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Journal of Thrombosis and Thrombolysis Feb 2023Tenecteplase (TNK) is a promising candidate to replace alteplase as the standard of care for acute ischemic stroke (AIS); however, the optimal dosage is still to be... (Meta-Analysis)
Meta-Analysis Review
The efficacy and safety of tenecteplase versus alteplase for acute ischemic stroke: an updated systematic review, pairwise, and network meta-analysis of randomized controlled trials.
Tenecteplase (TNK) is a promising candidate to replace alteplase as the standard of care for acute ischemic stroke (AIS); however, the optimal dosage is still to be investigated. Therefore, we aim to evaluate the safety and efficacy of TNK versus alteplase and to investigate the optimal TNK dosage. A systematic review, pairwise, and network meta-analysis synthesizing randomized controlled trials (RCTs) from WOS, SCOPUS, EMBASE, and PubMed until July 26, 2022. We used the risk ratio (RR) for dichotomous outcomes presented with the corresponding 95% confidence interval (CI). We registered our protocol in PROSPERO with ID: CRD42022352038. Nine RCTs with a total of 3,707 patients were included. TNK significantly led to complete recanalization (RR: 1.27 with 95% CI [1.02, 1.57], P = 0.03); however, we found no difference regarding early neurological improvement (RR: 1.07 with 95% CI [0.94, 1.21], P = 0.33) and excellent neurological recovery (RR: 1.03 with 95% CI [0.96, 1.10], P = 0.42). Also, TNK was similar to alteplase regarding mortality (RR: 0.99 with 95% CI [0.82, 1.18], P = 0.88), intracranial haemorrhage (RR: 1.00 with 95% CI [0.85, 1.18], P = 0.99), and parenchymal hematoma (RR: 1.13 with 95% CI [0.83, 1.54], P = 0.44). TNK in the dose of 0.25 mg is a viable candidate to displace alteplase as the standard of care in patients with an AIS within 4.5 h of presentation due to its better rate of early neurological recovery and non-inferiority in terms of safety outcomes. However, the evidence regarding TNK's role in AIS presenting after 4.5 h from symptoms onset, wake-up stroke, and minor stroke/TIA is still lacking, necessitating further double-blinded pragmatic RCTs in this regard.
Topics: Humans; Tissue Plasminogen Activator; Tenecteplase; Fibrinolytic Agents; Network Meta-Analysis; Randomized Controlled Trials as Topic; Stroke; Ischemic Stroke; Treatment Outcome; Brain Ischemia
PubMed: 36449231
DOI: 10.1007/s11239-022-02730-5 -
International Journal of Molecular... Feb 2023Stressful events trigger a set of complex biological responses which follow a bell-shaped pattern. Low-stress conditions have been shown to elicit beneficial effects,... (Review)
Review
Glucocorticoid-Responsive Tissue Plasminogen Activator (tPA) and Its Inhibitor Plasminogen Activator Inhibitor-1 (PAI-1): Relevance in Stress-Related Psychiatric Disorders.
Stressful events trigger a set of complex biological responses which follow a bell-shaped pattern. Low-stress conditions have been shown to elicit beneficial effects, notably on synaptic plasticity together with an increase in cognitive processes. In contrast, overly intense stress can have deleterious behavioral effects leading to several stress-related pathologies such as anxiety, depression, substance use, obsessive-compulsive and stressor- and trauma-related disorders (e.g., post-traumatic stress disorder or PTSD in the case of traumatic events). Over a number of years, we have demonstrated that in response to stress, glucocorticoid hormones (GCs) in the hippocampus mediate a molecular shift in the balance between the expression of the tissue plasminogen activator (tPA) and its own inhibitor plasminogen activator inhibitor-1 (PAI-1) proteins. Interestingly, a shift in favor of PAI-1 was responsible for PTSD-like memory induction. In this review, after describing the biological system involving GCs, we highlight the key role of tPA/PAI-1 imbalance observed in preclinical and clinical studies associated with the emergence of stress-related pathological conditions. Thus, tPA/PAI-1 protein levels could be predictive biomarkers of the subsequent onset of stress-related disorders, and pharmacological modulation of their activity could be a potential new therapeutic approach for these debilitating conditions.
