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Angiopoietin-2 Inhi...
Angiopoietin-2 Inhibition of Thrombomodulin-Mediated Anticoagulation : A Novel Mechanism That May Contribute to Hypercoagulation in Critically Ill COVID-19 Patients
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- Hultström, Michael, 1978- (författare)
- Uppsala universitet,Integrativ Fysiologi,Anestesiologi och intensivvård
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- Fromell, Karin (författare)
- Uppsala universitet,Klinisk immunologi
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- Larsson, Anders (författare)
- Uppsala universitet,Klinisk kemi
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- Persson, Barbro (författare)
- Uppsala universitet,Klinisk immunologi
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- Nilsson, Bo (författare)
- Uppsala universitet,Klinisk immunologi
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- Quaggin, Susan E. (författare)
- Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Division of Nephrology and Hypertension, Northwestern University, Chicago, IL 60611, USA
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- Betsholtz, Christer (författare)
- Uppsala universitet,Vaskulärbiologi,Karolinska institutet, Huddinge, Sweden
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- Frithiof, Robert (författare)
- Uppsala universitet,Anestesiologi och intensivvård
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- Lipcsey, Miklós (författare)
- Uppsala universitet,Hedenstiernalaboratoriet
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- Jeansson, Marie (författare)
- Karolinska Institutet,Uppsala universitet,Vaskulärbiologi,Karolinska institutet, Huddinge, Sweden
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(creator_code:org_t)
- 2022-06-06
- 2022
- Engelska.
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Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:6
- Relaterad länk:
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https://doi.org/10.3...
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https://uu.diva-port... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.3...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Kardiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)
Nyckelord
- COVID-19
- hypercoagulation
- thrombomodulin
- Angiopoietin-2
- endothelial dysfunction
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
Hitta via bibliotek
Till lärosätets databas
- Av författaren/redakt...
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Hultström, Micha ...
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Fromell, Karin
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Larsson, Anders
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Persson, Barbro
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Nilsson, Bo
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Quaggin, Susan E ...
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visa fler...
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Betsholtz, Chris ...
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Frithiof, Robert
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Lipcsey, Miklós
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Jeansson, Marie
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visa färre...
- Om ämnet
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Kardiologi
- Artiklar i publikationen
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Biomedicines
- Av lärosätet
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Uppsala universitet
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Karolinska Institutet