Background: Angiotensin-converting enzyme 2 (ACE2) is the main entry receptor for SARS-CoV-2, but how virus-receptor interactions affect the RAS-balance and COVID-19 pathology is largely unknown.

Aims: To measure soluble ACE2 (sACE2) and sACE during and after COVID-19 and investigate associations with risk factors for severe COVID-19, outcome and markers of thromboinflammation. 

Methods: Plasma sACE2 and sACE were measured by ELISA in 114 hospital-treated patients with COVID-19 and 10 healthy controls. Follow-up samples after four months were available for 58/114 patients. Markers of inflammation and endothelial dysfunction during COVID-19 were available from routine testing or had been previously determined (VWF, factor VIII, D-dimer, IL-6, TNFa and PAI-1).

Results: Levels of sACE2 were higher in COVID-19 patients than in healthy controls, median 5.0 (interquartile range 2.8-11.8) ng/ml versus 1.4 (1.1-1.6) ng/ml, p < 0.0001. sACE2 was higher in men than women, but was not affected by other risk factors for severe COVID-19. sACE2 decreased to 2.3 (1.6-3.9) ng/ml at follow-up, p < 0.0001, but remained higher than in healthy controls, p=0.012. Follow-up sACE2 was associated with several risk factors for severe COVID-19 and treatment with RAS-inhibition. sACE was marginally lower during COVID-19 compared with four months later 57 (45-70) ng/ml versus 72 (52-87) ng/ml, p=0.008. Levels of sACE2 and sACE were not associated with survival or disease severity (care level, respiratory support). sACE2 during COVID-19 correlated positively with monocyte count and platelet count, while sACE was negatively correlated with both. sACE2 correlated with VWF, fVIII and D-dimer, while sACE correlated with IL-6, TNFα and PAI-1.

sACE2 concentrations for 10 healthy controls (HC, left), 114 patients with COVID-19 (middle) and 58 patients at follow-up after four months (right). The differences between COVID-19 patients and HC were analyzed by Mann-Whitney U-test. The difference between acute COVID-19 and follow-up four months later was analyzed by Wilcoxon signed rank tests. ***) p < 0.0001, *) p < 0.05.

Spearman correlation coefficients for significant correlations between acute sACE2 respectively sACE and markers of inflammation and endothelial dysfunction. Correlation coefficients with│r│> 0.25 are reported. N: number of patients analyzed. WBC: white blood cell count; VWF: von Willebrand factor; PAI-1: plasminogen activator inhibitor 1; IL-6: interleukin 6; TNFα: tumor necrosis factor α.*) p 0.01-0.049, **) p 0.001-0.0099, ***) p < 0.001.

Conclusions: Shedding of ACE2 is increased and shedding of ACE is marginally decreased in COVID-19. sACE2 and sACE differ distinctly in correlations with markers of thromboinflammation, which may suggest different types of underlying endothelial injury, alternatively release from different cell types or vascular beds. 

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/ace2-ace-and-thromboinflammation-in-covid-19/