scholarly journals THE PROTHROMBOTIC STATE ASSOCIATED WITH SARS-COV-2 INFECTION: PATHOPHYSIOLOGICAL ASPECTS

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Nicola Semeraro ◽  
Mario Colucci
Keyword(s):  
Plasminogen Activator Inhibitor ◽  
Multiple Organ ◽  
Alveolar Epithelial Cells ◽  
Prothrombotic State ◽  
Plasminogen Activator Inhibitor 1 ◽  
Aberrant Expression ◽  
Alveolar Epithelial ◽  
Fibrinolysis Inhibitor ◽  
Thrombotic Complications ◽  
Therapeutic Tools

Severe coronavirus disease-2019 (COVID-19) is frequently associated with microvascular thrombosis, especially in the lung, or macrovascular thrombosis, mainly venous thromboembolism, that significantly contribute to the mortality burden of the disease. COVID-19 patients also exhibit distinctive laboratory abnormalities that are compatible with a prothrombotic state. The key event underlying COVID-19-associated thrombotic complications is an excessive host inflammatory response to severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection generating multiple inflammatory mediators, mainly cytokines and complement activation products. The latter, along with the virus itself, the increased levels of angiotensin II and hypoxia, drive the major cellular changes promoting thrombosis, which include: (1) aberrant expression of tissue factor by activated alveolar epithelial cells, monocytes-macrophages and neutrophils, and production of other prothrombotic factors by activated endothelial cells (ECs) and platelets; (2) reduced expression of physiological anticoagulants by dysfunctional ECs, and (3) suppression of fibrinolysis by the endothelial overproduction of plasminogen activator inhibitor-1 and, likely, by heightened thrombin-mediated activation of thrombin-activatable fibrinolysis inhibitor. Moreover, neutrophils and other cells, upon activation or death, release nuclear materials which are endowed with potent prothrombotic properties. The ensuing thrombosis significantly contributes to lung injury and, in most severe COVID-19 patients, to multiple organ dysfunction. Insights into the pathogenesis of COVID-19-associated thrombosis may have implications for the development of new diagnostic and therapeutic tools.

Rat alveolar epithelial cells concomitantly express plasminogen activator inhibitor-1 and urokinase

1991 ◽  
Vol 260 (4) ◽  
pp. L286-L295 ◽  
Author(s):  
T. J. Gross ◽  
R. H. Simon ◽  
C. J. Kelly ◽  
R. G. Sitrin
Keyword(s):  
Epithelial Cells ◽  
Plasminogen Activator ◽  
Alveolar Epithelium ◽  
Plasminogen Activator Inhibitor ◽  
Alveolar Epithelial Cells ◽  
Plasminogen Activator Inhibitor 1 ◽  
Necrosis Factor Alpha ◽  
Alveolar Epithelial ◽  
Pai 1

There is considerable evidence to suggest that intra-alveolar plasminogen activation is instrumental in many aspects of inflammatory lung injury and subsequent tissue repair. Rat alveolar epithelial cells produce large quantities of urokinase-type plasminogen activator (uPA) in vitro, and uPA expression is modulated in association with cellular differentiation and exposure to inflammatory mediators. We now report that these cells also secrete heat-stable PA inhibitory activity having the characteristics of PA inhibitor type 1 (PAI-1). In particular, immunoreactive PAI-1 was demonstrable in conditioned media, cell lysates, and extracellular matrix from epithelial cell cultures. As alveolar epithelial cells differentiated in vitro, secreted PA inhibitor activity increased significantly from 104 +/- PAI U/ml (n = 5, mean +/- SE) on day 2 to 442 +/- 150 on day 7 in parallel with increases in secreted and matrix-associated immunoreactive PAI-1. PAI-1 mRNA expression decreased over this same period suggesting posttranscriptional regulation. The levels of both newly synthesized antigen and PAI-1 mRNA were increased by exposure to lipopolysaccharide and tumor necrosis factor-alpha. Thus, by the coexpression of uPA and PAI-1, the alveolar epithelium may actively regulate the generation of plasmin in both the normal and injured alveolus.

Impaired Fibrinolysis in the Antiphospholipid Syndrome

2021 ◽  
Author(s):  
Aleksandra Antovic ◽  
Maria Bruzelius
Keyword(s):  
Plasminogen Activator ◽  
Antiphospholipid Syndrome ◽  
Real Life ◽  
Plasminogen Activator Inhibitor ◽  
Tissue Type ◽  
Plasminogen Activator Inhibitor 1 ◽  
Type Plasminogen Activator ◽  
Real Life Setting ◽  
Annexin 2 ◽  
Fibrinolysis Inhibitor

