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SARS‐CoV‐2 infection results in upregulation of Plasminogen Activator Inhibitor‐1 and Neuroserpin in the lungs, and an increase in fibrinolysis inhibitors associated with disease severity

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection results in coagulation activation although it is usually not associated with consumption coagulopathy. D‐dimers are also commonly elevated despite systemic hypofibrinolysis. To understand these unusual features of coronavirus dis...

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Autores principales: Toomer, Kevin H., Gerber, Gloria F., Zhang, Yifan, Daou, Laetitia, Tushek, Michael, Hooper, Jody E., Francischetti, Ivo M. B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10188457/
https://www.ncbi.nlm.nih.gov/pubmed/37206290
http://dx.doi.org/10.1002/jha2.654
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author Toomer, Kevin H.
Gerber, Gloria F.
Zhang, Yifan
Daou, Laetitia
Tushek, Michael
Hooper, Jody E.
Francischetti, Ivo M. B.
author_facet Toomer, Kevin H.
Gerber, Gloria F.
Zhang, Yifan
Daou, Laetitia
Tushek, Michael
Hooper, Jody E.
Francischetti, Ivo M. B.
author_sort Toomer, Kevin H.
collection PubMed
description Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection results in coagulation activation although it is usually not associated with consumption coagulopathy. D‐dimers are also commonly elevated despite systemic hypofibrinolysis. To understand these unusual features of coronavirus disease 2019 (COVID‐19) coagulopathy, 64 adult patients with SARS‐CoV‐2 infection (36 moderate and 28 severe) and 16 controls were studied. We evaluated the repertoire of plasma protease inhibitors (Serpins, Kunitz, Kazal, Cystatin‐like) targeting the fibrinolytic system: Plasminogen Activator Inhibitor‐1 (PAI‐1), Tissue Plasminogen Activator/Plasminogen Activator Inhibitor‐1 complex (t‐PA/PAI‐1), α‐2‐Antiplasmin, Plasmin‐α2‐Antiplasmin Complex, Thrombin‐activatable Fibrinolysis Inhibitor (TAFI)/TAFIa, Protease Nexin‐1 (PN‐1), and Neuroserpin (the main t‐PA inhibitor of the central nervous system). Inhibitors of the common (Antithrombin, Thrombin‐antithrombin complex, Protein Z [PZ]/PZ inhibitor, Heparin Cofactor II, and α2‐Macroglobulin), Protein C ([PC], Protein C inhibitor, and Protein S), contact (Kallistatin, Protease Nexin‐2/Amyloid Beta Precursor Protein, and α‐1‐Antitrypsin), and complement (C1‐Inhibitor) pathways, in addition to Factor XIII, Histidine‐rich glycoprotein (HRG) and Vaspin were also investigated by enzyme‐linked immunosorbent assay. The association of these markers with disease severity was evaluated by logistic regression. Pulmonary expression of PAI‐1 and Neuroserpin in the lungs from eight post‐mortem cases was assessed by immunohistochemistry. Results show that six patients (10%) developed thrombotic events, and mortality was 11%. There was no significant reduction in plasma anticoagulants, in keeping with a compensated state. However, an increase in fibrinolysis inhibitors (PAI‐1, Neuroserpin, PN‐1, PAP, and t‐PA/PAI‐1) was consistently observed, while HRG was reduced. Furthermore, these markers were associated with moderate and/or severe disease. Notably, immunostains demonstrated overexpression of PAI‐1 in epithelial cells, macrophages, and endothelial cells of fatal COVID‐19, while Neuroserpin was found in intraalveolar macrophages only. These results imply that the lungs in SARS‐CoV‐2 infection provide anti‐fibrinolytic activity resulting in a shift toward a local and systemic hypofibrinolytic state predisposing to (immuno)thrombosis, often in a background of compensated disseminated intravascular coagulation.
