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JAMA Neurology Aug 2023It is unknown whether intravenous thrombolysis using tenecteplase is noninferior or preferable compared with alteplase for patients with acute ischemic stroke. (Randomized Controlled Trial)
Randomized Controlled Trial
Safety and Efficacy of Tenecteplase Compared With Alteplase in Patients With Large Vessel Occlusion Stroke: A Prespecified Secondary Analysis of the ACT Randomized Clinical Trial.
IMPORTANCE
It is unknown whether intravenous thrombolysis using tenecteplase is noninferior or preferable compared with alteplase for patients with acute ischemic stroke.
OBJECTIVE
To examine the safety and efficacy of tenecteplase compared to alteplase among patients with large vessel occlusion (LVO) stroke.
DESIGN, SETTING, AND PARTICIPANTS
This was a prespecified analysis of the Intravenous Tenecteplase Compared With Alteplase for Acute Ischaemic Stroke in Canada (ACT) randomized clinical trial that enrolled patients from 22 primary and comprehensive stroke centers across Canada between December 10, 2019, and January 25, 2022. Patients 18 years and older with a disabling ischemic stroke within 4.5 hours of symptom onset were randomly assigned (1:1) to either intravenous tenecteplase or alteplase and were monitored for up to 120 days. Patients with baseline intracranial internal carotid artery (ICA), M1-middle cerebral artery (MCA), M2-MCA, and basilar occlusions were included in this analysis. A total of 1600 patients were enrolled, and 23 withdrew consent.
EXPOSURES
Intravenous tenecteplase (0.25 mg/kg) vs intravenous alteplase (0.9 mg/kg).
MAIN OUTCOMES AND MEASURES
The primary outcome was the proportion of modified Rankin scale (mRS) score 0-1 at 90 days. Secondary outcomes were an mRS score from 0 to 2, mortality, and symptomatic intracerebral hemorrhage. Angiographic outcomes were successful reperfusion (extended Thrombolysis in Cerebral Infarction scale score 2b-3) on first and final angiographic acquisitions. Multivariable analyses (adjusting for age, sex, National Institute of Health Stroke Scale score, onset-to-needle time, and occlusion location) were carried out.
RESULTS
Among 1577 patients, 520 (33.0%) had LVO (median [IQR] age, 74 [64-83] years; 283 [54.4%] women): 135 (26.0%) with ICA occlusion, 237 (45.6%) with M1-MCA, 117 (22.5%) with M2-MCA, and 31 (6.0%) with basilar occlusions. The primary outcome (mRS score 0-1) was achieved in 86 participants (32.7%) in the tenecteplase group vs 76 (29.6%) in the alteplase group. Rates of mRS 0-2 (129 [49.0%] vs 131 [51.0%]), symptomatic intracerebral hemorrhage (16 [6.1%] vs 11 [4.3%]), and mortality (19.9% vs 18.1%) were similar in the tenecteplase and alteplase groups, respectively. No difference was noted in successful reperfusion rates in the first (19 [9.2%] vs 21 [10.5%]) and final angiogram (174 [84.5%] vs 177 [88.9%]) among 405 patients who underwent thrombectomy.
CONCLUSIONS AND RELEVANCE
The findings in this study indicate that intravenous tenecteplase conferred similar reperfusion, safety, and functional outcomes compared to alteplase among patients with LVO.
Topics: Humans; Female; Aged; Male; Tissue Plasminogen Activator; Tenecteplase; Stroke; Fibrinolytic Agents; Brain Ischemia; Ischemic Stroke; Cerebral Hemorrhage; Arterial Occlusive Diseases; Treatment Outcome
PubMed: 37428494
DOI: 10.1001/jamaneurol.2023.2094 -
Advances in Clinical Chemistry 2024Soluble urokinase plasminogen activator receptor (suPAR), the soluble counterpart of urokinase plasminogen activator receptor, is found in the circulation at various... (Review)
Review
Soluble urokinase plasminogen activator receptor (suPAR), the soluble counterpart of urokinase plasminogen activator receptor, is found in the circulation at various levels. suPAR and its parent molecule, cell surface uPAR, exhibit similar structure and extracellular functional roles facilitating fibrinolysis, cellular adhesion, and migration. Studies have assessed the correlation between suPAR in cardiovascular disease (CVD). It is postulated that suPAR may serve as an indicator of inflammatory activation and burden during CVD progression. Increased suPAR independently predicts poorer outcomes in acute coronary syndromes, in heart failure, as well as in coronary artery disease and atherosclerosis. To guide translation into clinical utization, suPAR has been assessed in numerous CVD settings for improved risk discrimination independently or in association with established traditional risk factors. Whilst the involvement of suPAR has been explored in other diseases such as kidney diseases and cancer, there is only emerging evidence of suPAR's mechanistic involvement in cardiovascular disease. In this review, we provide a background into suPAR and its potential role as a biomarker in CVD.