AbstractThe pathogenesis of the antiphospholipid syndrome (APS) is complex and involves the persistent presence of antiphospholipid antibodies (aPL) in the bloodstream causing a prothrombotic condition. aPL induce excessive activation of the endothelium, monocytes, and platelets in consort with aberrations in hemostasis/clotting, fibrinolytic system, and complement activation. Impaired fibrinolysis has been found in APS patients with thrombotic as well as obstetric manifestations. Increased levels of plasminogen activator inhibitor-1 and thrombin-activatable fibrinolysis inhibitor, together with the presence of aPL against annexin-2, tissue-type plasminogen activator, and plasminogen contribute to the compromised fibrinolytic activity in these patients. Furthermore, unfavorably altered fibrin morphology, less amenable to fibrinolysis, has been proposed as a novel prothrombotic mechanism in APS. This review aims to summarize the present knowledge of the mechanisms involved in impaired fibrinolysis in APS patients. We also present a case from clinical practice as an illustration of fibrinolysis impairment in APS patients from a real-life setting.

scholarly journals Simvastatin improves the prognosis of endotoxin-induced disseminated intravascular coagulation by regulating the intestinal microenvironment

2020 ◽  
Author(s):  
Min Xu ◽  
Lili Luo ◽  
Mengyi Du ◽  
Lu Tang ◽  
Jie Zhou ◽  
...  
Keyword(s):  
Bacterial Translocation ◽  
Disseminated Intravascular Coagulation ◽  
Intestinal Barrier ◽  
Plasminogen Activator Inhibitor ◽  
Coagulation Factors ◽  
Organ Damage ◽  
Multiple Organ ◽  
Plasminogen Activator Inhibitor 1 ◽  
Intravascular Coagulation ◽  
Coagulation Dysfunction

Abstract Background: Disseminated intravascular coagulation (DIC) is characterized by extensive endothelial injury and coagulation activation that is primarily caused by infection and can be aggravated by the gut due to increased permeability and bacterial translocation. Studies have shown that statins play an important role in reducing inflammation, protecting the endothelium and improving coagulation. In addition, statins regulate tight junction (TJ) proteins and gut microbes. Therefore, we aimed to investigate whether simvastatin improves DIC prognosis by regulating the intestinal microenvironment. Methods: Mice were administered 20 mg/kg simvastatin by gavage for 2 weeks and then intraperitoneally injected with 50 mg/kg endotoxin. Twelve hours later, cytokine release, coagulation dysfunction, multiple organ damage and survival were assessed. In addition, intestinal barrier and permeability and bacteria and bacteria translocation were evaluated. Results: We found that the severity of endotoxin-induced DIC was significantly improved in simvastatin-pretreated mice, who showed attenuated depletion of coagulation factors and platelets, decreased plasminogen activator inhibitor-1 (PAI-1) expression, reduced organ fibrin deposition and an improved survival rate. In addition, simvastatin reduced epithelial apoptosis, increased TJ gene expression, and upregulated antimicrobial peptides, lysozyme and mucins. Simvastatin-pretreated mice showed increased Lactobacillales counts, while the LPS group had increased numbers of Desulfovibrio and Mucispirillum, which produce harmful toxins and damage the intestinal epithelium and mucosa. Finally, with the decreased intestinal permeability in the simvastatin group, bacterial translocation in the organs and blood was significantly reduced, both in quantity and species. Conclusions: Simvastatin improves DIC prognosis, and the intestinal microenvironment participates in this process.

Release of biologically active TGF-β1 by alveolar epithelial cells results in pulmonary fibrosis

2003 ◽  
Vol 285 (3) ◽  
pp. L527-L539 ◽  
Author(s):  
Ying Dong Xu ◽  
Jiesong Hua ◽  
Alice Mui ◽  
Robert O'Connor ◽  
Gary Grotendorst ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Inflammatory Cells ◽  
Alveolar Epithelial Cells ◽  
Biologically Active ◽  
Aberrant Expression ◽  
Alveolar Epithelial ◽  
Fibrotic Lung Disease ◽  
Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is a progressive fatal fibrotic lung disease. Transforming growth factor (TGF)-β1 is present in a biologically active conformation in the epithelial cells lining lesions with advanced IPF. To determine the role of aberrant expression of biologically active TGF-β1 by alveolar epithelial cells (AECs), the AECs of explanted normal rat lungs were transfected with the TGF-β1 gene using the retrovirus pMX-L-s223,225-TGF-β1. In situ hybridization using a digoxigenin-labeled cDNA of the puromycin resistance gene contained in the pMX demonstrated that pMX-L-s233,225-TGF-β1 was selectively transfected into AECs of the explants. Conditioned media overlying explants obtained 7 days after being treated with pMX-L-s223,225-TGF-β1 contained 14.5 ± 3.15 pg/ml of active TGF-β1. With the use of Masson's trichrome staining of explant sections obtained 14 days after transfection, there were lesions similar to those in IPF, characterized by type II AEC hyperplasia, interstitial thickening, extensive increase in interstitial and subepithelial collagen, an increase in the number of fibroblasts, and areas resembling fibroblast buds. Collagens I, III, IV, and V and fibronectin were increased in explants treated with pMX-L-s223,225-TGF-β1. The findings in the current study suggest that IPF may be a disorder of epithelial cells and not inflammatory cells.

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