Topics: Humans; Tissue Plasminogen Activator; Plasminogen Activator Inhibitor 1; Glucocorticoids; Mental Disorders
PubMed: 36901924
DOI: 10.3390/ijms24054496 -
International Journal of Molecular... May 2022The fibrinolytic system is composed of the protease plasmin, its precursor plasminogen and their respective activators, tissue-type plasminogen activator (tPA) and...
The fibrinolytic system is composed of the protease plasmin, its precursor plasminogen and their respective activators, tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA), counteracted by their inhibitors, plasminogen activator inhibitor type 1 (PAI-1), plasminogen activator inhibitor type 2 (PAI-2), protein C inhibitor (PCI), thrombin activable fibrinolysis inhibitor (TAFI), protease nexin 1 (PN-1) and neuroserpin. The action of plasmin is counteracted by α2-antiplasmin, α2-macroglobulin, TAFI, and other serine protease inhibitors (antithrombin and α2-antitrypsin) and PN-1 (protease nexin 1). These components are essential regulators of many physiologic processes. They are also involved in the pathogenesis of many disorders. Recent advancements in our understanding of these processes enable the opportunity of drug development in treating many of these disorders.
Topics: Fibrinolysin; Fibrinolysis; Plasminogen; Plasminogen Activator Inhibitor 1; Protease Nexins; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator; alpha-2-Antiplasmin
PubMed: 35563651
DOI: 10.3390/ijms23095262 -
Frontiers in Immunology 2022Stroke is a disease with high incidence, mortality and disability rates. It is also the main cause of adult disability in developed countries. Stroke is often caused by... (Review)
Review
Stroke is a disease with high incidence, mortality and disability rates. It is also the main cause of adult disability in developed countries. Stroke is often caused by small emboli on the inner wall of the blood vessels supplying the brain, which can lead to arterial embolism, and can also be caused by cerebrovascular or thrombotic bleeding. With the exception of recombinant tissue plasminogen activator (rt-PA), which is a thrombolytic drug used to recanalize the occluded artery, most treatments have been demonstrated to be ineffective. Stroke can also induce peripheral organ damage. Most stroke patients have different degrees of injury to one or more organs, including the lung, heart, kidney, spleen, gastrointestinal tract and so on. In the acute phase of stroke, severe inflammation occurs in the brain, but there is strong immunosuppression in the peripheral organs, which greatly increases the risk of peripheral organ infection and aggravates organ damage. Nonneurological complications of stroke can affect treatment and prognosis, may cause serious short-term and long-term consequences and are associated with prolonged hospitalization and increased mortality. Many of these complications are preventable, and their adverse effects can be effectively mitigated by early detection and appropriate treatment with various medical measures. This article reviews the pathophysiological mechanism, clinical manifestations and treatment of peripheral organ injury after stroke.
Topics: Brain Ischemia; Fibrinolytic Agents; Humans; Stroke; Thrombolytic Therapy; Tissue Plasminogen Activator
PubMed: 35720359
DOI: 10.3389/fimmu.2022.901209 -
Journal of Thrombosis and Haemostasis :... Dec 2019Fibrinolytic agents including plasmin and plasminogen activators improve outcomes in acute ischemic stroke and thrombosis by recanalizing occluded vessels. In the... (Review)
Review
Fibrinolytic agents including plasmin and plasminogen activators improve outcomes in acute ischemic stroke and thrombosis by recanalizing occluded vessels. In the decades since their introduction into clinical practice, several limitations of have been identified in terms of both efficacy and bleeding risk associated with these agents. Engineered nanoparticles and microparticles address some of these limitations by improving circulation time, reducing inhibition and degradation in circulation, accelerating recanalization, improving targeting to thrombotic occlusions, and reducing off-target effects; however, many particle-based approaches have only been used in preclinical studies to date. This review covers four advances in coupling fibrinolytic agents with engineered particles: (a) modifications of plasminogen activators with macromolecules, (b) encapsulation of plasminogen activators and plasmin in polymer and liposomal particles, (c) triggered release of encapsulated fibrinolytic agents and mechanical disruption of clots with ultrasound, and (d) enhancing targeting with magnetic particles and magnetic fields. Technical challenges for the translation of these approaches to the clinic are discussed.
