Mechanisms of fibrinolysis resistance and potential targets for thrombolysis in acute ischaemic stroke: lessons from retrieved stroke emboli.
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ABSTRACT:
SUBMITTER: Brinjikji W
PROVIDER: S-EPMC8717785 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Intravenous thrombolysis is the only approved systemic reperfusion treatment for patients with acute ischaemic stroke. These European Stroke Organisation (ESO) guidelines provide evidence-based recommendations to assist physicians in their clinical decisions with regard to intravenous thrombolysis for acute ischaemic stroke. These guidelines were developed based on the ESO standard operating procedure and followed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. The working group identified relevant clinical questions, performed systematic reviews and meta-analyses of the literature, assessed the quality of the available evidence, and wrote recommendations. Expert consensus statements were provided if not enough evidence was available to provide recommendations based on the GRADE approach. We found high quality evidence to recommend intravenous thrombolysis with alteplase to improve functional outcome in patients with acute ischemic stroke within 4.5 h after symptom onset. We also found high quality evidence to recommend intravenous thrombolysis with alteplase in patients with acute ischaemic stroke on awakening from sleep, who were last seen well more than 4.5 h earlier, who have MRI DWI-FLAIR mismatch, and for whom mechanical thrombectomy is not planned. These guidelines provide further recommendations regarding patient subgroups, late time windows, imaging selection strategies, relative and absolute contraindications to alteplase, and tenecteplase. Intravenous thrombolysis remains a cornerstone of acute stroke management. Appropriate patient selection and timely treatment are crucial. Further randomized controlled clinical trials are needed to inform clinical decision-making with regard to tenecteplase and the use of intravenous thrombolysis before mechanical thrombectomy in patients with large vessel occlusion.
| S-EPMC7995316 | biostudies-literature
Project description:BackgroundIntravenous recombinant tissue plasminogen activator (rt-PA) is approved for use in selected patients with ischaemic stroke within 3 hours of symptom onset. IST-3 seeks to determine whether a wider range of patients may benefit.DesignInternational, multi-centre, prospective, randomized, open, blinded endpoint (PROBE) trial of intravenous rt-PA in acute ischaemic stroke. Suitable patients must be assessed and able to start treatment within 6 hours of developing symptoms, and brain imaging must have excluded intracerebral haemorrhage. With 1000 patients, the trial can detect a 7% absolute difference in the primary outcome. With 3500 patients, it can detect a 4.0% absolute benefit & with 6000, (mostly treated between 3 & 6 hours), it can detect a 3% benefit. TRIAL PROCEDURES: Patients are entered into the trial by telephoning a fast, secure computerised central randomisation system or via a secure web interface. Repeat brain imaging must be performed at 24-48 hours. The scans are reviewed 'blind' by expert readers. The primary measure of outcome is the proportion of patients alive and independent (Modified Rankin 0-2) at six months (assessed via a postal questionnaire mailed directly to the patient). Secondary outcomes include: events within 7 days (death, recurrent stroke, symptomatic intracranial haemorrhage), outcome at six months (death, functional status, EuroQol).Trial registrationISRCTN25765518.
| S-EPMC2442584 | biostudies-literature
Project description:Despite the common use of thrombolytic drugs, especially in stroke treatment, there are many conflicting studies on factors affecting fibrinolysis. Because of the complexity of the fibrinolytic system, mathematical models closely tied with experiments can be used to understand relationships within the system. When tPA is introduced at the clot or thrombus edge, lysis proceeds as a front. We developed a multiscale model of fibrinolysis that includes the main chemical reactions: the microscale model represents a single fiber cross-section; the macroscale model represents a three-dimensional fibrin clot. The model successfully simulates the spatial and temporal locations of all components and elucidates how lysis rates are determined by the interplay between the number of tPA molecules in the system and clot structure. We used the model to identify kinetic conditions necessary for fibrinolysis to proceed as a front. We found that plasmin regulates the local concentration of tPA through forced unbinding via degradation of fibrin and tPA release. The mechanism of action of tPA is affected by the number of molecules present with respect to fibrin fibers. The physical mechanism of plasmin action (crawling) and avoidance of inhibition is defined. Many of these new findings have significant implications for thrombolytic treatment.
| S-EPMC5547096 | biostudies-literature
Project description:Introduction:The inadvertent or purposeful introduction of foreign bodies or substances can lead to cerebral infarction if they embolize to the brain. Individual reports of these events are uncommon but may increase with the increased occurrences of their risk factors, for example, intra-arterial procedures. Method:We searched EMBASE and MEDLINE for articles on embolic stroke of nontissue origin. 1889 articles were identified and screened and 216 articles were ultimately reviewed in full text and included in qualitative analysis. Articles deemed relevant were assessed by a second reviewer to confirm compatibility with the inclusion criteria. References of included articles were reviewed for relevant publications. We categorized the pathology of the emboli into the following groups: air embolism (141 reports), other arterial gas embolisms (49 reports), missiles and foreign bodies (16 reports), and others, including drug embolism, cotton wool, and vascular sclerosant agents. Conclusion:Air and gaseous embolism are becoming more common with increased use of interventional medical procedures and increased popularity of sports such as diving. There is increasing evidence for the use of hyperbaric oxygen for such events. Causes of solid emboli are diverse. More commonly reported causes include bullets, missiles, and substances used in medical procedures.
