Abstract Number: OC 57.3
Meeting: ISTH 2022 Congress
Theme: COVID and Coagulation » COVID and Coagulation, Basic Science
Background: A major complication of COVID19 is severe endothelial injury with micro- and macro-thrombotic disease in the lung and other organs. Several studies have identified high levels of inflammatory cytokines (“cytokine storm”), powerful activators of the endothelium, in plasma of severe COVID19 patients; indeed, COVID19 plasma was shown to activate endothelial cells (EC) in vitro. A consequence of EC activation is loss of anti-coagulant function, with release of pro-thrombotic Von Willebrand Factor (VWF). High levels of plasma VWF in severe COVID19 patients indicate systemic endothelial activation and increased risk of thrombosis.
Aims: To identify drugs that decrease endothelial activation and VWF release, which may have a therapeutic impact in COVID19 patients.
Methods: We established an in vitro model of endothelial activation driven by 6 cytokines selected because of their high levels in COVID19 plasma. Cells were treated with the 6-cytokine cocktail for 24 hr; endothelial activation was confirmed by a panel of markers including ICAM1, measured by RT-qPCR and immunofluorescence (IF).
Results: The treatment induced release of VWF and increased VWF-platelet string formation in a platelet flow-based assay. To identify drugs that blocked cytokine-induced VWF release, a high-throughput screening was carried out in human umbilical vein EC (HUVEC); VWF and ICAM1 expression were detected by IF; DAPI was used as nuclear stain. High content imaging screen of 3049 drugs from FDA/EMA-approved drug libraries identified drugs able to decrease VWF release following cytokine treatment. Top hits from several therapeutic classes including anti-inflammatory, anti-viral and hormones were taken forward for validation. Two hits were confirmed to inhibit cytokine-induced VWF release and VWF-platelet string formation. Selected findings were validated in lung microvascular EC.
Conclusion(s): This study identified candidate drugs that reduce the enhanced VWF release caused by the “cytokine storm” typical of severe COVID19; these may be beneficial in the treatment of the pro-thrombotic risk in COVID19 patients.
To cite this abstract in AMA style:
Jones D, Saginc Giannoustas G, Peghaire C, Pirri D, Braga L, Schneider E, Appiah M, Birdsey G, McKinnon T, Thwaites R, Giacca M, Randi A. Cell-based high throughput screening to identify FDA/EMA approved drugs that inhibit the endothelial pro-thrombotic switch during severe COVID19 infection [abstract]. https://abstracts.isth.org/abstract/cell-based-high-throughput-screening-to-identify-fda-ema-approved-drugs-that-inhibit-the-endothelial-pro-thrombotic-switch-during-severe-covid19-infection/. Accessed March 21, 2024.« Back to ISTH 2022 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/cell-based-high-throughput-screening-to-identify-fda-ema-approved-drugs-that-inhibit-the-endothelial-pro-thrombotic-switch-during-severe-covid19-infection/