Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly become a global pandemic. In addition to the acute pulmonary symptoms of coronavirus disease (COVID-19) (the disease associated with
SARS-CoV-2 infection), pulmonary and distal coagulopathies have caused morbidity and mortality in many patients. Currently, the molecular pathogenesis underlying COVID-19-associated coagulopathies are unknown. Identifying the molecular basis of how SARS-CoV-2 drives coagulation is essential to mitigating short- and long-term thrombotic risks of sick and recovered patients with
COVID-19. We aimed to perform coagulation-focused transcriptome analysis of in vitro infected primary respiratory epithelial cells, patient-derived bronchial alveolar lavage cells, and circulating immune cells during
SARS-CoV-2 infection. Our objective was to identify transcription-mediated signaling networks driving coagulopathies associated with
COVID-19. We analyzed recently published experimentally and clinically derived bulk or single-cell
RNA sequencing datasets of
SARS-CoV-2 infection to identify changes in transcriptional regulation of blood coagulation. We also confirmed that the transcriptional expression of a key coagulation regulator was recapitulated at the
protein level. We specifically focused our analysis on lung tissue-expressed genes regulating the extrinsic coagulation cascade and the
plasminogen activation system. Analyzing transcriptomic data of in vitro infected normal human bronchial epithelial cells and patient-derived bronchial alveolar lavage samples revealed that
SARS-CoV-2 infection induces the extrinsic blood coagulation cascade and suppresses the
plasminogen activation system. We also performed in vitro
SARS-CoV-2 infection experiments on primary human lung epithelial cells to confirm that transcriptional upregulation of
tissue factor, the extrinsic coagulation cascade master regulator, manifested at the
protein level. Furthermore,
infection of normal human bronchial epithelial cells with influenza A virus did not drive key regulators of blood coagulation in a similar manner as SARS-CoV-2. In addition, peripheral blood mononuclear cells did not differentially express genes regulating the extrinsic coagulation cascade or
plasminogen activation system during
SARS-CoV-2 infection, suggesting that they are not directly inducing coagulopathy through these pathways. The hyperactivation of the extrinsic blood coagulation cascade and the suppression of the
plasminogen activation system in SARS-CoV-2-infected epithelial cells may drive diverse coagulopathies in the lung and distal organ systems. Understanding how hosts drive such transcriptional changes with
SARS-CoV-2 infection may enable the design of host-directed therapeutic strategies to treat
COVID-19 and other coronaviruses inducing hypercoagulation.