Topics: Humans; Receptors, Urokinase Plasminogen Activator; Cardiovascular Diseases; Biomarkers
PubMed: 38797545
DOI: 10.1016/bs.acc.2024.04.005 -
Genesis (New York, N.Y. : 2000) Feb 2024Epithelial-mesenchymal transition (EMT) is an important biological process contributing to kidney fibrosis and chronic kidney disease. This process is characterized by... (Review)
Review
Epithelial-mesenchymal transition (EMT) is an important biological process contributing to kidney fibrosis and chronic kidney disease. This process is characterized by decreased epithelial phenotypes/markers and increased mesenchymal phenotypes/markers. Tubular epithelial cells (TECs) are commonly susceptible to EMT by various stimuli, for example, transforming growth factor-β (TGF-β), cellular communication network factor 2, angiotensin-II, fibroblast growth factor-2, oncostatin M, matrix metalloproteinase-2, tissue plasminogen activator (t-PA), plasmin, interleukin-1β, and reactive oxygen species. Similarly, glomerular podocytes can undergo EMT via these stimuli and by high glucose condition in diabetic kidney disease. EMT of TECs and podocytes leads to tubulointerstitial fibrosis and glomerulosclerosis, respectively. Signaling pathways involved in EMT-mediated kidney fibrosis are diverse and complex. TGF-β1/Smad and Wnt/β-catenin pathways are the major venues triggering EMT in TECs and podocytes. These two pathways thus serve as the major therapeutic targets against EMT-mediated kidney fibrosis. To date, a number of EMT inhibitors have been identified and characterized. As expected, the majority of these EMT inhibitors affect TGF-β1/Smad and Wnt/β-catenin pathways. In addition to kidney fibrosis, these EMT-targeted antifibrotic inhibitors are expected to be effective for treatment against fibrosis in other organs/tissues.
Topics: Humans; Transforming Growth Factor beta1; beta Catenin; Matrix Metalloproteinase 2; Tissue Plasminogen Activator; Epithelial Cells; Wnt Signaling Pathway; Epithelial-Mesenchymal Transition; Kidney; Fibrosis
PubMed: 37345818
DOI: 10.1002/dvg.23529 -
Current Opinion in Pediatrics Dec 2023The purpose of this paper is to review recent updates in the acute management of childhood arterial ischemic stroke, including reperfusion therapies and neuroprotective... (Review)
Review
PURPOSE OF REVIEW
The purpose of this paper is to review recent updates in the acute management of childhood arterial ischemic stroke, including reperfusion therapies and neuroprotective measures.
RECENT FINDINGS
With the emergence of pediatric stroke centers in recent years, processes facilitating rapid diagnosis and treatment have resulted in improved implementation of early targeted neuroprotective measures as well as the increased use of reperfusion therapies in childhood arterial ischemic stroke. Retrospective data has demonstrated that alteplase is safe in carefully selected children with arterial ischemic stroke in the first 4.5 h from symptom onset, though data regarding its efficacy in children are still lacking. There is also increasing data that suggests that thrombectomy in children with large vessel occlusion improves functional outcomes. Recent adult studies, including the use of Tenecteplase as an alteplase alternative and expansion of late thrombectomy to include patients with large ischemic cores, also are reviewed along with limitations to application of the adult data to pediatric care.
