Tissue factor upregulation is associated with SARS‐CoV‐2 in the lungs of COVID‐19 patients

Subrahmanian, Sandeep; Salvatore, Steven; Fung, Kar‐Ming; Merrill, Joan T.; Laurence, Jeffrey; Ahamed, Jasimuddin

doi:10.1111/jth.15451

Cited by 35 publications

(34 citation statements)

References 29 publications

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“…Elevated levels of TF and increased TF patient with COVID-19 compared to non-COVID-19 patients. 18 , 50 The current study found significantly increased levels of TF-bearing MVs in the circulation of patient group, which is similar to previously published findings related to COVID-19 18 , 21 and viral infections. 17 In COVID-19, TF-bearing MVs have been suggested to play a role in thrombosis and even the severity and mortality.…”

Section: Discussionsupporting

confidence: 92%

Procoagulant Microvesicles in COVID-19 Patients: Possible Modulators of Inflammation and Prothrombotic Tendency

Hamali¹,

Saboor²,

Dobie³

et al. 2022

IDR

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Background The hypercoagulability and thrombotic tendency in coronavirus disease 2019 (COVID-19) is multifactorial, driven mainly by inflammation, and endothelial dysfunction. Elevated levels of procoagulant microvesicles (MVs) and tissue factor–bearing microvesicles (TF-bearing MVs) have been observed in many diseases with thrombotic tendency. The current study aimed to measure the levels of procoagulant MVs and TF-bearing MVs in patients with COVID-19 and healthy controls and to correlate their levels with platelet counts, D-Dimer levels, and other proposed calculated inflammatory markers. Materials and Methods Forty ICU-admitted patients with COVID-19 and 37 healthy controls were recruited in the study. Levels of procoagulant MVs and TF-bearing MVs in the plasma of the study population were measured using enzyme linked immunosorbent assay. Results COVID-19 patients had significantly elevated levels of procoagulant MVs and TF-bearing MVs as compared with healthy controls (P<0.001). Procoagulant MVs significantly correlated with TF-bearing MVs, D-dimer levels, and platelet count, but not with calculated inflammatory markers (neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, and platelet/neutrophil ratio). Conclusion Elevated levels of procoagulant MVs and TF-bearing MVs in patients with COVID-19 are suggested to be (i) early potential markers to predict the severity of COVID-19 (ii) a novel circulatory biomarker to evaluate the procoagulant activity and severity of COVID-19.

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Section: Discussionsupporting

confidence: 92%

Procoagulant Microvesicles in COVID-19 Patients: Possible Modulators of Inflammation and Prothrombotic Tendency

Hamali¹,

Saboor²,

Dobie³

et al. 2022

IDR

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“…For instance, patients with COVID-19 have been shown to have elevated levels of tissue factor laden microvesicles circulating in their blood, along with other markers of the extrinsic coagulation cascade ( Rosell et al, 2021 ). Further, autopsy studies of COVID-19 patients have also found that tissue factor protein expression is approximately doubled in the lungs of patients that succumbed to COVID-19 ( Subrahmanian et al, 2021 ). Tissue factor upregulation in the BALF of COVID-19 patients has also been observed at the RNA level using both single cell and bulk RNA-sequencing, and the observed increase correlated with severity ( FitzGerald et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…This method of data reporting obscures the extremely low counts for many genes of interest. Many other publications in the field, including bioinformatics analyses, in-vitro studies, clinical research, and post-clinical autopsies directly contradict the findings of Mast et al ( Subrahmanian et al, 2021 ; Rosell et al, 2021 ; FitzGerald et al, 2021 ). The initial publication of inaccurate findings could have been avoided by applying quality control standards to the libraries included in the analysis.…”

Section: Introductionmentioning

confidence: 88%

Comment on ‘SARS-CoV-2 suppresses anticoagulant and fibrinolytic gene expression in the lung’

