Response by Mackman et al to Letter Regarding Article, “Patients With COVID-19 Have Elevated Levels of Circulating Extracellular Vesicle Tissue Factor Activity That Is Associated With Severity and Mortality—Brief Report”

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

doi:10.1161/atvbaha.121.316203

Cited by 10 publications

(10 citation statements)

References 14 publications

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“…We do not add substantial advancing in the debate concerning whether it is better to measure levels of TF activity or TF protein as marker of thrombotic risk, [ 23 , 24 ] however we clearly show that the TF protein level on the surface of EV consistently predict the severity of COVID-19 disease. We have also shown that CD142-bearing EVs have an augmented enzymatic activity when isolated from serum of patients with severe disease and a poor prognosis, regardless the method of isolation.…”

Section: Discussionmentioning

confidence: 63%

Risk stratification of patients with SARS-CoV-2 by tissue factor expression in circulating extracellular vesicles

Burrello¹,

Caporali²,

Gauthier³

et al. 2022

Vascular Pharmacology

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Section: Discussionmentioning

confidence: 63%

Risk stratification of patients with SARS-CoV-2 by tissue factor expression in circulating extracellular vesicles

Burrello¹,

Caporali²,

Gauthier³

et al. 2022

Vascular Pharmacology

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“…We did not investigate other possible origins of TF + EVs (i.e., platelets) which may account for this finding. It is worth mentioning that there is some controversy surrounding the use of flow cytometry for TF + EVs detection, since the suggested method to measure TF + MVs is EV-associated TF activity ( Nieuwland et al, 2019 ; Mackman et al, 2021 ). Rosell A. et al reported that EV-TF activity was significantly higher in patients with COVID-19 vs. healthy controls ( Rosell et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Longitudinal Trend of Plasma Concentrations of Extracellular Vesicles in Patients Hospitalized for COVID-19

Campello

Radu

Simion

et al. 2022

Front. Cell Dev. Biol.

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Plasma concentrations of extracellular vesicles (EVs) originating from cells involved in COVID-19-associated coagulopathy (CAC), their longitudinal trend and association with clinical outcomes were evaluated. Blood samples of consecutive COVID-19 patients admitted to a medical Unit were longitudinally collected within 48 h of admission, at discharge and 30 days post-discharge. EVs were analyzed using high sensitivity flow cytometry and phospholipid-dependent clotting time (PPL). The following EVs were measured: endothelium-, platelet-, leukocyte-derived, bearing tissue factor (TF)+, angiotensin-converting enzyme (ACE2)+, platelet-derived growth factor receptor-β (PDGF-β)+ and SARS-CoV-2-nucleoprotein (NP)+. 91 patients were recruited for baseline EV analysis (mean age 67 ± 14 years, 50.5% male) and 48 underwent the longitudinal evaluation. From baseline to 30-days post-discharge, we observed significantly decreased plasma concentrations of endothelium-derived EVs (E-Selectin+), endothelium-derived bearing TF (E-Selectin+ TF+), endothelium-derived bearing ACE2 (E-Selectin+ACE2+) and leukocyte-EVs bearing TF (CD45+TF+), p < 0.001, p = 0.03, p = 0.001, p = 0.001, respectively. Conversely, platelet-derived (P-Selectin+) and leukocyte-derived EVs (CD45+) increased from baseline to 30-days post-discharge (p = 0.038 and 0.032, respectively). EVs TF+, ACE2+, PDGF-β+, and SARS-CoV-2-NP+ did not significantly change during the monitoring. PPL increased from baseline to 30-days post-discharge (+ 6.3 s, p = 0.006). P-Selectin + EVs >1,054/µL were associated with thrombosis (p = 0.024), E-Selectin + EVs ≤531/µL with worsening/death (p 0.026) and 30-days P-Selectin+ and CD45 + EVs with persistent symptoms (p < 0.0001). We confirmed increased EVs originating from cells involved in CAC at admission and discharge. EVs derived from activated pericytes and expressing SARS-CoV-2-NP were also detected. 30-days post-discharge, endothelium-EVs decreased, while platelet- and leukocyte-EVs further increased, indicating that cellular activation persists long after the acute phase.

