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Med (New York, N.Y.) Aug 2022The standard medical therapy for intravenous thrombolysis in patients with stroke presenting within 3 h is alteplase, a tissue plasminogen activator. Menon and...
The standard medical therapy for intravenous thrombolysis in patients with stroke presenting within 3 h is alteplase, a tissue plasminogen activator. Menon and colleagues assessed the non-inferiority, efficacy, and safety of tenecteplase, a modified version of alteplase, in patients with acute ischemic stroke presenting within 4.5 h of onset.
Topics: Brain Ischemia; Fibrinolytic Agents; Humans; Ischemic Stroke; Tenecteplase; Tissue Plasminogen Activator
PubMed: 35963230
DOI: 10.1016/j.medj.2022.07.006 -
ESC Heart Failure Aug 2023We sought to investigate the relationship between circulating tissue plasminogen activator (t-PA) level and long-term outcomes in stable coronary artery disease patients...
AIMS
We sought to investigate the relationship between circulating tissue plasminogen activator (t-PA) level and long-term outcomes in stable coronary artery disease patients with or without aortic valve sclerosis (AVSc).
METHODS AND RESULTS
Serum levels of t-PA were determined in 347 consecutive stable angina patients with (n = 183) or without (n = 164) AVSc. Outcomes were prospectively recorded as planned clinic evaluations every 6 months up to 7 years. The primary endpoint was a composite of cardiovascular death and rehospitalization due to heart failure. The secondary endpoint included all-cause mortality, cardiovascular death, and rehospitalization due to heart failure. Serum t-PA was significantly higher in AVSc than in non-AVSc patients (2131.22 pg/mL vs. 1495.85 pg/mL, P < 0.001). For patients with AVSc, those with t-PA level above the median (>1840.68 pg/mL) were more likely to meet the primary and secondary endpoints (all P < 0.001). After adjusting for potential confounding factors, serum t-PA level remained significantly predictive for each endpoint in the Cox proportional hazard models. The prognostic value of t-PA was good, with an AUC-ROC of 0.753 (P < 0.001). The combination of t-PA with traditional risk factors improved the risk reclassification of AVSc patients, with a net reclassification index of 0.857 and an integrated discrimination improvement of 0.217 (all P < 0.001). However, for patients without AVSc, both primary and secondary endpoints were similar, irrespective of t-PA levels.
CONCLUSIONS
Elevated circulating t-PA confers an increased risk for poor long-term clinical outcomes in stable coronary artery disease patients with AVSc.
Topics: Humans; Coronary Artery Disease; Tissue Plasminogen Activator; Prognosis; Aortic Valve; Sclerosis; Heart Failure
PubMed: 37308095
DOI: 10.1002/ehf2.14420 -
Journal of Thrombosis and Haemostasis :... Oct 2022Severe COVID-19 disease is associated with thrombotic complications and extensive fibrin deposition. This study investigates whether the hemostatic complications in...
BACKGROUND
Severe COVID-19 disease is associated with thrombotic complications and extensive fibrin deposition. This study investigates whether the hemostatic complications in COVID-19 disease arise due to dysregulation of the fibrinolytic system.
METHODS
This prospective study analyzed fibrinolytic profiles of 113 patients hospitalized with COVID-19 disease with 24 patients with non-COVID-19 respiratory infection and healthy controls. Antigens were quantified by Ella system or ELISA, clot lysis by turbidimetric assay, and plasminogen activator inhibitor-1 (PAI-1)/plasmin activity using chromogenic substrates. Clot structure was visualized by confocal microscopy.