FitzGerald

Jamieson

2022

eLife

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Mast et al. analyzed transcriptome data derived from RNA-sequencing (RNA-seq) of COVID-19 patient bronchoalveolar lavage fluid (BALF) samples, as compared to BALF RNA-seq samples from a study investigating microbiome and inflammatory interactions in obese and asthmatic adults (Mast et al., 2021). Based on their analysis of these data, Mast et al. concluded that mRNA expression of key regulators of the extrinsic coagulation cascade and fibrinolysis were significantly reduced in COVID-19 patients. Notably, they reported that the expression of the extrinsic coagulation cascade master regulator Tissue Factor (F3) remained unchanged, while there was an 8-fold upregulation of its cognate inhibitor Tissue Factor Pathway Inhibitor (TFPI). From this they conclude that “pulmonary fibrin deposition does not stem from enhanced local [tissue factor] production and that counterintuitively, COVID-19 may dampen [tissue factor]-dependent mechanisms in the lungs”. They also reported decreased Activated Protein C (aPC) mediated anticoagulant activity and major increases in fibrinogen expression and other key regulators of clot formation. Many of these results are contradictory to findings in most of the field, particularly the findings regarding extrinsic coagulation cascade mediated coagulopathies. Here, we present a complete re-analysis of the data sets analyzed by Mast et al. This re-analysis demonstrates that the two data sets utilized were not comparable between one another, and that the COVID-19 sample set was not suitable for the transcriptomic analysis Mast et al. performed. We also identified other significant flaws in the design of their retrospective analysis, such as poor-quality control and filtering standards. Given the issues with the datasets and analysis, their conclusions are not supported.

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“…COVID-19 patients show elevated TF activity in circulating extracellular vesicles associated with disease severity and mortality [120]. Pulmonary histopathology studies with the characterization of CD61+ platelet thrombi in COVID-19 patients with ARDS showed that CD61+ areas were higher in COVID-19 vs. non-COVID-19 ARDS samples [121]. Interestingly, the same authors found that higher levels of fibrin and activated platelets in PF4-positive thrombi correlated to high TF protein expression throughout lung tissue samples in which both arterial and venous thrombi and microangiopathy were observed [121].…”

Section: Sars-cov-2 Effects On Plateletsmentioning

confidence: 99%

Prothrombotic Phenotype in COVID-19: Focus on Platelets

Barale

Melchionda

Morotti

et al. 2021

IJMS

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COVID-19 infection is associated with a broad spectrum of presentations, but alveolar capillary microthrombi have been described as a common finding in COVID-19 patients, appearing as a consequence of a severe endothelial injury with endothelial cell membrane disruption. These observations clearly point to the identification of a COVID-19-associated coagulopathy, which may contribute to thrombosis, multi-organ damage, and cause of severity and fatality. One significant finding that emerges in prothrombotic abnormalities observed in COVID-19 patients is that the coagulation alterations are mainly mediated by the activation of platelets and intrinsically related to viral-mediated endothelial inflammation. Beyond the well-known role in hemostasis, the ability of platelets to also release various potent cytokines and chemokines has elevated these small cells from simple cell fragments to crucial modulators in the blood, including their inflammatory functions, that have a large influence on the immune response during infectious disease. Indeed, platelets are involved in the pathogenesis of acute lung injury also by promoting NET formation and affecting vascular permeability. Specifically, the deposition by activated platelets of the chemokine platelet factor 4 at sites of inflammation promotes adhesion of neutrophils on endothelial cells and thrombogenesis, and it seems deeply involved in the phenomenon of vaccine-induced thrombocytopenia and thrombosis. Importantly, the hyperactivated platelet phenotype along with evidence of cytokine storm, high levels of P-selectin, D-dimer, and, on the other hand, decreased levels of fibrinogen, von Willebrand factor, and thrombocytopenia may be considered suitable biomarkers that distinguish the late stage of COVID-19 progression in critically ill patients.

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Tissue factor upregulation is associated with SARS‐CoV‐2 in the lungs of COVID‐19 patients

Cited by 35 publications

References 29 publications

Procoagulant Microvesicles in COVID-19 Patients: Possible Modulators of Inflammation and Prothrombotic Tendency

Procoagulant Microvesicles in COVID-19 Patients: Possible Modulators of Inflammation and Prothrombotic Tendency

Comment on ‘SARS-CoV-2 suppresses anticoagulant and fibrinolytic gene expression in the lung’

Prothrombotic Phenotype in COVID-19: Focus on Platelets

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