| S-EPMC5662829 | biostudies-literature
Project description:A State of the Art lecture titled "Thrombus Composition and Thrombolysis Resistance in Stroke" was presented at the ISTH Congress in 2022. Intravenous thrombolysis (IVT) remains the only pharmacologic option to re-establish cerebral perfusion at the acute phase of ischemic stroke. IVT is based on the administration of recombinant tissue plasminogen activator with the objective of dissolving fibrin, the major fibrillar protein component of thrombi. Almost 30 years on from its introduction, although the clinical benefits of IVT have been clearly demonstrated, IVT still suffers from a relatively low efficacy, with a rate of successful early recanalization below 50% overall. Analyses of thrombectomy-recovered acute ischemic stroke (AIS) thrombi have shown that apart from occlusion site, thrombus length, and collateral status, AIS thrombus structure and composition are also important modulators of IVT efficacy. In this article, after a brief presentation of IVT principle and current knowledge on IVT resistance, we review recent findings on how compaction and structural alterations of fibrin together with nonfibrin thrombus components such as neutrophil extracellular traps and von Willebrand factor interfere with IVT in AIS. We further discuss how these new insights could soon result in the development of original adjuvant therapies for improved IVT in AIS. Finally, we summarize relevant new data presented during the 2022 ISTH Congress.
| S-EPMC10394565 | biostudies-literature
Project description:BackgroundImatinib, a tyrosine kinase inhibitor, has been shown to restore blood-brain barrier integrity and reduce infarct size, haemorrhagic transformation and cerebral oedema in stroke models treated with tissue plasminogen activator. We evaluated the safety of imatinib, based on clinical and neuroradiological data, and its potential influence on neurological and functional outcomes.MethodsA phase II randomized trial was performed in patients with acute ischaemic stroke treated with intravenous thrombolysis. A total of 60 patients were randomly assigned to four groups [3 (active): 1 (control)]; the active treatment groups received oral imatinib for 6 days at three dose levels (400, 600 and 800 mg). Primary outcome was any adverse event; secondary outcomes were haemorrhagic transformation, cerebral oedema, neurological severity on the National Institutes of Health Stroke Scale (NIHSS) at 7 days and at 3 months and functional outcomes on the modified Rankin scale (mRS).ResultsFour serious adverse events were reported, which resulted in three deaths (one in the control group and two in the 400-mg dose group; one patient in the latter group did not receive active treatment and the other received two doses). Nonserious adverse events were mostly mild, resulting in full recovery. Imatinib ameliorated neurological outcomes with an improvement of 0.6 NIHSS points per 100 mg imatinib (P = 0.02). For the 800-mg group, the mean unadjusted and adjusted NIHSS improvements were 4 (P = 0.037) and 5 points (P = 0.012), respectively, versus controls. Functional independence (mRS 0-2) increased by 18% versus controls (61 vs. 79; P = 0.296).ConclusionThis phase II study showed that imatinib is safe and tolerable and may reduce neurological disability in patients treated with intravenous thrombolysis after ischaemic stroke. A confirmatory randomized trial is currently underway.
| S-EPMC5573589 | biostudies-literature
Project description:ObjectivesTo determine whether consumer involvement would help to solve some of the ethical problems associated with research into thrombolysis for acute ischaemic stroke, with its inherent risk of fatal intracranial haemorrhage.DesignQuantitative and qualitative research.Setting and participantsCONSULTATION PHASE: three meetings were held to discuss the planned research, and participants completed a questionnaire. QUALITATIVE WORK: focus group meetings explored the issues raised during the consultation phase. Design of information leaflets for patients and relatives: trial materials were drafted during the consultation phase and revised in the light of feedback from the focus group meetings and review by patients and carers on a stroke rehabilitation unit.Results54 people attended the consultation meetings. Four (9%) participants considered the risks of thrombolysis too great, but most (89%) were prepared to accept the treatment in a clinical trial. Nearly all would accept treatment if it was shown to be effective. Most (85%) would give their consent to enter the planned trial. The focus group meetings and feedback from patients and carers led to significant changes in the information leaflets. The revised trial materials were considered ethical by a national multicentre research ethics committee.ConclusionsConsumers generally supported a planned trial, and their involvement helped to refine trial consent procedures and led to an ethically acceptable trial design.
