Upregulation of pulmonary tissue factor, loss of thrombomodulin and immunothrombosis in SARS-CoV-2 infection.
EClinicalMedicine
; 39: 101069, 2021 Sep.
Article
in English
| MEDLINE | ID: covidwho-1499821
ABSTRACT
BACKGROUND:
SARS-CoV-2 infection is associated with thrombotic and microvascular complications. The cause of coagulopathy in the disease is incompletely understood.METHODS:
A single-center cross-sectional study including 66 adult COVID-19 patients (40 moderate, 26 severe disease), and 9 controls, performed between 04/2020 and 10/2020. Markers of coagulation, endothelial cell function [angiopoietin-1,-2, P-selectin, von Willebrand Factor Antigen (WFAg), von Willebrand Factor Ristocetin Cofactor, ADAMTS13, thrombomodulin, soluble Endothelial cell Protein C Receptor (sEPCR), Tissue Factor Pathway Inhibitor], neutrophil activation (elastase, citrullinated histones) and fibrinolysis (tissue-type plasminogen activator, plasminogen activator inhibitor-1) were evaluated using ELISA. Tissue Factor (TF) was estimated by antithrombin-FVIIa complex (AT/FVIIa) and microparticles-TF (MP-TF). We correlated each marker and determined its association with severity. Expression of pulmonary TF, thrombomodulin and EPCR was determined by immunohistochemistry in 9 autopsies.FINDINGS:
Comorbidities were frequent in both groups, with older age associated with severe disease. All patients were on prophylactic anticoagulants. Three patients (4.5%) developed pulmonary embolism. Mortality was 7.5%. Patients presented with mild alterations in the coagulogram (compensated state). Biomarkers of endothelial cell, neutrophil activation and fibrinolysis were elevated in severe vs moderate disease; AT/FVIIa and MP-TF levels were higher in severe patients. Logistic regression revealed an association of D-dimers, angiopoietin-1, vWFAg, thrombomodulin, white blood cells, absolute neutrophil count (ANC) and hemoglobin levels with severity, with ANC and vWFAg identified as independent factors. Notably, postmortem specimens demonstrated epithelial expression of TF in the lung of fatal COVID-19 cases with loss of thrombomodulin staining, implying in a shift towards a procoagulant state.INTERPRETATION:
Coagulation dysregulation has multifactorial etiology in SARS-Cov-2 infection. Upregulation of pulmonary TF with loss of thrombomodulin emerge as a potential link to immunothrombosis, and therapeutic targets in the disease.FUNDING:
John Hopkins University School of Medicine.
ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; ALC, absolute lymphocyte count; ALI, Acute Lung Injury; AMC, absolute monocyte count; ANC, absolute neutrophil count; AT/VIIa, antithrombin-FVIIa complex; Coagulation; ELISA, enzyme-linked immunosorbent assay; Hb, hemoglobin; Hemostasis; ICU, intensive care unit; Ixolaris; LMWH, low molecular weight heparin; MP-TF, Microparticles-Tissue Factor; PAI-1, plasminogen activator inhibitor-1; PAR, protease-activated receptor; TF, Tissue Factor; TFPI, Tissue Factor Pathway Inhibitor; Thrombosis; WBC, white blood cells; sEPCR, soluble Endothelial cell Protein C Receptor; t-PA, tissue-type plasminogen activator; vWF, von Willebrand Factor; vWF:Ag, von Willebrand Factor Antigen; vWF:RCo, von Willebrand Factor Ristocetin Cofactor
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Type of study:
Etiology study
/
Experimental Studies
/
Observational study
/
Prognostic study
/
Randomized controlled trials
Language:
English
Journal:
EClinicalMedicine
Year:
2021
Document Type:
Article
Affiliation country:
J.eclinm.2021.101069
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