Patients With COVID-19 Have Elevated Levels of Circulating Extracellular Vesicle Tissue Factor Activity That Is Associated With Severity and Mortality—Brief Report

Rosell, Axel; Havervall, Sebastian; Meijenfeldt, Fien A. von; Hisada, Yohei; Aguilera, Katherina; Grover, Steven P.; Lisman, Ton; Mackman, Nigel; Thålin, Charlotte

doi:10.1161/atvbaha.120.315547

Cited by 181 publications

(211 citation statements)

References 29 publications

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“…Patients treated for COVID-19 at Danderyd Hospital 15 th of April to 11 th of June 2020 were offered participation in the COMMUNITY project, as previously described (31-33). Inclusion criteria were COVID-19 diagnosis, either PCR-confirmed (110 patients) or by clinical presentation and typical radiology (4 patients).…”

Section: Methodsmentioning

confidence: 99%

Soluble angiotensin-converting enzyme 2 is transiently elevated in COVID-19 and correlates with specific inflammatory and endothelial markers

Lundström

Ziegler

Havervall

et al. 2021

Preprint

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Rationale: Angiotensin-converting enzyme 2 (ACE2) is the main entry receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but how SARS-CoV-2 interactions with ACE2 influences the renin-angiotensin system (RAS) in Coronavirus disease 2019 (COVID-19) is unknown. Objective: To measure circulating ACE2 and ACE levels in COVID-19 patients and investigate associations with risk factors, outcome and inflammatory markers. Methods and results: Soluble ACE2 (sACE2) and sACE concentrations were measured by ELISA in plasma samples from 114 hospital-treated COVID-19 patients and 10 healthy controls. Follow-up samples after four months were available for 58/114 patients. Von Willebrand factor (VWF), factor VIII (fVIII), D-dimer, interleukin 6 (IL-6), tumor necrosis factor α and plasminogen activator inhibitor 1 (PAI-1) had previously been determined. 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 were 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 levels were higher with increasing age, BMI, total number of comorbidities, for patients with diabetes and patients on RAS-inhibition. sACE was marginally lower during COVID-19 compared with at follow-up, 57 (45-70) ng/ml versus 72 (52-87) ng/ml, p=0.008. Levels of sACE2 and sACE did not differ depending on survival or disease severity (care level, respiratory support). sACE2 during COVID-19 correlated with VWF, fVIII and D-dimer, while sACE correlated with IL-6, TNFα and PAI-1. Conclusions: sACE2 was transiently elevated in COVID-19, likely due to increased shedding from infected cells. sACE2 and sACE during COVID-19 differed distinctly in their correlations with markers of inflammation and endothelial dysfunction, suggesting release from different cell types and/or vascular beds.

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Section: Methodsmentioning

confidence: 99%

Soluble angiotensin-converting enzyme 2 is transiently elevated in COVID-19 and correlates with specific inflammatory and endothelial markers

Lundström

Ziegler

Havervall

et al. 2021

Preprint

Self Cite

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“…• Patients with coronavirus disease 2019 (COVID- 19) have lower levels of D-dimer than patients with sepsis.…”

Section: Essentialsmentioning

confidence: 99%

Comparison of the coagulopathies associated with COVID‐19 and sepsis

Campbell

Hisada

Denorme

et al. 2021

Research and Practice in Thrombosis and Haemostasis

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“… 32 – 34 The correlation between TF expression and the severity of COVID-19 has been studied both its expression in monocytes 103 and in extracellular vesicles. 104 Platelets from severe COVID-19 patients were able to induce TF expression ex vivo in monocytes from healthy volunteers. 105 TF can increase its expression during hypoxia and generate a thrombotic tendency; phenomenon that is mediated through extracellular RNA activated Toll-like receptor 3-activated protein 1 signaling.…”

Section: Tf In Covid-19mentioning

confidence: 99%

Role of Tissue Factor in the Pathogenesis of COVID-19 and the Possible Ways to Inhibit It

Cañas

Cañas²,

Bautista-Vargas

et al. 2021

Clin Appl Thromb Hemost

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COVID-19 (Coronavirus Disease 2019) is a highly contagious infection and associated with high mortality rates, primarily in elderly; patients with heart failure; high blood pressure; diabetes mellitus; and those who are smokers. These conditions are associated to increase in the level of the pulmonary epithelium expression of angiotensin-converting enzyme 2 (ACE-2), which is a recognized receptor of the S protein of the causative agent SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2). Severe cases are manifested by parenchymal lung involvement with a significant inflammatory response and the development of microvascular thrombosis. Several factors have been involved in developing this prothrombotic state, including the inflammatory reaction itself with the participation of proinflammatory cytokines, endothelial dysfunction/endotheliitis, the presence of antiphospholipid antibodies, and possibly the tissue factor (TF) overexpression. ARS-Cov-19 ACE-2 down-regulation has been associated with an increase in angiotensin 2 (AT2). The action of proinflammatory cytokines, the increase in AT2 and the presence of antiphospholipid antibodies are known factors for TF activation and overexpression. It is very likely that the overexpression of TF in COVID-19 may be related to the pathogenesis of the disease, hence the importance of knowing the aspects related to this protein and the therapeutic strategies that can be derived. Different therapeutic strategies are being built to curb the expression of TF as a therapeutic target for various prothrombotic events; therefore, analyzing this treatment strategy for COVID-19-associated coagulopathy is rational. Medications such as celecoxib, cyclosporine or colchicine can impact on COVID-19, in addition to its anti-inflammatory effect, through inhibition of TF.

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Patients With COVID-19 Have Elevated Levels of Circulating Extracellular Vesicle Tissue Factor Activity That Is Associated With Severity and Mortality—Brief Report

Cited by 181 publications

References 29 publications

Soluble angiotensin-converting enzyme 2 is transiently elevated in COVID-19 and correlates with specific inflammatory and endothelial markers

Soluble angiotensin-converting enzyme 2 is transiently elevated in COVID-19 and correlates with specific inflammatory and endothelial markers

Comparison of the coagulopathies associated with COVID‐19 and sepsis

Role of Tissue Factor in the Pathogenesis of COVID-19 and the Possible Ways to Inhibit It

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