Upregulation of pulmonary tissue factor, loss of thrombomodulin and immunothrombosis in SARS-CoV-2 infection. (September 2021)

• Record Type: Journal Article
• Authors: Francischetti, Ivo M.B.; Toomer, Kevin; Zhang, Yifan; Jani, Jayesh; Siddiqui, Zishan; Brotman, Daniel J.; Hooper, Jody E.; Kickler, Thomas S.
• Is Part Of: EClinicalMedicine. Volume 39(2021)
• Publication Date: 2021-09
• Subjects: Thrombosis -- Hemostasis -- Coagulation -- Ixolaris; vWF von Willebrand Factor -- vWF:Ag von Willebrand Factor Antigen -- vWF:RCo von Willebrand Factor Ristocetin Cofactor -- ADAMTS13 a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 -- sEPCR soluble Endothelial cell Protein C Receptor -- TFPI Tissue Factor Pathway Inhibitor -- t-PA tissue-type plasminogen activator -- PAI-1 plasminogen activator inhibitor-1 -- TF Tissue Factor -- AT/VIIa antithrombin-FVIIa complex -- MP-TF Microparticles-Tissue Factor -- Hb hemoglobin -- ANC absolute neutrophil count -- AMC absolute monocyte count -- ALC absolute lymphocyte count -- WBC white blood cells -- ELISA enzyme-linked immunosorbent assay -- PAR protease-activated receptor -- ICU intensive care unit -- LMWH low molecular weight heparin -- ALI Acute Lung Injury; Medicine -- Research -- Periodicals; Medical policy -- Periodicals; Clinical Medicine; Health Policy; Public Health; Medical policy; Medicine -- Research; Periodical; Electronic journals; Periodicals; 613
• DOI: 10.1016/j.eclinm.2021.101069
• Languages: English
• ISSNs: 2589-5370

Abstract

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 (WF:Ag), 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, vWF:Ag, thrombomodulin, white blood cells, absolute neutrophil count (ANC) and hemoglobin levels with severity, with ANC and vWF:Ag 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.