SUMMARY
There have been significant advances in the hyperacute care of children with ischemic stroke and early diagnosis and targeted management are of the upmost importance in improving long-term outcomes.
Topics: Adult; Child; Humans; Tissue Plasminogen Activator; Fibrinolytic Agents; Retrospective Studies; Stroke; Ischemic Stroke; Treatment Outcome; Brain Ischemia
PubMed: 37800414
DOI: 10.1097/MOP.0000000000001295 -
Critical Care Medicine May 2024Systemic thrombolysis improves outcomes in patients with pulmonary embolism (PE) but is associated with the risk of hemorrhage. The data on efficacy and safety of... (Observational Study)
Observational Study
OBJECTIVES
Systemic thrombolysis improves outcomes in patients with pulmonary embolism (PE) but is associated with the risk of hemorrhage. The data on efficacy and safety of reduced-dose alteplase are limited. The study objective was to compare the characteristics, outcomes, and complications of patients with PE treated with full- or reduced-dose alteplase regimens.
DESIGN
Multicenter retrospective observational study.
SETTING
Tertiary care hospital and 15 community and academic centers of a large healthcare system.
PATIENTS
Hospitalized patients with PE treated with systemic alteplase.
INTERVENTIONS
None.
MEASUREMENTS AND MAIN RESULTS
Pre- and post-alteplase hemodynamic and respiratory variables, patient outcomes, and complications were compared. Propensity score (PS) weighting was used to adjust for imbalances of baseline characteristics between reduced- and full-dose patients. Separate analyses were performed using the unweighted and weighted cohorts. Ninety-eight patients were treated with full-dose (100 mg) and 186 with reduced-dose (50 mg) regimens. Following alteplase, significant improvements in shock index, blood pressure, heart rate, respiratory rate, and supplemental oxygen requirements were observed in both groups. Hemorrhagic complications were lower with the reduced-dose compared with the full-dose regimen (13% vs. 24.5%, p = 0.014), and most were minor. Major extracranial hemorrhage occurred in 1.1% versus 6.1%, respectively ( p = 0.022). Complications were associated with supratherapeutic levels of heparin anticoagulation in 37.5% of cases and invasive procedures in 31.3% of cases. The differences in complications persisted after PS weighting (15.4% vs. 24.7%, p = 0.12 and 1.3% vs. 7.1%, p = 0.067), but did not reach statistical significance. There were no significant differences in mortality, discharge destination, ICU or hospital length of stay, or readmission after PS weighting.
CONCLUSIONS
In a retrospective, PS-weighted observational study, when compared with the full-dose, reduced-dose alteplase results in similar outcomes but fewer hemorrhagic complications. Avoidance of excessive levels of anticoagulation or invasive procedures should be considered to further reduce complications.
Topics: Humans; Tissue Plasminogen Activator; Retrospective Studies; Pulmonary Embolism; Thrombolytic Therapy; Hemorrhage; Acute Disease; Anticoagulants; Fibrinolytic Agents; Treatment Outcome
PubMed: 38165776
DOI: 10.1097/CCM.0000000000006162 -
ACS Chemical Neuroscience Jul 2023Stroke is a disease with high disability and high mortality in the world. Due to the existence of the blood-brain barrier (BBB), complex brain structure, and numerous... (Review)
Review
Stroke is a disease with high disability and high mortality in the world. Due to the existence of the blood-brain barrier (BBB), complex brain structure, and numerous neural signal pathways, the treatment methods are limited, so new drugs and new treatments need to be developed urgently. Thankfully, the advent of nanotechnology offered a new opportunity for biomedical development because of the unique properties of nanoparticles that give them the ability to traverse the BBB and accumulate in relevant regions of the brain. More importantly, nanoparticles could be modified on the surface to meet a variety of specific properties that people need. Some could be used for effective drug delivery, including tissue plasminogen activator (tPA), neuroprotective agents, genes, and cytokines; some nanoparticles were used as contrast agents and biosensors in medical imaging for further diagnosis of stroke; some were used to track target cells for prognosis of stroke; and some were used to detect pathological markers of stroke that appear at different stages. This Review looks at the application and research progress of nanoparticles in the diagnosis and treatment of stroke, hoping to bring some help to researchers.
