Sandeep Subrahmanian1, Alain Borczuk2, Steven Salvatore2, Kar-Ming Fung3, Joan T Merrill4, Jeffrey Laurence5, Jasimuddin Ahamed1,3,6. 1. Cardiovascular Biology Research Program, University of Oklahoma (HSC), Oklahoma City, OK, USA. 2. Department of Pathology, Weill Cornell Medical College, New York, NY, USA. 3. Department of Pathology, University of Oklahoma (HSC), Oklahoma City, OK, USA. 4. Arthritis & Clinical Immunology Research Program, Oklahoma Medical Research Foundation (OMRF), University of Oklahoma (HSC), Oklahoma City, OK, USA. 5. Department of Medicine, Weill Cornell Medical College, New York, NY, USA. 6. Department of Physiology, University of Oklahoma (HSC), Oklahoma City, OK, USA.
Abstract
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. This article is protected by copyright. All rights reserved.
BACKGROUND: A substantial proportion of patientsinfected 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-19ARDS) 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-19ARDS 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-19ARDS 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-19ARDS 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. This article is protected by copyright. All rights reserved.
Authors: Hassan A Hamali; Muhammad Saboor; Gasim Dobie; Aymen M Madkhali; Mohammad S Akhter; Ali Hakamy; Hesham M Al-Mekhlafi; Denise E Jackson; Yahya H Matari; Abdullah A Mobarki Journal: Infect Drug Resist Date: 2022-04-29 Impact factor: 4.177
Authors: Alexey A Martyanov; Anna E Boldova; Maria G Stepanyan; Olga I An; Alexander S Gur'ev; Darya V Kassina; Alexey Y Volkov; Alexandr V Balatskiy; Andrei A Butylin; Sergei S Karamzin; Elena V Filimonova; Sergei V Tsarenko; Sergei A Roumiantsev; Alexander G Rumyantsev; Mikhail A Panteleev; Fazoil I Ataullakhanov; Anastasia N Sveshnikova Journal: Thromb Res Date: 2022-01-15 Impact factor: 3.944