Tissue Factor upregulation is associated with SARS-CoV-2 in the lungs of COVID-19 patients.

Subrahmanian, Sandeep; Borczuk, Alain; Salvatore, Steven; Fung, Kar-Ming; Merrill, Joan T; Laurence, Jeffrey; Ahamed, Jasimuddin

BACKGROUND A substantial proportion of patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop severe/critical coronavirus disease 2019 (COVID-19) characterized by acute respiratory distress syndrome (ARDS) with thrombosis. OBJECTIVES We tested the hypothesis that SARS-CoV-2-induced upregulation of tissue factor (TF) expression may be responsible for thrombus formation in COVID-19. METHODS We compared autopsy lung tissues from eleven patients with COVID-19-associated ARDS with samples from six patients with ARDS from other causes (non-COVID-19 ARDS) and eleven normal control lungs. RESULTS Dual RNA in situ hybridization for SARS-CoV-2 and TF identified sporadic clustered SARS-CoV-2 with prominent co-localization of SARS-CoV-2 and TF RNA. TF expression was 2-fold higher in COVID-19 than in non-COVID-19 ARDS lungs (p=0.017) and correlated with the intensity of SARS-CoV-2 staining (R2 =0.36, p=0.04). By immunofluorescence, TF protein expression was 2.1-fold higher in COVID-19 vs. non-COVID-19 ARDS lungs (p=0.0048) and 11-fold (p<0.001) higher than control lungs. Fibrin thrombi and thrombi positive for platelet factor 4 were found in close proximity to regions expressing TF in COVID-19 ARDS lung, and correlated with TF expression (fibrin, R2 =0.52, p<0.001; PF4, R2 =0.59, p<0.001). CONCLUSIONS These data suggest that upregulation of TF expression is associated with thrombus formation in COVID-19 lungs and could be a key therapeutic target. Correlation of TF expression with SARS-CoV-2 in lungs of COVID-19 also raises the possibility of direct TF induction by the virus.