Cargando…
Angiopoietin-2 Inhibition of Thrombomodulin-Mediated Anticoagulation—A Novel Mechanism That May Contribute to Hypercoagulation in Critically Ill COVID-19 Patients
Hypercoagulation and endothelial dysfunction play central roles in severe forms of COVID-19 infections, but the molecular mechanisms involved are unclear. Increased plasma levels of the inflammatory cytokine and TIE2 receptor antagonist Angiopoietin-2 were reported in severely ill COVID-19 patients....
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9220312/ https://www.ncbi.nlm.nih.gov/pubmed/35740360 http://dx.doi.org/10.3390/biomedicines10061333 |
_version_ | 1784732342902849536 |
---|---|
author | Hultström, Michael Fromell, Karin Larsson, Anders Persson, Barbro Nilsson, Bo Quaggin, Susan E. Betsholtz, Christer Frithiof, Robert Lipcsey, Miklos Jeansson, Marie |
author_facet | Hultström, Michael Fromell, Karin Larsson, Anders Persson, Barbro Nilsson, Bo Quaggin, Susan E. Betsholtz, Christer Frithiof, Robert Lipcsey, Miklos Jeansson, Marie |
author_sort | Hultström, Michael |
collection | PubMed |
description | Hypercoagulation and endothelial dysfunction play central roles in severe forms of COVID-19 infections, but the molecular mechanisms involved are unclear. Increased plasma levels of the inflammatory cytokine and TIE2 receptor antagonist Angiopoietin-2 were reported in severely ill COVID-19 patients. In vitro experiments suggest that Angiopoietin-2 bind and inhibits thrombomodulin. Thrombomodulin is expressed on the luminal surface of endothelial cells where it is an important member of the intrinsic anticoagulant pathway through activation of protein C. Using clinical data, mouse models, and in vitro assays, we tested if Angiopoietin-2 plays a causal role in COVID-19-associated hypercoagulation through direct inhibition of thrombin/thrombomodulin-mediated physiological anticoagulation. Angiopoietin-2 was measured in 61 patients at admission, and after 10 days in the 40 patients remaining in the ICU. We found that Angiopoietin-2 levels were increased in COVID-19 patients in correlation with disease severity, hypercoagulation, and mortality. In support of a direct effect of Angiopoietin-2 on coagulation, we found that injected Angiopoietin-2 in mice associated to thrombomodulin and resulted in a shortened tail bleeding time, decreased circulating levels of activated protein C, and increased plasma thrombin/antithrombin complexes. Conversely, bleeding time was increased in endothelial-specific Angiopoietin-2 knockout mice, while knockout of Tie2 had no effect on tail bleeding. Using in vitro assays, we found that Angiopoietin-2 inhibited thrombomodulin-mediated anticoagulation and protein C activation in human donor plasma. Our data suggest a novel in vivo mechanism for Angiopoietin-2 in COVID-19-associated hypercoagulation, implicating that Angiopoietin-2 inhibitors may be effective in the treatment of hypercoagulation in severe COVID-19 infection. |
format | Online Article Text |
id | pubmed-9220312 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-92203122022-06-24 Angiopoietin-2 Inhibition of Thrombomodulin-Mediated Anticoagulation—A Novel Mechanism That May Contribute to Hypercoagulation in Critically Ill COVID-19 Patients Hultström, Michael Fromell, Karin Larsson, Anders Persson, Barbro Nilsson, Bo Quaggin, Susan E. Betsholtz, Christer Frithiof, Robert Lipcsey, Miklos Jeansson, Marie Biomedicines Article Hypercoagulation and endothelial dysfunction play central roles in severe forms of COVID-19 infections, but the molecular mechanisms involved are unclear. Increased plasma levels of the inflammatory cytokine and TIE2 receptor antagonist Angiopoietin-2 were reported in severely ill COVID-19 patients. In vitro experiments suggest that Angiopoietin-2 bind and inhibits thrombomodulin. Thrombomodulin is expressed on the luminal surface of endothelial cells where it is an important member of the intrinsic anticoagulant pathway through activation of protein C. Using clinical data, mouse models, and in vitro assays, we tested if Angiopoietin-2 plays a causal role in COVID-19-associated hypercoagulation through direct inhibition of thrombin/thrombomodulin-mediated physiological anticoagulation. Angiopoietin-2 was measured in 61 patients at admission, and after 10 days in the 40 