Angiopoietin-2 as a marker of endothelial activation is a good predictor factor for intensive care unit admission of COVID-19 patients

Abstract

Background Coronavirus disease-2019 (COVID-19), a respiratory disease has been associated with ischemic complications, coagulation disorders, and an endotheliitis. Objectives To explore endothelial damage and activation-related biomarkers in COVID-19 patients with criteria of hospitalization for referral to intensive care unit (ICU) and/or respiratory worsening. Methods Analysis of endothelial and angiogenic soluble markers in plasma from patients at admission. Results Study enrolled 40 consecutive COVID-19 patients admitted to emergency department that fulfilled criteria for hospitalization. Half of them were admitted in conventional wards without any ICU transfer during hospitalization; whereas the 20 others were directly transferred to ICU. Patients transferred in ICU were more likely to have lymphopenia, decreased SpO2 and increased D-dimer, CRP and creatinine levels. In those patients, soluble E-selectin and angiopoietin-2 were significantly increased (p value at 0.009 and 0.003, respectively). Increase in SELE gene expression (gene coding for E-selectin protein) was confirmed in an independent cohort of 32 patients using a whole blood gene expression profile analysis. In plasma, we found a strong association between angiopoetin-2 and CRP, creatinine and D-dimers (with p value at 0.001, 0.001 and 0.003, respectively). ROC curve analysis identified an Angiopoietin-2 cut-off of 5000 pg/mL as the best predictor for ICU outcome (Se = 80.1%, Sp = 70%, PPV = 72.7%, NPV = 77%), further confirmed in multivariate analysis after adjustment for creatinine, CRP or D-dimers. Conclusion Angiopoietin-2 is a relevant predictive factor for ICU direct admission in COVID-19 patients. This result showing an endothelial activation reinforces the hypothesis of a COVID-19-associated microvascular dysfunction.

D-dimers at hospital admission for COVID-19 are associated with in hospital mortality independently of venous thromboembolism: Insight from a French multicenter cohort study

“…Infection of endothelial cells could therefore induce endothelial lesions triggering massive activation of coagulation and diffuse microthrombotic process impairing renal function and respiratory gas exchanges. We previously described increased numbers of circulating endothelial cells in COVID-19 patients (4) and an association between circulating biomarkers of endothelial activation in COVID-19 and ICU admission (5). Angiopoietin-2 was also inversely correlated to respiratory system compliance in this study, paving the way of relationship between endothelial dysfunction and pulmonary disease severity.…”

“…Indeed, adding a D-dimer cut-off beyond 500 ng/mL to female gender and absence of pneumonia at CT scan could exclude COVID-19 diagnosis with a high sensitivity and speci city (4). Moreover, we and others previously showed that D-dimer level at admission was higher in patients needing ICU referral compared to those who did not require it (5,20).…”

“…COVID-19-induced vascular disease is also associated to an increased level of circulating endothelial cells (4). Moreover, plasma biomarkers of endothelial lesion are also predictive factors for future referral to intensive care unit (ICU), reinforcing the hypothesis of a COVID-19-associated vascular injury (5). SARS-CoV-2 virus has been shown to infect blood vessels and induce vascular damage (6) and brin deposits in lung but also in kidney has been found in vascular beds.…”

Curative anticoagulation prevents endothelial lesion in COVID‐19 patients

“…The hypothesis of microthrombi in kidneys was also suggested in COVID‐19 patients because high creatinine level was correlated with D‐dimers above 500 ng/mL 9 . Finally, endothelial dysfunction might also play a role in the incidence of severe respiratory symptoms and viral systemic dissemination 10 . Indeed, the SARS‐CoV‐2 receptor ACE2 is strongly expressed on endothelial cells 11 .…”

From SARS-CoV-2 hematogenous spreading to endothelial dysfunction: clinical-histopathological study of cutaneous signs of COVID-19.

“…Indeed, SARS-CoV-2 can infect cells by angiotensin-converting enzyme 2 receptor, largely expressed in endothelial cells. 6,7 An endotheliitis has been hypothesized as the origin of compromised microcirculation affecting lungs and kidneys in COVID-19. 7 Endothelial cells' infection could trigger activation of coagulation and diffuse microthrombosis.…”