SARS-CoV-2 suppresses anticoagulant and fibrinolytic gene expression in the lung

Abstract

Extensive fibrin deposition in the lungs and altered levels of circulating blood coagulation proteins in COVID-19 patients imply local derangement of pathways that limit fibrin formation and/or promote its clearance. We examined transcriptional profiles of bronchoalveolar lavage fluid (BALF) samples to identify molecular mechanisms underlying these coagulopathies. mRNA levels for regulators of the kallikrein-kinin (C1-inhibitor), coagulation (thrombomodulin, endothelial protein C receptor), and fibrinolytic (urokinase and urokinase receptor) pathways were significantly reduced in COVID-19 patients. While transcripts for several coagulation proteins were increased, those encoding tissue factor, the protein that initiates coagulation and whose expression is frequently increased in inflammatory disorders, were not increased in BALF from COVID-19 patients. Our analysis implicates enhanced propagation of coagulation and decreased fibrinolysis as drivers of the coagulopathy in the lungs of COVID-19 patients.

Keywords: COVID-19; SARS-CoV-2; bronchoalvelolar; coagulation; epidemiology; fibrinolysis; global health; human; medicine.

Figure 1.. Transcriptional changes in lung induced by COVID-19 infection did not alter F3, but decreased aPC anticoagulant capacity, suggesting decreased inhibition of the propagation phase of coagulation.

Figure shows differential gene expression (log₂ fold change) of coagulation pathway transcripts in BALF of COVID-19 patients; the image illustrates mechanistic relationships of the protein products of the identified transcripts during coagulation. Shading indicates relative expression in COVID-19 patients compared to controls: increased (red) or decreased (blue). There was minimal change in F3 (encoding tissue factor ) and increased TFPI (encoding the major inhibitor of tissue factor activity). There was decreased THBD, PROCR, and PROS1 (encoding proteins that enhance anticoagulant activity) and increased SERPINA5 (encoding protein C inhibitor). There was also decreased SERPING1 (encoding C1-Inhibitor). Other transcripts showing changes (e.g., F11, F10, F7, F2) encode proteins typically produced in the liver; local expression of these proteins is unclear.

Figure 2.. Transcriptional changes in lung induced by COVID-19 infection decreased PLAU and PLAUR, suggesting diminished fibrinolytic activity.

Figure shows differential gene expression (log₂ fold change) of fibrinolytic pathway transcripts in BALF of COVID-19 patients; the image illustrates mechanistic relationships of the protein products of the identified transcripts during fibrinolysis. Shading indicates relative expression in COVID-19 patients compared to controls: increased (red) or decreased (blue). There was a moderate increase in PLAT (encoding tPA). There was also enhanced expression of FGB, FGA, and FGG (encoding fibrinogen chains) and decreased expression of PLAU and PLAUR (encoding uPA and uPAR, respectively). Other transcripts showing changes (e.g., F2, PLG) encode proteins typically produced in the liver; local expression of these proteins is unclear.