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Neurologic Clinics Feb 2022Ischemic stroke affects 2.5% of the population of the United States and is the leading cause of disability. This article outlines the evidence to support intravenous... (Review)
Review
Ischemic stroke affects 2.5% of the population of the United States and is the leading cause of disability. This article outlines the evidence to support intravenous thrombolysis with alteplase and tenecteplase, thrombolysis in the setting of DWI/flair mismatch, endovascular treatment in the 6-hour and 6- to 24-hour window, and the use of telemedicine in acute stroke. Current controversies and ongoing trials within endovascular treatment are also detailed. Case presentations are included to provide clinical context and the application of data to practice.
Topics: Brain Ischemia; Fibrinolytic Agents; Humans; Ischemic Stroke; Stroke; Tenecteplase; Thrombolytic Therapy; Tissue Plasminogen Activator; Treatment Outcome; United States
PubMed: 34798968
DOI: 10.1016/j.ncl.2021.08.002 -
Transfusion and Apheresis Science :... Oct 2019Deficiencies or excessive activation of the fibrinolytic system can result in severe, lifelong bleeding disorders. The most severe clinical phenotype is caused by... (Review)
Review
Deficiencies or excessive activation of the fibrinolytic system can result in severe, lifelong bleeding disorders. The most severe clinical phenotype is caused by α2-Antiplasmin (α2-AP) deficiency which results in excess fibrinolysis due to the inability to inhibit plasmin. Another bleeding disorder due to a defect in the fibrinolytic pathway results from Plasminogen activator inhibitor-1 (PAI-1) deficiency causing enhanced fibrinolysis due to the decreased inhibition of plasminogen activators resulting in increased conversion of plasminogen to plasmin. Both these disorders are rare and have an autosomal recessive pattern of inheritance. They can remain undetected as routine coagulation and platelet function tests are normal. A unique gain-of-function defect in fibrinolysis causes the Quebec platelet disorder (QPD) which is characterized by profibrinolytic platelets containing increased urokinase-type plasminogen activator (uPA) in the α-granules. A high index of suspicion based on clinical phenotype along with the availability of specialized hemostasis testing is required for timely and accurate diagnosis. Antifibrinolytic agents, such as tranexamic acid or ε-aminocaproic acid, are the mainstays of treatment which inhibit fibrinolysis by preventing the binding of plasminogen to fibrin and thereby stabilizing the fibrin clot. The purpose of this review is to summarize the pathogenesis, clinical phenotype, approaches to diagnosis and treatment for these three major disorders of fibrinolysis.
Topics: Antifibrinolytic Agents; Blood Platelets; Factor V Deficiency; Fibrinolysis; Hemorrhagic Disorders; Humans; Plasminogen Activator Inhibitor 1; Tranexamic Acid; Urokinase-Type Plasminogen Activator; alpha-2-Antiplasmin
PubMed: 31427261
DOI: 10.1016/j.transci.2019.08.007 -
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 -
Seminars in Thrombosis and Hemostasis Jun 2023The relationship between depression and reduced fibrinolytic activity reflects the role of tissue plasminogen activator and plasmin in brain remodeling underlying...
The relationship between depression and reduced fibrinolytic activity reflects the role of tissue plasminogen activator and plasmin in brain remodeling underlying resilience, depression remission, and reward processing, rather than the dissolution of fibrin clots. Individuals who experience depression demonstrate hippocampal and prefrontal cortex atrophy, as well as impaired neuronal connectivity. Brain-derived neurotrophic factor (BDNF), synthesized as a precursor that is activated through cleavage by tissue plasminogen activator and plasmin, influences adult neurogenesis and neuronal plasticity in the hippocampus and prefrontal cortex. Depression is associated with decreased brain levels of BDNF, due to reduced activity of tissue plasminogen activator and plasmin. Tissue plasminogen activator and plasmin also mediate the release of dopamine, a neurotransmitter implicated in motivation and reward. Peripartum depression defines a depressive episode that occurs during pregnancy or in the first month after delivery, reinforcing the concept that postpartum depression may be a continuum of antenatal depression. This article describes the fibrinolytic status in the healthy brain, in stress and depression, emphasizing the links between biological markers of depression and defective fibrinolysis. It also discusses the association between hypofibrinolysis and risk factors for perinatal depression, including polycystic ovary syndrome, early miscarriage, preeclampsia, stressful life events, sedentariness, eating habits, gestational and type 2 diabetes, and antithyroid peroxidase antibodies. In addition, it reviews the evidence that antidepressant medications and interventions as diverse as placebo, psychotherapy, massage, video game playing, regular exercise, dietary modifications, omega 3 fatty acid supplementation, neurohormones, and cigarette smoking may reduce depression by restoring the fibrinolytic activity. Last, it suggests new directions for research.
