Biomarkers of endothelial dysfunction are associated with poor outcome in COVID‐19 patients: A systematic review and meta‐analysis

Abstract

Numerous studies have linked coronavirus disease 2019 (COVID‐19) with endothelial dysfunction and reported elevated levels of endothelial biomarkers in this disease. We conducted a systematic review and meta‐analysis of the published evidence in this respect. A systematic literature search of PubMed and Scopus databases was performed to find studies investigating biomarkers of endothelial dysfunction in COVID‐19 patients. Pooled standardized mean differences and their 95% confidence intervals were calculated for each biomarker using random effect model. 74 studies with 7668 patients were included. In comparison to patients with good outcome, those with poor outcome had higher levels of von Willebrand factor (vWF) (SMD: 0.83, 95% CI: 0.59–1.07, p < 0.00001), vWF:ADAMTS13 (1.23, (0.77–1.7), p < 0.00001), angiopoietin‐2 (Ang‐2) (1.06 (0.6–1.51), p < 0.0001), E‐selectin (1.09 (0.55–1.63), p < 0.0001), P‐selectin (0.59 (0.24–0.94), p = 0.001), syndecan‐1 (0.99 (0.6–1.37), p < 0.00001), mid‐regional pro‐adrenomedullin (MR‐proADM) (1.52 (1.35–1.68), p < 0.00001), vascular endothelial growth factor (0.27 (0.02–0.53), p = 0.03), soluble fms‐like tyrosine kinase‐1 (sFLT‐1) (1.93 (0.65–3.21), p = 0.03) and lower levels of ADAMTS13 antigen (−0.69 (−0.9 to −0.47) p < 0.00001) and activity (−0.84 (−1.06 to −0.61) p < 0.0000). Plasminogen activator inhibitor‐1 and tissue plasminogen activator levels were not different between the two groups (p < 0.05). There were elevated levels of endothelial dysfunction biomarkers in COVID‐19 patients with poor outcome, indicating their possible role in disease severity and prognosis. In particular, MR‐proADM, vWF, syndecan‐1 and sFLT‐1 showed a significant association with poor outcome in these patients.

MR-proADM as Prognostic Factor of Outcome in COVID-19 Patients

“…This may be explained by its higher specificity for endothelial damage, which in turn is associated with the severest forms of the disease [ 17 , 18 ]. The potential of endothelial-derived serum proteins for a more accurate prognostic estimation in this field is further sustained by studies investigating the performance of other biomarkers (such as serum von Willebrand factor, endocan and vascular endothelial growth factor) in predicting mortality, need for IC or major thrombotic events [ 32 , 33 , 34 , 35 ]. Unfortunately, we did not include evaluation of these biomarkers in our study protocol, so we were unable to compare MR-proADM values with other markers of endothelial dysfunction.…”

COVID-19 vaccine adverse events: Evaluating the pathophysiology from an undersulfated and degraded glycocalyx perspective

“…Seeing that vaccine recipients with only brief and mild symptoms showed elevated levels of sdc1, compared to a 2-fold increase in sdc1 level in VITT patients, it is clear that some initial endotheliopathy has developed, which then increased significantly in the VITT group 5 . As in the case of severe COVID-19 disease, therefore, increased levels of soluble En activation markers, such as sdc1, endocan, selectin and angiopoietin-2, can be expected in vaccine recipients with severe AEs 30,190 . The effect of DNA and mRNA vaccines on the endothelium warrants further research.…”

“…AST and ALT levels were elevated in mice treated with PEG-LNP 36 . To identify EnGL damage, elevated plasma levels of sdc1, endocan, CS, HA, and HS would be useful markers 221 , as in the case of COVID-19 30 .…”

Neutrophil degranulation, endothelial and metabolic dysfunction in unvaccinated long COVID patients

“…A persistently abnormal inflammatory cytokine profile has been described also in long COVID patients up to 8 months, as compared with COVID‐19 asymptomatic survivors 15 . Potential candidates are a number of molecules involving neutrophil degranulation, 16–18 endothelial 19–21 and metabolic dysfunction (i.e. adipokines 22–25 ), but the ultimate role of such mediators is still unclear.…”