Topics: Humans; Tissue Plasminogen Activator; Stroke; Brain; Blood-Brain Barrier; Brain Ischemia; Nanotechnology
PubMed: 37310096
DOI: 10.1021/acschemneuro.2c00804 -
International Journal of Hematology May 2024Acute promyelocytic leukemia (APL) is associated with a high incidence of early death, which occurs within 30 days of diagnosis. The major cause of early death in APL... (Review)
Review
Acute promyelocytic leukemia (APL) is associated with a high incidence of early death, which occurs within 30 days of diagnosis. The major cause of early death in APL is severe bleeding, particularly intracranial bleeding. Although APL is known to be associated with activation of coagulation, hyperfibrinolysis, and thrombocytopenia, the precise mechanisms that cause bleeding have not yet been elucidated. I propose that a combination of four pathways may contribute to bleeding in APL: (1) tissue factor, (2) the urokinase plasminogen activator/urokinase plasminogen activator receptor, (3) the annexin A2/S100A100/tissue plasminogen activator, and (4) the podoplanin/C-type lectin-like receptor 2. A better understanding of these pathways will identify new biomarkers to determine which APL patients are at high risk of bleeding and allow the development of new treatments for APL-associated bleeding.
Topics: Humans; Leukemia, Promyelocytic, Acute; Hemostasis; Annexin A2; Hemorrhage; Thromboplastin; Membrane Glycoproteins; Tissue Plasminogen Activator; Receptors, Urokinase Plasminogen Activator; S100 Proteins
PubMed: 38341391
DOI: 10.1007/s12185-024-03708-0 -
Experimental Eye Research Aug 2023Urokinase-type plasminogen activator (uPA) is a serine protease that plays a central role in the pericellular fibrinolytic system, mediates the degradation of...
Urokinase-type plasminogen activator (uPA) is a serine protease that plays a central role in the pericellular fibrinolytic system, mediates the degradation of extracellular matrix proteins and activation of growth factors, and contributes to the regulation of various cellular processes including cell migration and adhesion, chemotaxis, and angiogenesis. The corneal epithelium responds rapidly to injury by initiating a wound healing process that involves cell migration, cell proliferation, and tissue remodeling. It is innervated by sensory nerve endings that play an important role in the maintenance of corneal epithelial homeostasis and in the wound healing response. We here investigated the role of uPA in corneal nerve regeneration and epithelial resurfacing after corneal injury with the use of uPA-deficient mice. Both the structure of the corneal epithelium and the pattern of corneal innervation in uPA mice appeared indistinguishable from those in uPA mice. Whereas the cornea was completely resurfaced by 36-48 h after epithelial scraping in uPA mice, however, such resurfacing required at least 72 h in uPA mice. Restoration of epithelial stratification was also impaired in the mutant mice. Fibrin zymography revealed that the expression of uPA increased after corneal epithelial scraping and returned to basal levels in association with completion of re-epithelialization in wild-type animals. Staining of corneal whole-mount preparations for βIII-tubulin also revealed that the regeneration of corneal nerves after injury was markedly delayed in uPA mice compared with uPA mice. Our results thus demonstrate an important role for uPA in both corneal nerve regeneration and epithelial migration after epithelial debridement, and they may provide a basis for the development of new treatments for neurotrophic keratopathy.
Topics: Animals; Mice; Cell Movement; Cornea; Epithelium, Corneal; Nerve Regeneration; Urokinase-Type Plasminogen Activator
PubMed: 37385532
DOI: 10.1016/j.exer.2023.109559 -
Stroke and Vascular Neurology Feb 2024Recombinant human TNK tissue-type plasminogen activator (rhTNK-tPA) was not inferior to alteplase for ischaemic stroke within 4.5 hours. Our study aimed to investigate... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND PURPOSE
Recombinant human TNK tissue-type plasminogen activator (rhTNK-tPA) was not inferior to alteplase for ischaemic stroke within 4.5 hours. Our study aimed to investigate the efficacy and safety of rhTNK-tPA in patients who had an ischaemic stroke due to large vessel occlusion (LVO) of anterior circulation beyond 4.5 hours.
