative thrombolytic agents. Second, means of extending the 4.5-h therapeutic time window up to 6 h, or even up to 9 h in patients selected on the basis of imaging, are being investigated in clinical trials. Prolongation of the time window using neuroprotection to 'freeze' penumbral tissue is also being attempted. Third, attempts are underway to reduce the risk of symptomatic intracerebral hemorrhage (currently affecting about 7% of cases) by refining imaging selection criteria, and through the use of alternative thrombolytic agents, lower doses of tissue plasminogen activator, blood-based biomarkers, and neuroprotectants. Last, in an effort to include more people within the currently accepted therapeutic time window, improvements in prehospital management strategies are being introduced. Elimination of prehospital and in-hospital delays is an urgent priority.

An Alternative Treatment Strategy for Pump Thrombus in the DeBakey VAD Child: Use of Clopidogrel as a Thrombolytic Agent

Our institution has used the DeBakey VAD Child as a bridge to heart transplantation in select pediatric patients. Pump thrombus is a potentially serious complication with few available treatment options. Only surgical device exchange or the use of tissue plasminogen activator are reported in the literature. We report the use of clopidogrel as an alternative thrombolytic agent in the presence of pump thrombus in an adolescent patient with a DeBakey VAD Child heart pump.

Association between tPA therapy and raised early matrix metalloproteinase-9 in acute stroke

Matrix metalloproteinase-9 (MMP9) is expressed in acute ischemic stroke and up-regulated by tissue plasminogen activator (tPA) in animal models. The authors investigated plasma MMP9 and its endogenous inhibitor, tissue inhibitor of metalloproteinase (TIMP1), in tPA-treated and -untreated stroke patients. Nonstroke control subjects and consecutive ischemic stroke patients presenting within 8 hours of onset were enrolled. Blood was sampled within 8 hours and at 24 hours, 2 to 5 days and 4 to 6 weeks. MMP9 and TIMP1 were analyzed by ELISA and gel zymography. Fifty-two cases (26 tPA treated, 26 tPA untreated) and 27 nonstroke control subjects were enrolled. Hyperacute MMP9 was elevated in tPA-treated vs tPA-untreated patients (medians 43 vs 28 ng/mL; p = 0.01). tPA therapy independently predicted hyperacute MMP9 after adjustment for stroke severity, volume, and hemorrhagic transformation (p = 0.01). There was a trend toward lower hyperacute TIMP1 levels in tPA-treated vs tPA-untreated patients (p = 0.06). Hyperacute MMP9 was correlated to poor 3-month modified Rankin Scale outcome (r = 0.58, p = 0.0005). Tissue plasminogen activator independently predicted plasma matrix metalloproteinase-9 (MMP9) in the first 8 hours after human ischemic stroke. As MMP9 may be an important mediator of hemorrhagic transformation, alternative thrombolytic agents or therapeutic MMP9 inhibition may increase the safety profile of acute stroke thrombolysis.