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“…Although some investigators have used flow cytometry to determine the cellular origin of circulating TF-positive EVs, we feel that this technique is not sensitive enough to simultaneously measure levels of cell typespecific markers and TF on EVs because of the low levels of TF. 69 We speculate that a likely source of circulating TF-positive EVs is activated monocytes because these cells have been shown to express it is possible that other cell types, such as endothelial cells, neutrophils, and epithelial cells, also release TF-positive EVs into the circulation in COVID-19 patients.…”

Section: Sars-cov-2mentioning

confidence: 90%

“…At present, we do not know the cellular origins of the TF‐positive EVs present in the circulation of COVID‐19 patients. Although some investigators have used flow cytometry to determine the cellular origin of circulating TF‐positive EVs, we feel that this technique is not sensitive enough to simultaneously measure levels of cell type‐specific markers and TF on EVs because of the low levels of TF 69 . We speculate that a likely source of circulating TF‐positive EVs is activated monocytes because these cells have been shown to express TF in COVID‐19 patients.…”

Section: Tf Expression and Coronavirusesmentioning

confidence: 96%

Tissue factor expression, extracellular vesicles, and thrombosis after infection with the respiratory viruses influenza A virus and coronavirus

Mackman

Grover

Antoniak

2021

Journal of Thrombosis and Haemostasis

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Tissue factor (TF) is induced in a variety of cell types during viral infection, which likely contributes to disseminated intravascular coagulation and thrombosis. TFexpressing cells also release TF-positive extracellular vesicles (EVs) into the circulation that can be measured using an EVTF activity assay. This review summarizes studies that analyze TF expression, TF-positive EVs, activation of coagulation, and thrombosis after infection with influenza A virus (IAV) and coronaviruses (CoVs), including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), SARS-CoV, and Middle East respiratory syndrome CoV (MERS-CoV). The current pandemic of coronavirus disease 2019 (COVID-19) is caused by infection with SARS-CoV-2. Infection of mice with IAV increased TF expression in lung epithelial cells as well as increased EVTF activity and activation of coagulation in the bronchoalveolar lavage fluid (BALF). Infection of mice with MERS-CoV, SARS-CoV, and SARS-CoV-2 also increased lung TF expression. Single-cell RNA sequencing analysis on the BALF from severe COVID-19 patients revealed increased TF mRNA expression in epithelial cells. TF expression was observed in peripheral blood mononuclear cells infected with SARS-CoV. TF was also expressed by peripheral blood mononuclear cells, monocytes in platelet-monocyte aggregates, and neutrophils isolated from COVID-19 patients. Elevated circulating EVTF activity was observed in severe IAV and COVID-19 patients. Importantly, EVTF activity was associated with mortality in severe IAV patients and with plasma D-dimer, severity, thrombosis, and mortality in COVID-19 patients. These studies strongly suggest that increased TF expression in patients infected with IAV and pathogenic CoVs contributes to thrombosis.

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Response by Mackman et al to Letter Regarding Article, “Patients With COVID-19 Have Elevated Levels of Circulating Extracellular Vesicle Tissue Factor Activity That Is Associated With Severity and Mortality—Brief Report”

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Cited by 10 publications

References 14 publications

Risk stratification of patients with SARS-CoV-2 by tissue factor expression in circulating extracellular vesicles

Risk stratification of patients with SARS-CoV-2 by tissue factor expression in circulating extracellular vesicles

Longitudinal Trend of Plasma Concentrations of Extracellular Vesicles in Patients Hospitalized for COVID-19

Tissue factor expression, extracellular vesicles, and thrombosis after infection with the respiratory viruses influenza A virus and coronavirus

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