Angiopoietin-2 is predictive for intensive care unit admission of patients with SARS-CoV-2
Studies show that Angiopoietin-2 is a strong predictor in patients with SARS-CoV-2
Two research teams find that increased levels of the proinflammatory cytokine Angiopoietin-2 is crucial to predict transfer to the intensive care units and is responsible for hypercoagulation observed in critically ill patients infected with SARS-CoV-2.
Angiopoietin-2 as a marker of endothelial activation is a good predictor factor for intensive care unit admission of … patients. Smadja DM et al., Angiogenesis, 2020;1-10. Full text
Elevated Angiopoietin-2 inhibits thrombomodulin-mediated anticoagulation in critically ill … patients. Hultstrom M et al., MedRxiv preprint server, 2021. Full text
SARS-CoV-2 infection has a diverse range of symptoms and may cause severe illness, in particular in patients with cardiovascular risk factors (1).
The infection is associated with an increase in procoagulant factors that have been shown to be associated with a higher mortality in patients with SARS-CoV-2 pneumonia (2). Pulmonary embolism and microvascular thrombosis in the lungs have been described in several reports in acute respiratory distress syndrome as well as in patients infected with SARS-CoV-2 (3).
Endothelial damage and inflammation in SARS-CoV-2 infection
The inflammatory cytokine storm occurring in patients infected with SARS-CoV-2, leads to the recruitment of leukocytes which damage the capillary endothelium. The disruption of the thromboprotective effect of endothelial cells likely leads to microvascular thrombosis. Thus, the endothelial damage and inflammation in several organs in patients with SARS-CoV-2 infection is a direct consequence of viral involvement and of the host inflammatory response (4).
Despite the routine thrombosis prophylaxis as standard of care treatment, the major complication in patients infected with SARS-CoV-2 is the hyperactivation of the coagulation system indicating a poor prognosis among these patients in intensive care (5).
Angiopoietin-2 (ANG2) is a soluble marker of endothelial activation
Angiopoietin-2 is a soluble protein that is involved in the regulation of vascular integrity, quiescence, and inflammation (6). ANG2 contributes to the formation of new vasculature. During angiogenesis, ANG2 exerts its effects via the angiopoietin-1/TIE2 receptor signaling system on endothelial cells. Disruption of this signaling leads to the loss of endothelial integrity. In consequence, the endothelium responds to various pro-inflammatory cytokines and growth factors.
Thus, Angiopoietin-2 is a soluble marker of endothelial activation and is involved in hemostasis, thrombo-inflammatory events or sepsis (7, 8).
ANG2 is a crucial factor to predict transfer to the intensive care unit
ANG2 induces inflammation and vascular hyperpermeability and correlates with adverse outcomes in several critical care syndromes (9). In patients infected with SARS-CoV-2, ANG2 was recently reported by Smadja and colleagues to be a relevant factor to predict transfer to the intensive care unit as it was associated with poor lung compliance (7). Thus, showing that endothelial activation reinforces the hypothesis of an infection-associated microvascular dysfunction.
Angiopoietin-2 inhibits anticoagulation in critically ill patients infected with SARS-CoV-2
Based on the above findings, Hulstrom and colleagues investigated if the highly elevated inflammatory cytokine ANG2 levels observed in SARS-CoV-2 patients had a direct effect on the coagulation system (10). Animal models and in vitro assays were included in their investigation. As thrombomodulin is expressed on the surface of endothelial cells where it binds thrombin and inhibits the intrinsic coagulation process, the scientists observed that ANG2 inhibits thrombomodulin-mediated anticoagulation and activation of protein C in human donor plasma. Furthermore, the increased ANG2 levels in patients infected with SARS-CoV-2 correlated with disease severity, hypercoagulation, and mortality by promoting hypercoagulation.
Revealing this novel mechanism for ANGPT2 in hypercoagulation the scientists suggest that inhibition of Angiopoietin-2 may be tested for treating severe cases of SARS-CoV-2 infection, as well as in certain other conditions, including sepsis (10).
Did you know?
Angiopoietin-2 (ANG-2) can reliably be measured by ELISA in human serum, plasma and urine samples with Biomedica’s fully validated assay kit. Only 20 µl of sample volume is required! The kit incorporates characterized epitope mapped antibodies and ready to use standards and controls. The assay range is optimized for clinical samples- no sample dilution required!
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- Clinical course and risk factors for mortality of adult inpatients with … in Wuhan, China: a retrospective cohort study. Zhou F et al., Lancet, 2020; 395(10229):1054-1062. https://pubmed.ncbi.nlm.nih.gov/32171076/ PMID: 32171076
- Abnormal Coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. Tang N et al., J Thromb Haemost, 2020; 18(4): 844-847. https://pubmed.ncbi.nlm.nih.gov/32073213/ PMID: 32073213
- Pulmonary embolism in … patients: awareness of an increased prevalence. Poissy J et al, Circulation, 2020; 14; 142(2):184-186. https://pubmed.ncbi.nlm.nih.gov/32330083/ PMID: 32330083
- Endotheliitis in …. Varga S. Der Pathologe, 2020; 41(Suppl 2):99-102. https://pubmed.ncbi.nlm.nih.gov/33306138/ PMID: 33306138
- … and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection. Al-Samkari H et al., Blood, 2020:136, 489-500. https://pubmed.ncbi.nlm.nih.gov/32492712/ PMID: 32492712
- Role of Angiopoietin-2 in Vascular Physiology and Pathophysiology. Akwii RG et al., Cells, 2019; 8(5): 471. https://pubmed.ncbi.nlm.nih.gov/31108880/ PMID: 31108880
- Angiopoietin-2 as a marker of endothelial activation is a good predictor factor for intensive care unit admission of … patients. Smadja DM et al., Angiogenesis, 2020;1-10. https://pubmed.ncbi.nlm.nih.gov/32458111/ PMID: 32458111
- Angiopoietin 2 levels in the risk stratification and mortality outcome prediction of sepsis-associated coagulopathy. Statz S et al., Clin Appl Thromb Hemost 24(8):1223–1233. https://pubmed.ncbi.nlm.nih.gov/29996658/ PMID: 29996658
- Circulating angiopoietin-2 and the risk of mortality in patients with acute respiratory distress syndrome: a systematic review and meta-analysis of 10 prospective cohort studies. Li F et al., Therapeutic advances in respiratory disease, 2020; 14, 1753466620905274 (2020). https://pubmed.ncbi.nlm.nih.gov/32043429/ PMID: 32043429
- Elevated Angiopoietin-2 inhibits thrombomodulin-mediated anticoagulation in critically ill … patients. Hultstrom M et al., MedRxiv preprint server, 2021. https://www.medrxiv.org/content/10.1101/2021.01.13.21249429v1.full