Topics: Animals; Drug Carriers; Drug Compounding; Fibrinolysin; Fibrinolysis; Fibrinolytic Agents; High-Energy Shock Waves; Humans; Liposomes; Magnetite Nanoparticles; Nanomedicine; Nanoparticles; Plasminogen Activators; Thrombolytic Therapy
PubMed: 31529593
DOI: 10.1111/jth.14637 -
Cellular Signalling Nov 2020A fine-tuned activation and deactivation of proteases and their inhibitors are involved in the execution of the inflammatory response. The zymogen/proenzyme plasminogen... (Review)
Review
A fine-tuned activation and deactivation of proteases and their inhibitors are involved in the execution of the inflammatory response. The zymogen/proenzyme plasminogen is converted to the serine protease plasmin, a key fibrinolytic factor by plasminogen activators including tissue-type plasminogen activator (tPA). Plasmin is part of an intricate protease network controlling proteins of initial hemostasis/coagulation, fibrinolytic and complement system. Activation of these protease cascades is required to mount a proper inflammatory response. Although best known for its ability to dissolve clots and cleave fibrin, recent studies point to the importance of fibrin-independent functions of plasmin during acute inflammation and inflammation resolution. In this review, we provide an up-to-date overview of the current knowledge of the enzymatic and cytokine-like effects of tPA and describe the role of tPA and plasminogen receptors in the regulation of the inflammatory response with emphasis on the cytokine storm syndrome such as observed during coronavirus disease 2019 or macrophage activation syndrome. We discuss tPA as a modulator of Toll like receptor signaling, plasmin as an activator of NFkB signaling, and summarize recent studies on the role of plasminogen receptors as controllers of the macrophage conversion into the M2 type and as mediators of efferocytosis during inflammation resolution.
Topics: Animals; Blood Coagulation; COVID-19; Complement Activation; Coronavirus Infections; Cytokine Release Syndrome; Cytokines; Humans; Immune System; Inflammation; Low Density Lipoprotein Receptor-Related Protein-1; NF-kappa B; Pandemics; Plasminogen; Pneumonia, Viral; Tissue Plasminogen Activator
PubMed: 32861744
DOI: 10.1016/j.cellsig.2020.109761 -
International Journal of Molecular... Apr 2021The neurovascular unit (NVU) is a dynamic structure assembled by endothelial cells surrounded by a basement membrane, pericytes, astrocytes, microglia and neurons. A... (Review)
Review
The neurovascular unit (NVU) is a dynamic structure assembled by endothelial cells surrounded by a basement membrane, pericytes, astrocytes, microglia and neurons. A carefully coordinated interplay between these cellular and non-cellular components is required to maintain normal neuronal function, and in line with these observations, a growing body of evidence has linked NVU dysfunction to neurodegeneration. Plasminogen activators catalyze the conversion of the zymogen plasminogen into the two-chain protease plasmin, which in turn triggers a plethora of physiological events including wound healing, angiogenesis, cell migration and inflammation. The last four decades of research have revealed that the two mammalian plasminogen activators, tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA), are pivotal regulators of NVU function during physiological and pathological conditions. Here, we will review the most relevant data on their expression and function in the NVU and their role in neurovascular and neurodegenerative disorders.
Topics: Animals; Cerebrovascular Disorders; Humans; Neurodegenerative Diseases; Plasminogen Activators; Receptors, Urokinase Plasminogen Activator
PubMed: 33922229
DOI: 10.3390/ijms22094380 -
Clinical and Applied... 2023Sepsis-induced coagulopathy (SIC) is a life-threatening complication characterized by the systemic activation of coagulation in sepsis. The diagnostic criteria of SIC... (Review)
Review
Sepsis-induced coagulopathy (SIC) is a life-threatening complication characterized by the systemic activation of coagulation in sepsis. The diagnostic criteria of SIC consist of three items, including Sequential Organ Failure Assessment (SOFA) score, platelet count, and prothrombin time (PT)-international normalized ratio (INR). SIC has a high prevalence and it can lead to a higher mortality rate and longer length of hospital and ICU stay. Thus, the early detection of SIC is extremely important. It is unfortunate that there is still no precise biomarker for early diagnosis and assessment of the prognosis of SIC. We reviewed the current literature and discovered that some potential biomarkers, such as soluble thrombomodulin (sTM), thrombin-antithrombin complex (TAT), tissue plasminogen activator-inhibitor complex (t-PAIC), α2-plasmin inhibitor-plasmin complex (PIC), C-type lectin-like receptor 2 (CLEC-2), neutrophil extracellular traps (NETs), prothrombin fragment 1.2 (F1.2), Angiopoietin-2 (Ang-2), plasminogen activator inhibitor-1 (PAI-1), and tissue inhibitor of metalloproteinase-1 (TIMP-1) may be useful for early diagnosis, evaluation, and prognosis of SIC. Early initiation of treatment without missing any therapeutic opportunities may improve SIC patients' prognosis. Further large-scale clinical studies are still needed to confirm the role of these biomarkers in the diagnosis and prognosis assessment of SIC.
