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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2023
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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. |
format | Online Article Text |
id | pubmed-10188457 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
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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