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spelling pubmed-101884572023-05-18 SARS‐CoV‐2 infection results in upregulation of Plasminogen Activator Inhibitor‐1 and Neuroserpin in the lungs, and an increase in fibrinolysis inhibitors associated with disease severity Toomer, Kevin H. Gerber, Gloria F. Zhang, Yifan Daou, Laetitia Tushek, Michael Hooper, Jody E. Francischetti, Ivo M. B. EJHaem Sickle Cell, Thrombosis, and Classical Haematology Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection results in coagulation activation although it is usually not associated with consumption coagulopathy. D‐dimers are also commonly elevated despite systemic hypofibrinolysis. To understand these unusual features of coronavirus disease 2019 (COVID‐19) coagulopathy, 64 adult patients with SARS‐CoV‐2 infection (36 moderate and 28 severe) and 16 controls were studied. We evaluated the repertoire of plasma protease inhibitors (Serpins, Kunitz, Kazal, Cystatin‐like) targeting the fibrinolytic system: Plasminogen Activator Inhibitor‐1 (PAI‐1), Tissue Plasminogen Activator/Plasminogen Activator Inhibitor‐1 complex (t‐PA/PAI‐1), α‐2‐Antiplasmin, Plasmin‐α2‐Antiplasmin Complex, Thrombin‐activatable Fibrinolysis Inhibitor (TAFI)/TAFIa, Protease Nexin‐1 (PN‐1), and Neuroserpin (the main t‐PA inhibitor of the central nervous system). Inhibitors of the common (Antithrombin, Thrombin‐antithrombin complex, Protein Z [PZ]/PZ inhibitor, Heparin Cofactor II, and α2‐Macroglobulin), Protein C ([PC], Protein C inhibitor, and Protein S), contact (Kallistatin, Protease Nexin‐2/Amyloid Beta Precursor Protein, and α‐1‐Antitrypsin), and complement (C1‐Inhibitor) pathways, in addition to Factor XIII, Histidine‐rich glycoprotein (HRG) and Vaspin were also investigated by enzyme‐linked immunosorbent assay. The association of these markers with disease severity was evaluated by logistic regression. Pulmonary expression of PAI‐1 and Neuroserpin in the lungs from eight post‐mortem cases was assessed by immunohistochemistry. Results show that six patients (10%) developed thrombotic events, and mortality was 11%. There was no significant reduction in plasma anticoagulants, in keeping with a compensated state. However, an increase in fibrinolysis inhibitors (PAI‐1, Neuroserpin, PN‐1, PAP, and t‐PA/PAI‐1) was consistently observed, while HRG was reduced. Furthermore, these markers were associated with moderate and/or severe disease. Notably, immunostains demonstrated overexpression of PAI‐1 in epithelial cells, macrophages, and endothelial cells of fatal COVID‐19, while Neuroserpin was found in intraalveolar macrophages only. These results imply that the lungs in SARS‐CoV‐2 infection provide anti‐fibrinolytic activity resulting in a shift toward a local and systemic hypofibrinolytic state predisposing to (immuno)thrombosis, often in a background of compensated disseminated intravascular coagulation. John Wiley and Sons Inc. 2023-02-23 /pmc/articles/PMC10188457/ /pubmed/37206290 http://dx.doi.org/10.1002/jha2.654 Text en © 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Sickle Cell, Thrombosis, and Classical Haematology
Toomer, Kevin H.
Gerber, Gloria F.
Zhang, Yifan
Daou, Laetitia
Tushek, Michael
Hooper, Jody E.
Francischetti, Ivo M. B.
SARS‐CoV‐2 infection results in upregulation of Plasminogen Activator Inhibitor‐1 and Neuroserpin in the lungs, and an increase in fibrinolysis inhibitors associated with disease severity
title SARS‐CoV‐2 infection results in upregulation of Plasminogen Activator Inhibitor‐1 and Neuroserpin in the lungs, and an increase in fibrinolysis inhibitors associated with disease severity
title_full SARS‐CoV‐2 infection results in upregulation of Plasminogen Activator Inhibitor‐1 and Neuroserpin in the lungs, and an increase in fibrinolysis inhibitors associated with disease severity
title_fullStr SARS‐CoV‐2 infection results in upregulation of Plasminogen Activator Inhibitor‐1 and Neuroserpin in the lungs, and an increase in fibrinolysis inhibitors associated with disease severity
title_full_unstemmed SARS‐CoV‐2 infection results in upregulation of Plasminogen Activator Inhibitor‐1 and Neuroserpin in the lungs, and an increase in fibrinolysis inhibitors associated with disease severity
title_short SARS‐CoV‐2 infection results in upregulation of Plasminogen Activator Inhibitor‐1 and Neuroserpin in the lungs, and an increase in fibrinolysis inhibitors associated with disease severity
title_sort sars‐cov‐2 infection results in upregulation of plasminogen activator inhibitor‐1 and neuroserpin in the lungs, and an increase in fibrinolysis inhibitors associated with disease severity
topic Sickle Cell, Thrombosis, and Classical Haematology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10188457/
https://www.ncbi.nlm.nih.gov/pubmed/37206290
http://dx.doi.org/10.1002/jha2.654
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