Topics: Female; Humans; Pregnancy; Tissue Plasminogen Activator; Fibrinolysin; Brain-Derived Neurotrophic Factor; Diabetes Mellitus, Type 2; Depression; Peripartum Period; Fibrinolysis
PubMed: 36113504
DOI: 10.1055/s-0042-1756194 -
European Journal of Drug Metabolism and... Mar 2022Desmoteplase is a bat (Desmodus rotundus) saliva-derived fibrinolytic enzyme resembling a urokinase and tissue plasminogen activator. It is highly dependent on fibrin... (Review)
Review
Desmoteplase is a bat (Desmodus rotundus) saliva-derived fibrinolytic enzyme resembling a urokinase and tissue plasminogen activator. It is highly dependent on fibrin and has some neuroprotective attributes. Intravenous administration of desmoteplase is safe and well tolerated in healthy subjects. Plasma fibrinolytic activity is linearly related to its blood concentration, its terminal elimination half-life ranges from 3.8 to 4.92 h (50 vs. 90 μg/kg dose). Administration of desmoteplase leads to transitory derangement of fibrinogen, D-dimer, alpha2-antiplasmin, and plasmin and antiplasmin complex which normalize within 4-12 h. It does not alter a prothrombin test, international normalized ratio, activated partial thromboplastin time, and prothrombin fragment 1.2. Desmoteplase was tested in myocardial infarction and pulmonary embolism and showed promising results versus alteplase. In ischemic stroke trials, desmoteplase was linked to increased rates of symptomatic intracranial hemorrhages and case fatality. However, data from "The desmoteplase in Acute Ischemic Stroke" Trials, DIAS-3 and DIAS-J, suggest that the drug is well tolerated and its safety profile is comparable to placebo. Desmoteplase is theoretically a superior thrombolytic because of high fibrin specificity, no activation of beta-amyloid, and lack of neurotoxicity. It was associated with better outcomes in patients with significant stenosis or occlusion of a proximal precerebral vessels. However, DIAS-4 was stopped as it might have not reached its primary endpoint. Due to its promising properties, desmoteplase may be added into treatment of ischemic stroke with extension of the time window and special emphasis on patients presenting outside the 4.5-h thrombolysis window, with wake-up strokes and strokes of unknown onset.
Topics: Fibrinolytic Agents; Humans; Ischemic Stroke; Plasminogen Activators
PubMed: 34893967
DOI: 10.1007/s13318-021-00743-8 -
Cancer Letters Apr 2023The fibrinolytic system is involved in many physiological functions, among which the important members can interact with each other, either synergistically or... (Review)
Review
The fibrinolytic system is involved in many physiological functions, among which the important members can interact with each other, either synergistically or antagonistically to participate in the pathogenesis of many diseases. Plasminogen activator inhibitor 1 (PAI-1) acts as a crucial element of the fibrinolytic system and functions in an anti-fibrinolytic manner in the normal coagulation process. It inhibits plasminogen activator, and affects the relationship between cells and extracellular matrix. PAI-1 not only involved in blood diseases, inflammation, obesity and metabolic syndrome but also in tumor pathology. Especially PAI-1 plays a different role in different digestive tumors as an oncogene or cancer suppressor, even a dual role for the same cancer. We term this phenomenon "PAI-1 paradox". PAI-1 is acknowledged to have both uPA-dependent and -independent effects, and its different actions can result in both beneficial and adverse consequences. Therefore, this review will elaborate on PAI-1 structure, the dual value of PAI-1 in different digestive system tumors, gene polymorphisms, the uPA-dependent and -independent mechanisms of regulatory networks, and the drugs targeted by PAI-1 to deepen the comprehensive understanding of PAI-1 in digestive system tumors.