| S-EPMC119434 | biostudies-literature
Project description:This case report discusses a previously healthy young male who suffered an in hospital cardiac arrest, found to be secondary to massive pulmonary emboli (PE). This patient was not a candidate for PE dosing of tPA, but continued to have worsening cardiogenic shock and acute hypoxic respiratory failure. The decision was made to initiate venoarterial extracorporeal membrane oxygenation (VA ECMO) in combination with catheter assisted thrombolysis. With time, the sequelae of his disease process changed. Although his cardiogenic shock improved, the hypoxemia worsened, and the patient was transitioned from VA to venovenous (VV) ECMO, while managing further complications due to multiple episodes of cardiac arrest and severe coagulopathy with multiple, acute, life-threatening bleeding events. Albeit a growing field, VA and VV ECMO are less than common, individually, however this case reports outlines the even rarer event of transition from VA to VV ECMO in combination with catheter assisted thrombolysis treatment via the EKOS EndoWave Infusion Catheter System. Providing care for critically ill patients often demands a collaborative effort between multiple specialties. This case report exemplifies this collaboration, leading to the combination and unification of alternative treatments: ECMO and catheter assisted thrombolysis.
| S-EPMC5986164 | biostudies-other
Project description:OBJECTIVES:Alteplase is commonly recommended for acute ischaemic stroke within 4.5?hours after stroke onset. The Third European Cooperative Acute Stroke Study (ECASS III) is the only trial reporting statistically significant efficacy for clinical outcomes for alteplase use 3-4.5?hours after stroke onset. However, baseline imbalances in history of prior stroke and stroke severity score may confound this apparent finding of efficacy. We reanalysed the ECASS III trial data adjusting for baseline imbalances to determine the robustness or sensitivity of the efficacy estimates. DESIGN:Reanalysis of randomised placebo-controlled trial. We obtained access to the ECASS III trial data and replicated the previously reported analyses to confirm our understanding of the data. We adjusted for baseline imbalances using multivariable analyses and stratified analyses and performed sensitivity analysis for missing data. SETTING:Emergency care. PARTICIPANTS:821 adults with acute ischaemic stroke who could be treated 3-4.5?hours after symptom onset. INTERVENTIONS:Intravenous alteplase (0.9?mg/kg of body weight) or placebo. MAIN OUTCOME MEASURES:The original primary efficacy outcome was modified Rankin Scale (mRS) score 0 or 1 (ie, being alive without any disability) and the original secondary efficacy outcome was a global outcome based on a composite of functional end points, both at 90 days. Adjusted analyses were only reported for the primary efficacy outcome and the original study protocol did not specify methods for adjusted analyses. Our adjusted reanalysis included these outcomes, symptom-free status (mRS 0), dependence-free status (mRS 0-2), mortality (mRS 6) and change across the mRS 0-6 spectrum at 90 days; and mortality and symptomatic intracranial haemorrhage at 7 days. RESULTS:We replicated previously reported unadjusted analyses but discovered they were based on a modified interpretation of the National Institutes of Health Stroke Scale (NIHSS) score. The secondary efficacy outcome was no longer significant using the original NIHSS score. Previously reported adjusted analyses could only be replicated with significant effects for the primary efficacy outcome by using statistical approaches not reported in the trial protocol or statistical analysis plan. In analyses adjusting for baseline imbalances, all efficacy outcomes were not significant, but increases in symptomatic intracranial haemorrhage remained significant. CONCLUSIONS:Reanalysis of the ECASS III trial data with multiple approaches adjusting for baseline imbalances does not support any significant benefits and continues to support harms for the use of alteplase 3-4.5?hours after stroke onset. Clinicians, patients and policymakers should reconsider interpretations and decisions regarding management of acute ischaemic stroke that were based on ECASS III results. TRIAL REGISTRATION NUMBER:NCT00153036.
| S-EPMC7548536 | biostudies-literature
Project description:ObjectiveSeveral studies indicate that only a small proportion of patients with acute ischaemic stroke are treated with intravenous thrombolysis. Indications and contraindications for this treatment are usually based on the inclusion and exclusion criteria of randomised clinical trials. The trial context of these criteria hampers implementation in real life settings. We therefore aimed to obtain specialist opinion in a Delphi consensus on these contraindications.MethodsWe used the Delphi approach on an international group of specialists in the field of thrombolysis. Inclusion and exclusion criteria were reworded into 18 quantitatively phrased propositions. Feedback consisted of the median score, interquartile range and the panellist's own score in the previous round. For each item, we defined consensus as the achievement of an interdecile range within two prespecified clinically relevant units.ResultsThirty-one specialists participated in the first round and 30 completed all three rounds. Consensus was reached on 12 of the 18 propositions: previous ischaemic stroke, head trauma and gastrointestinal tract bleeding should not have taken place earlier than 1.5 months, 2 months and 14 days, respectively; the severity of the neurological deficit is defined as a National Institutes of Health Stroke Scale (NIHSS) score of 2-3 or more, and blood pressure level should not be >185/110 mmHg; platelet count should be >90x10(12)/l, glucose levels 2.7-22 mmol/l, international normalised ratio <1.5 and activated partial thromboplastin time <50 s. No consensus was reached on propositions concerning the stroke onset to treatment time, patient's age, recent medical procedures, spontaneous improvement rate and blood pressure treatment.ConclusionsWe present specialists' opinion on contraindications for intravenous thrombolysis in ischaemic stroke. The results of this study may be relevant for routine clinical practice as they may help to increase the number of treated patients.
| S-EPMC2117697 | biostudies-literature