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ACE2, ACE and Thromboinflammation in COVID-19

A. Lundström1, L. Ziegler1, S. Havervall1, A.-S. Rudberg1, F. Von Meijenfeldt2, T. Lisman2, N. Mackman3, P. Sandén1, C. Thålin1

1Karolinska Institutet, Dept of Clinical Sciences Danderyd Hospital, Stockholm, Sweden, 2University of Groningen, Dept of Surgery, Groningen, Netherlands, 3University of North Carolina at Chapel Hill, Div of Hematology, Dept of Medicine, Chapel Hill, United States

Abstract Number: PB0190

Meeting: ISTH 2021 Congress

Theme: COVID and Coagulation » COVID and Coagulation, Clinical

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.

sACE2 sACE
White blood cell count 0.26* NS
Monocyte count 0.39*** -0.26*
Platelet count 0.32** -0.34**
VWF 0.36*** NS
Factor VIII 0.55*** NS
D-dimer 0.30** NS
IL-6 NS 0.43***
TNFa NS 0.43***
PAI-1 NS 0.44***

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. 

To cite this abstract in AMA style:

Lundström A, Ziegler L, Havervall S, Rudberg A-, Von Meijenfeldt F, Lisman T, Mackman N, Sandén P, Thålin C. ACE2, ACE and Thromboinflammation in COVID-19 [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/ace2-ace-and-thromboinflammation-in-covid-19/. Accessed August 16, 2022.

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