Topics: Humans; Tissue Plasminogen Activator; Tissue Inhibitor of Metalloproteinase-1; Blood Coagulation Disorders; Prognosis; Biomarkers; Early Diagnosis; Sepsis; Disseminated Intravascular Coagulation
PubMed: 37605466
DOI: 10.1177/10760296231195089 -
International Journal of Molecular... Dec 2021Angiogenesis is a process associated with the migration and proliferation of endothelial cells (EC) to form new blood vessels. It is involved in various physiological... (Review)
Review
Angiogenesis is a process associated with the migration and proliferation of endothelial cells (EC) to form new blood vessels. It is involved in various physiological and pathophysiological conditions and is controlled by a wide range of proangiogenic and antiangiogenic molecules. The plasminogen activator-plasmin system plays a major role in the extracellular matrix remodeling process necessary for angiogenesis. Urokinase/tissue-type plasminogen activators (uPA/tPA) convert plasminogen into the active enzyme plasmin, which in turn activates matrix metalloproteinases and degrades the extracellular matrix releasing growth factors and proangiogenic molecules such as the vascular endothelial growth factor (VEGF-A). The plasminogen activator inhibitor-1 (PAI-1) is the main inhibitor of uPA and tPA, thereby an inhibitor of pericellular proteolysis and intravascular fibrinolysis, respectively. Paradoxically, PAI-1, which is expressed by EC during angiogenesis, is elevated in several cancers and is found to promote angiogenesis by regulating plasmin-mediated proteolysis and by promoting cellular migration through vitronectin. The urokinase-type plasminogen activator receptor (uPAR) also induces EC cellular migration during angiogenesis via interacting with signaling partners. Understanding the molecular functions of the plasminogen activator plasmin system and targeting angiogenesis via blocking serine proteases or their interactions with other molecules is one of the major therapeutic strategies scientists have been attracted to in controlling tumor growth and other pathological conditions characterized by neovascularization.
Topics: Animals; Humans; Models, Biological; Neovascularization, Pathologic; Neovascularization, Physiologic; Plasminogen; Serine Proteases; Tissue Plasminogen Activator
PubMed: 35008762
DOI: 10.3390/ijms23010337 -
Translational Stroke Research Dec 2022Stroke, which continues to be a leading cause of death and long-term disability worldwide, has often been described as a clinical graveyard. While multiple small... (Review)
Review
Stroke, which continues to be a leading cause of death and long-term disability worldwide, has often been described as a clinical graveyard. While multiple small molecule therapeutics have undergone clinical trials in stroke, currently only one Food and Drug Administration (FDA)-approved medication exists for the treatment of stroke, the biological, recombinant tissue plasminogen activator (rt-PA). Repurposing of therapeutics which have previously gained FDA approval for alternative indications serves as a prospective option for stroke therapeutic translation. In contrast to de novo drug development, repurposing strategies have patient-centered and economic advantages. These include increased safety, increased chance of approval, decreased time to approval, and decreased capital investment. Presently, 37 active stroke clinical trials utilize repurposed therapeutics with various initial indications and dosing paradigms. The currently studied repurposed therapeutics fall into six mechanistic categories: (1) anticoagulation; (2) vasculature integrity, response, or red blood cell (RBC) alterations; (3) immune system regulation; (4) neurotransmission; and (5) neuroprotection. Directed hypothesis-driven computational investigation utilizing drug databases, in silico drug-protein interaction modeling, genomic data, and consensus methodology can determine if the current mechanistic repurposing categories have the highest chance of translational success or if other mechanistic avenues should be explored. With this increased focus on repurposed therapeutic strategies over de novo strategies, evolution and optimization of regulatory protections are needed to incentivize innovators and investigators.
Topics: Humans; Tissue Plasminogen Activator; Drug Repositioning; Pharmaceutical Preparations; Prospective Studies; Stroke
PubMed: 35218497
DOI: 10.1007/s12975-022-01000-z