ArticleBiomedicines2022
Angiopoietin-2 Inhibition of Thrombomodulin-Mediated Anticoagulation-A Novel Mechanism That May Contribute to Hypercoagulation in Critically Ill COVID-19 Patients.
Article in Biomedicines, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
20 citing papers in PubMed, 1 synthesis or guideline pooled it, 24 citations in OpenAlex.
- Endotheliopathy in Acute COVID-19 and Long COVID.International journal of molecular sciences · 2023Pooled it
- Phase 2 randomised placebo-controlled trial of spironolactone and dexamethasone versus dexamethasone in COVID-19 hospitalised patients in Delhi.BMC infectious diseases · 2023Trial
- Angiopoietin-2 and Progressive Kidney Disease.Journal of the American Society of Nephrology : JASN · 2026Article
- Unveiling the role of ANGPT2 in esophageal cancer: A prognostic factor and potential oncogene.Oncology reports · 2026Article
- Renal microthrombosis and thrombomodulin deficiency in COVID-19-associated acute kidney injury.BMC nephrology · 2026Observational
- Role of Tie-2 Axis in Sepsis: A Potential Therapeutic Target.Journal of cellular and molecular medicine · 2025Review
- Thrombomodulin resistance as a novel prothrombotic pathway in COVID-19.Scientific reports · 2025Article
- Current and novel biomarkers in cardiogenic shock.European journal of heart failure · 2025Review
- Enhanced prediction of thrombotic events in hospitalized COVID-19 patients with soluble thrombomodulin.PloS one · 2025Article
- Cellular Mechanisms of Lung Injury: Current Perspectives.Clinics in chest medicine · 2024Review
- Angiopoietin2 is associated with coagulation activation and tissue factor expression in extracellular vesicles in COVID-19.Frontiers in medicine · 2024Article
- Organotypic heterogeneity in microvascular endothelial cell responses in sepsis-a molecular treasure trove and pharmacological Gordian knot.Frontiers in medicine · 2023Review
- Association of Ang/Tie2 pathway mediators with endothelial barrier integrity and disease severity in COVID-19.Frontiers in physiology · 2023Article
- Dysregulated Hemostasis and Immunothrombosis in Cerebral Cavernous Malformations.International journal of molecular sciences · 2022Review
- Antithrombin as Therapeutic Intervention against Sepsis-Induced Coagulopathy and Disseminated Intravascular Coagulation: Lessons Learned from COVID-19-Associated Coagulopathy.International journal of molecular sciences · 2022Review
- Gene Networks of Hyperglycemia, Diabetic Complications, and Human Proteins Targeted by SARS-CoV-2: What Is the Molecular Basis for Comorbidity?International journal of molecular sciences · 2022Article
- High-mobility group box 1 (HMGB1) in COVID-19: extrapolation of dangerous liaisons.Inflammopharmacology · 2022Review
- Heparan sulfate mimetic fucoidan restores the endothelial glycocalyx and protects against dysfunction induced by serum of COVID-19 patients in the intensive care unit.ERJ open research · 2022Article
- Neutrophil Extracellular Traps (NETs) and Covid-19: A new frontiers for therapeutic modality.International immunopharmacology · 2022Review
- TIM3+ TRBV11-2 T cells and IFNγ signature in patrolling monocytes and CD16+ NK cells delineate MIS-C.The Journal of experimental medicine · 2022Article
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.