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

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 11 patients with COVID‐19‐‐associated ARDS with samples from 6 patients with ARDS from other causes (non‐COVID‐19 ARDS) and 11 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 = .017) and correlated with the intensity of SARS‐CoV‐2 staining (R(2) = .36, P = .04). By immunofluorescence, TF protein expression was 2.1‐fold higher in COVID‐19 versus non‐COVID‐19 ARDS lungs (P = .0048) and 11‐fold (P < .001) higher than control lungs. Fibrin thrombi and thrombi positive for platelet factor 4 (PF4) were found in close proximity to regions expressing TF in COVID‐19 ARDS lung, and correlated with TF expression (fibrin, R(2) = .52, P < .001; PF4, R(2) = .59, P < .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 patients also raises the possibility of direct TF induction by the virus.