METHODS AND DESIGN
Tenecteplase Reperfusion Therapy in Acute Ischaemic Cerebrovascular Events-III (TRACE III) is a multicentre, prospective, randomised, open-label, blind endpoint, controlled clinical trial. Patients who had an ischaemic stroke due to anterior circulation LVO (internal carotid artery, middle cerebral artery M1 and M2 segments) within 4.5-24 hours from last known well (including wake-up stroke and no witness stroke) and with salvageable tissue (ischaemic core volume <70 mL, mismatch ratio ≥1.8 and mismatch volume ≥15 mL) based on CT perfusion or MRI perfusion-weighted imaging (PWI) were included and randomised to rhTNK-tPA 0.25 mg/kg (single bolus) to a maximum of 25 mg or standard medical therapy. Specially, we will exclude patients who are intended for direct thrombectomy. All will be followed up for 90 days.
STUDY OUTCOMES
Primary efficacy outcome is modified Rankin Scale (mRS) score ≤1 at 90 days. Secondary efficacy outcomes include ordinal distribution of mRS at 90 days, major neurological improvement defined by a decrease ≥8 points compared with the initial deficit or a score ≤1 on the National Institutes of Health Stroke Scale (NIHSS) at 72 hours, mRS score ≤2 at 90 days, the rate of improvement on Tmax >6 s at 24 hours and NIHSS score change from baseline at 7 days. Safety outcomes are symptomatic intracerebral haemorrhage within 36 hours and mortality at 90 days.
DISCUSSION
TRACE III will provide evidence for the efficacy and safety of rhTNK-tPA in patients who had an ischaemic strokes due to anterior circulation LVO beyond 4.5 hours.
TRIAL REGISTRATION NUMBER
NCT05141305.
Topics: United States; Humans; Tenecteplase; Fibrinolytic Agents; Stroke; Brain Ischemia; Prospective Studies; Treatment Outcome; Ischemic Stroke; Reperfusion
PubMed: 37247876
DOI: 10.1136/svn-2023-002310 -
American Family Physician Nov 2023Pleural effusion affects 1.5 million patients in the United States each year. New effusions require expedited investigation because treatments range from common medical...
Pleural effusion affects 1.5 million patients in the United States each year. New effusions require expedited investigation because treatments range from common medical therapies to invasive surgical procedures. The leading causes of pleural effusion in adults are heart failure, infection, malignancy, and pulmonary embolism. The patient's history and physical examination should guide evaluation. Small bilateral effusions in patients with decompensated heart failure, cirrhosis, or kidney failure are likely transudative and do not require diagnostic thoracentesis. In contrast, pleural effusion in the setting of pneumonia (parapneumonic effusion) may require additional testing. Multiple guidelines recommend early use of point-of-care ultrasound in addition to chest radiography to evaluate the pleural space. Chest radiography is helpful in determining laterality and detecting moderate to large pleural effusions, whereas ultrasonography can detect small effusions and features that could indicate complicated effusion (i.e., infection of the pleural space) and malignancy. Point-of-care ultrasound should also guide thoracentesis because it reduces complications. Computed tomography of the chest can exclude other causes of dyspnea and suggest complicated parapneumonic or malignant effusion. When diagnostic thoracentesis is indicated, Light's criteria can help differentiate exudates from transudates. Pleural aspirate should routinely be evaluated using Gram stain, cell count with differential, culture, cytology, protein, l-lactate dehydrogenase, and pH levels. Additional assessments should be individualized, such as tuberculosis testing in high-prevalence regions. Parapneumonic effusions are the most common cause of exudates. A pH level less than 7.2 is indicative of complicated parapneumonic effusion and warrants prompt consultation for catheter or chest tube drainage, possible tissue plasminogen activator/deoxyribonuclease therapy, or thoracoscopy. Malignant effusions are another common cause of exudative effusions, with recurrent effusions having a poor prognosis.
Topics: Humans; Adult; Tissue Plasminogen Activator; Pleural Effusion; Exudates and Transudates; Neoplasms; Heart Failure
PubMed: 37983698
DOI: No ID Found