RESULTS
PAI-1 and its cofactor, vitronectin, are significantly elevated in patients with COVID-19 disease compared with those with non-COVID-19 respiratory infection and healthy control groups. Thrombin activatable fibrinolysis inhibitor and tissue plasminogen activator were elevated in patients with COVID-19 disease relative to healthy controls. PAI-1 and tissue plasminogen activator (tPA) were associated with more severe COVID-19 disease severity. Clots formed from COVID-19 plasma demonstrate an altered fibrin network, with attenuated fiber length and increased branching. Functional studies reveal that plasmin generation and clot lysis were markedly attenuated in COVID-19 disease, while PAI-1 activity was elevated. Clot lysis time significantly correlated with PAI-1 levels. Stratification of COVID-19 samples according to PAI-1 levels reveals significantly faster lysis when using the PAI-1 resistant (tPA) variant, tenecteplase, over alteplase lysis.
CONCLUSION
This study shows that the suboptimal fibrinolytic response in COVID-19 disease is directly attributable to elevated levels of PAI-1, which attenuate plasmin generation. These data highlight the important prognostic potential of PAI-1 and the possibility of using pre-existing drugs, such as tenecteplase, to treat COVID-19 disease and potentially other respiratory diseases.
Topics: Carboxypeptidase B2; Chromogenic Compounds; Fibrin; Fibrinolysin; Fibrinolysis; Hemostatics; Humans; Plasminogen Activator Inhibitor 1; Prospective Studies; Tenecteplase; Thrombosis; Tissue Plasminogen Activator; Vitronectin; COVID-19 Drug Treatment
PubMed: 35780481
DOI: 10.1111/jth.15806 -
Scientific Reports Apr 2021Plasmin is the key enzyme in fibrinolysis. Upon interaction with plasminogen activators, the zymogen plasminogen is converted to active plasmin. Some studies indicate...
Plasmin is the key enzyme in fibrinolysis. Upon interaction with plasminogen activators, the zymogen plasminogen is converted to active plasmin. Some studies indicate plasminogen activation is regulated by cation-independent mannose 6-phosphate receptor (CI-MPR), a protein that facilitates lysosomal enzyme trafficking and insulin-like growth factor 2 downregulation. Plasminogen regulation may be accomplished by CI-MPR binding to plasminogen or urokinase plasminogen activator receptor. We asked whether other members of the plasminogen activation system, such as tissue plasminogen activator (tPA), also interact with CI-MPR. Because tPA is a glycoprotein with three N-linked glycosylation sites, we hypothesized that tPA contains mannose 6-phosphate (M6P) and binds CI-MPR in a M6P-dependent manner. Using surface plasmon resonance, we found that two sources of tPA bound the extracellular region of human and bovine CI-MPR with low-mid nanomolar affinities. Binding was partially inhibited with phosphatase treatment or M6P. Subsequent studies revealed that the five N-terminal domains of CI-MPR were sufficient for tPA binding, and this interaction was also partially mediated by M6P. The three glycosylation sites of tPA were analyzed by mass spectrometry, and glycoforms containing M6P and M6P-N-acetylglucosamine were identified at position N448 of tPA. In summary, we found that tPA contains M6P and is a CI-MPR ligand.
Topics: Acetylglucosamine; Animals; CHO Cells; Cells, Cultured; Cricetulus; Glycoproteins; Humans; Insulin-Like Growth Factor II; Ligands; Mannosephosphates; Phosphorylation; Protein Binding; Protein Interaction Domains and Motifs; Receptor, IGF Type 2; Sf9 Cells; Spodoptera; Tissue Plasminogen Activator
PubMed: 33859256
DOI: 10.1038/s41598-021-87579-z -
Cells Aug 2019Dysregulation of vascular networks is characteristic of eye diseases associated with retinal cell degeneration and visual loss. Visual impairment is also the consequence... (Review)
Review
Dysregulation of vascular networks is characteristic of eye diseases associated with retinal cell degeneration and visual loss. Visual impairment is also the consequence of photoreceptor degeneration in inherited eye diseases with a major inflammatory component, but without angiogenic profile. Among the pathways with high impact on vascular/degenerative diseases of the eye, a central role is played by a system formed by the ligand urokinase-type plasminogen activator (uPA) and its receptor uPAR. The uPAR system, although extensively investigated in tumors, still remains a key issue in vascular diseases of the eye and even less studied in inherited retinal pathologies such as retinitis pigmantosa (RP). Its spectrum of action has been extended far beyond a classical pro-angiogenic function and has emerged as a central actor in inflammation. Preclinical studies in more prevalent eye diseases characterized by neovascular formation, as in retinopathy of prematurity, wet macular degeneration and rubeosis iridis or vasopermeability excess as in diabetic retinopathy, suggest a critical role of increased uPAR signaling indicating the potentiality of its modulation to counteract neovessel formation and microvascular dysfunction. The additional observation that the uPAR system plays a major role in RP by limiting the inflammatory cascade triggered by rod degeneration rises further questions about its role in the diseased eye.