patients remaining in the ICU. We found that Angiopoietin-2 levels were increased in COVID-19 patients in correlation with disease severity, hypercoagulation, and mortality. In support of a direct effect of Angiopoietin-2 on coagulation, we found that injected Angiopoietin-2 in mice associated to thrombomodulin and resulted in a shortened tail bleeding time, decreased circulating levels of activated protein C, and increased plasma thrombin/antithrombin complexes. Conversely, bleeding time was increased in endothelial-specific Angiopoietin-2 knockout mice, while knockout of Tie2 had no effect on tail bleeding. Using in vitro assays, we found that Angiopoietin-2 inhibited thrombomodulin-mediated anticoagulation and protein C activation in human donor plasma. Our data suggest a novel in vivo mechanism for Angiopoietin-2 in COVID-19-associated hypercoagulation, implicating that Angiopoietin-2 inhibitors may be effective in the treatment of hypercoagulation in severe COVID-19 infection. MDPI 2022-06-06 /pmc/articles/PMC9220312/ /pubmed/35740360 http://dx.doi.org/10.3390/biomedicines10061333 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Hultström, Michael Fromell, Karin Larsson, Anders Persson, Barbro Nilsson, Bo Quaggin, Susan E. Betsholtz, Christer Frithiof, Robert Lipcsey, Miklos Jeansson, Marie Angiopoietin-2 Inhibition of Thrombomodulin-Mediated Anticoagulation—A Novel Mechanism That May Contribute to Hypercoagulation in Critically Ill COVID-19 Patients |
title | Angiopoietin-2 Inhibition of Thrombomodulin-Mediated Anticoagulation—A Novel Mechanism That May Contribute to Hypercoagulation in Critically Ill COVID-19 Patients |
title_full | Angiopoietin-2 Inhibition of Thrombomodulin-Mediated Anticoagulation—A Novel Mechanism That May Contribute to Hypercoagulation in Critically Ill COVID-19 Patients |
title_fullStr | Angiopoietin-2 Inhibition of Thrombomodulin-Mediated Anticoagulation—A Novel Mechanism That May Contribute to Hypercoagulation in Critically Ill COVID-19 Patients |
title_full_unstemmed | Angiopoietin-2 Inhibition of Thrombomodulin-Mediated Anticoagulation—A Novel Mechanism That May Contribute to Hypercoagulation in Critically Ill COVID-19 Patients |
title_short | Angiopoietin-2 Inhibition of Thrombomodulin-Mediated Anticoagulation—A Novel Mechanism That May Contribute to Hypercoagulation in Critically Ill COVID-19 Patients |
title_sort | angiopoietin-2 inhibition of thrombomodulin-mediated anticoagulation—a novel mechanism that may contribute to hypercoagulation in critically ill covid-19 patients |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9220312/ https://www.ncbi.nlm.nih.gov/pubmed/35740360 http://dx.doi.org/10.3390/biomedicines10061333 |
work_keys_str_mv | AT hultstrommichael angiopoietin2inhibitionofthrombomodulinmediatedanticoagulationanovelmechanismthatmaycontributetohypercoagulationincriticallyillcovid19patients AT fromellkarin angiopoietin2inhibitionofthrombomodulinmediatedanticoagulationanovelmechanismthatmaycontributetohypercoagulationincriticallyillcovid19patients AT larssonanders angiopoietin2inhibitionofthrombomodulinmediatedanticoagulationanovelmechanismthatmaycontributetohypercoagulationincriticallyillcovid19patients AT perssonbarbro angiopoietin2inhibitionofthrombomodulinmediatedanticoagulationanovelmechanismthatmaycontributetohypercoagulationincriticallyillcovid19patients AT nilssonbo angiopoietin2inhibitionofthrombomodulinmediatedanticoagulationanovelmechanismthatmaycontributetohypercoagulationincriticallyillcovid19patients AT quagginsusane angiopoietin2inhibitionofthrombomodulinmediatedanticoagulationanovelmechanismthatmaycontributetohypercoagulationincriticallyillcovid19patients AT betsholtzchrister angiopoietin2inhibitionofthrombomodulinmediatedanticoagulationanovelmechanismthatmaycontributetohypercoagulationincriticallyillcovid19patients AT frithiofrobert angiopoietin2inhibitionofthrombomodulinmediatedanticoagulationanovelmechanismthatmaycontributetohypercoagulationincriticallyillcovid19patients AT lipcseymiklos angiopoietin2inhibitionofthrombomodulinmediatedanticoagulationanovelmechanismthatmaycontributetohypercoagulationincriticallyillcovid19patients AT jeanssonmarie angiopoietin2inhibitionofthrombomodulinmediatedanticoagulationanovelmechanismthatmaycontributetohypercoagulationincriticallyillcovid19patients |