Topics: Humans; Digestive System Neoplasms; Gastrointestinal Neoplasms; Inflammation; Plasminogen Activator Inhibitor 1; Urokinase-Type Plasminogen Activator
PubMed: 36889376
DOI: 10.1016/j.canlet.2023.216117 -
Journal of Controlled Release :... Apr 2022Ischemic stroke is a vascular central nervous system (CNS) disease that leads a disability and death. Thrombolysis and neuroprotection are the primary treatment... (Review)
Review
Ischemic stroke is a vascular central nervous system (CNS) disease that leads a disability and death. Thrombolysis and neuroprotection are the primary treatment strategies of ischemic stroke. Recombinant tissue plasminogen activator (tPA) is currently the only therapeutic drug approved by the Food & Drug Administration (FDA) for the treatment of ischemic stroke, while the application of tPA is limited by narrow therapeutic window, rapid drug elimination, and risks of hemorrhagic transformation. Blood brain barrier (BBB) poses serious challenges to drug delivery into the brain, leading to many neuroprotective agents failing clinical trials. The drug delivery systems (DDS), including targeted nanocarriers and stimuli-responsive nanocarriers, could protect drugs from elimination, deliver drugs to desired sites such as thrombus and CNS, and specifically release drugs in preferred areas by responding to internal or external stimuli, thus increasing the therapeutic effects of drugs. This review summarizes some strategies employed in nanocarriers to achieve thrombus targeting or enhance the accumulation of neuroprotective agents in the brain and even ischemic regions and brain cells. Meanwhile, the stimuli responsive nanocarriers in response to different internal and external environments of thrombus or ischemic brain parenchyma are systematically discussed. This work also provides insights into the precise treatment of ischemic stroke.
Topics: Brain Ischemia; Drug Delivery Systems; Humans; Ischemic Stroke; Stroke; Tissue Plasminogen Activator
PubMed: 35248645
DOI: 10.1016/j.jconrel.2022.02.036 -
Protein and Peptide Letters 2020An imbalance in oxygen supply to cardiac tissues or formation of thrombus leads to deleterious results like pulmonary embolism, coronary heart disease and acute cardiac... (Review)
Review
An imbalance in oxygen supply to cardiac tissues or formation of thrombus leads to deleterious results like pulmonary embolism, coronary heart disease and acute cardiac failure. The formation of thrombus requires clinical encounter with fibrinolytic agents including streptokinase, urokinase or tissue plasminogen activator. Irrespective to urokinase and tissue plasminogen activator, streptokinase is still a significant agent in treatment of cardiovascular diseases. Streptokinase, being so economical, has an important value in treating cardiac diseases in developing countries. This review paper will provide the maximum information to enlighten all the pros and cons of streptokinase up till now. It has been concluded that recent advances in structural/synthetic biology improved SK with enhanced half-life and least antigenicity. Such enzyme preparations would be the best thrombolytic agents.
Topics: Cardiovascular Diseases; Drug Stability; Half-Life; Humans; Protein Engineering; Recombinant Proteins; Streptokinase; Synthetic Biology
PubMed: 31612811
DOI: 10.2174/0929866526666191014150408 -
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 -
Seminars in Thrombosis and Hemostasis Apr 2022Tissue plasminogen activator's (tPA) fibrinolytic function in the vasculature is well-established. This specific role for tPA in the vasculature, however, contrasts with... (Review)
Review
Tissue plasminogen activator's (tPA) fibrinolytic function in the vasculature is well-established. This specific role for tPA in the vasculature, however, contrasts with its pleiotropic activities in the central nervous system. Numerous physiological and pathological functions have been attributed to tPA in the central nervous system, including neurite outgrowth and regeneration; synaptic and spine plasticity; neurovascular coupling; neurodegeneration; microglial activation; and blood-brain barrier permeability. In addition, multiple substrates, both plasminogen-dependent and -independent, have been proposed to be responsible for tPA's action(s) in the central nervous system. This review aims to dissect a subset of these different functions and the different molecular mechanisms attributed to tPA in the context of learning and memory. We start from the original research that identified tPA as an immediate-early gene with a putative role in synaptic plasticity to what is currently known about tPA's role in a learning and memory disorder, Alzheimer's disease. We specifically focus on studies demonstrating tPA's involvement in the clearance of amyloid-β and neurovascular coupling. In addition, given that tPA has been shown to regulate blood-brain barrier permeability, which is perturbed in Alzheimer's disease, this review also discusses tPA-mediated vascular dysfunction and possible alternative mechanisms of action for tPA in Alzheimer's disease pathology.
Topics: Alzheimer Disease; Humans; Neuronal Plasticity; Tissue Plasminogen Activator
PubMed: 34942669
DOI: 10.1055/s-0041-1740265