Topics: Animals; Disease Models, Animal; Humans; Inflammation; Mice; Mice, Inbred BALB C; Neovascularization, Pathologic; Rats; Rats, Sprague-Dawley; Receptors, Urokinase Plasminogen Activator; Retinal Diseases; Urokinase-Type Plasminogen Activator
PubMed: 31426601
DOI: 10.3390/cells8080925 -
Journal of the American College of... Mar 2020
Topics: Darkness; Percutaneous Coronary Intervention; Thrombolytic Therapy; Time; Tissue Plasminogen Activator
PubMed: 32216910
DOI: 10.1016/j.jacc.2020.02.007 -
Nutrients Dec 2022Cardiovascular disease is a major threat to global public health. Tissue plasminogen activator (TPA) is a serine protease that dissolves blood clots, which can also lead...
Cardiovascular disease is a major threat to global public health. Tissue plasminogen activator (TPA) is a serine protease that dissolves blood clots, which can also lead to excessive bleeding. Fibrinogen (FIBR), a glycoprotein, is converted by thrombin to fibrin and then to a fibrin-based blood clot. Both TPA and FIBR levels in the blood are associated with an increased risk of coronary heart disease, and the levels of the two factors are also positively correlated with total adipose tissue amounts. Visceral and subcutaneous adipose tissues (VAT and SAT) can contribute differently to whole-body metabolism. In this study, we sought to assess: (1) the strength of the correlation between the changing levels of the two factors and the changing amounts of VAT/SAT during exercise-induced weight loss, (2) whether there is any difference between the two types of adipose tissues in terms of the correlation, and (3) which factor, TPA or FIBR, is more sensitive to changes in adiposity? For this study, we analyzed the data from the diabetes prevention program (DPP), in which the participants were divided into three groups, with one group undergoing a lifestyle change that involved maintaining a minimum of 7% weight loss with physical activity. We found that the basal amounts of VAT and SAT were correlated with TPA and FIBR levels. However, following weight loss, adiposity changes were strongly correlated with the changing levels of TPA, but not FIBR, for both men and women. Therefore, TPA, but not FIBR, is sensitive to changes in adiposity. Furthermore, regarding TPA, weight loss sensitized its correlation with SAT, but not VAT. This study shows how adipose tissues distinctively affect TPA and FIBR levels, two factors associated with cardiovascular disease and ischemic stroke.
Topics: Male; Female; Humans; Tissue Plasminogen Activator; Intra-Abdominal Fat; Cardiovascular Diseases; Adiposity; Obesity; Weight Loss; Subcutaneous Fat
PubMed: 36501190
DOI: 10.3390/nu14235159 -
Cells Mar 2024Chronic inflammatory diseases, such as rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, Crohn's disease, periodontitis, and carcinoma metastasis... (Review)
Review
Chronic inflammatory diseases, such as rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, Crohn's disease, periodontitis, and carcinoma metastasis frequently result in bone destruction. Pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, and IL-17 are known to influence bone loss by promoting the differentiation and activation of osteoclasts. Fibrinolytic factors, such as plasminogen (Plg), plasmin, urokinase-type plasminogen activator (uPA), its receptor (uPAR), tissue-type plasminogen activator (tPA), α2-antiplasmin (α2AP), and plasminogen activator inhibitor-1 (PAI-1) are expressed in osteoclasts and osteoblasts and are considered essential in maintaining bone homeostasis by regulating the functions of both osteoclasts and osteoblasts. Additionally, fibrinolytic factors are associated with the regulation of inflammation and the immune system. This review explores the roles of fibrinolytic factors in bone destruction caused by inflammation.
Topics: Humans; Urokinase-Type Plasminogen Activator; Inflammation; Osteoclasts; Osteoblasts; Bone and Bones
PubMed: 38534360
DOI: 10.3390/cells13060516 -
Journal of Controlled Release :... Oct 2022Sonothrombolysis with recombinant tissue plasminogen activator (rtPA) and microbubbles has been widely studied to enhance thrombolytic potential. Here, we report...
Sonothrombolysis with recombinant tissue plasminogen activator (rtPA) and microbubbles has been widely studied to enhance thrombolytic potential. Here, we report different sonothrombolysis strategy in nanoparticles using microbubbles cavitation. We found that different particles in shape exhibited different reactivity toward the cavitation, leading to a distinct sonothrombolytic potential. Two different gold nanoparticles in shape were functionalized with the rtPA: rtPA-functionalized gold nanospheres (NPt) and gold nanostars (NSt). NPt could not accelerate the thrombolytic potential with a sole acoustic stimulus. Importantly, NSt enhanced the potential with acoustic stimulus and microbubble-mediated cavitation, while NPt were not reactive to cavitation. Coadministration of NSt and microbubbles resulted in a dramatic reduction of the infarcts in a photothrombotic model and recovery in the cerebral blood flow. Given the synergistic effect and in vivo feasibility of this strategy, cavitation-assisted sonothrombolysis by asymmetrical NSt might be useful for treating acute ischemic stroke.
Topics: Fibrinolytic Agents; Gold; Humans; Ischemic Stroke; Metal Nanoparticles; Thrombolytic Therapy; Tissue Plasminogen Activator
PubMed: 36096365
DOI: 10.1016/j.jconrel.2022.09.008 -
Clinical and Applied... 2022The antiphospholipid syndrome (APS), a systemic autoimmune disease characterized by a hypercoagulability associated to vascular thrombosis and/or obstetric morbidity, is... (Review)
Review
The antiphospholipid syndrome (APS), a systemic autoimmune disease characterized by a hypercoagulability associated to vascular thrombosis and/or obstetric morbidity, is caused by the presence of antiphospholipid antibodies such as lupus anticoagulant, anti-β-2-glycoprotein 1, and/or anticardiolipin antibodies. In the obstetrical APS, antiphospholipid antibodies induce the production of proinflammatory cytokines and tissue factor by placental tissues and recruited neutrophils. Moreover, antiphospholipid antibodies activate the complement system which, in turn, induces a positive feedback leading to recruitment of neutrophils as well as activation of the placenta. Activation of these cells triggers myometrial contractions and cervical ripening provoking the induction of labor. In thrombotic and obstetrical APS, antiphospholipid antibodies activate endothelial cells, platelets, and neutrophils and they may alter the multimeric pattern and concentration of von Willebrand factor, increase the concentration of thrombospondin 1, reduce the inactivation of factor XI by antithrombin, increase the activation of factor XII, and reduce the activity of tissue plasminogen activator with the subsequent production of plasmin. All these effects result in less permeable clots, denser, thinner, and with more branched fibrin fibers which are more difficult to lysate. As a consequence, thrombosis, the defining clinical criterion of APS, complicates the clinical course of the patient.
Topics: Antiphospholipid Syndrome; Blood Coagulation; Endothelial Cells; Female; Humans; Placenta; Pregnancy; Tissue Plasminogen Activator
PubMed: 35317658
DOI: 10.1177/10760296221088576