| Title | Defibrotide mitigates endothelial cell injury induced by plasmas from patients with COVID-19 and related vasculopathies. |
| Publication Type | Journal Article |
| Year of Publication | 2023 |
| Authors | Elhadad S, Redmond D, Tan A, Huang J, Rodriguez BLorenzo, Racine-Brzostek SE, Subrahmanian S, Ahamed J, Laurence J |
| Journal | Thromb Res |
| Volume | 225 |
| Pagination | 47-56 |
| Date Published | 2023 May |
| ISSN | 1879-2472 |
| Keywords | Anticoagulants, Caspase 8, COVID-19, Endothelial Cells, Hematopoietic Stem Cell Transplantation, Humans, Vascular Diseases |
| Abstract | <p><b>BACKGROUND AND OBJECTIVES: </b>COVID-19 progression is characterized by systemic small vessel arterial and venous thrombosis. Microvascular endothelial cell (MVEC) activation and injury, platelet activation, and histopathologic features characteristic of acute COVID-19 also describe certain thrombotic microangiopathies, including atypical hemolytic-uremic syndrome (aHUS), thrombotic thrombocytopenic purpura (TTP), and hematopoietic stem cell transplant (HSCT)-associated veno-occlusive disease (VOD). We explored the effect of clinically relevant doses of defibrotide, approved for HSCT-associated VOD, on MVEC activation/injury.</p><p><b>METHODS: </b>Human dermal MVEC were exposed to plasmas from patients with acute TMAs or acute COVID-19 in the presence and absence of defibrotide (5μg/ml) and caspase 8, a marker of EC activation and apoptosis, was assessed. RNAseq was used to explore potential mechanisms of defibrotide activity.</p><p><b>RESULTS: </b>Defibrotide suppressed TMA plasma-induced caspase 8 activation in MVEC (mean 60.2 % inhibition for COVID-19; p = 0.0008). RNAseq identified six major cellular pathways associated with defibrotide's alteration of COVID-19-associated MVEC changes: TNF-α signaling; IL-17 signaling; extracellular matrix (ECM)-EC receptor and platelet receptor interactions; ECM formation; endothelin activity; and fibrosis. Communications across these pathways were revealed by STRING analyses. Forty transcripts showing the greatest changes induced by defibrotide in COVID-19 plasma/MVEC cultures included: claudin 14 and F11R (JAM), important in maintaining EC tight junctions; SOCS3 and TNFRSF18, involved in suppression of inflammation; RAMP3 and transgelin, which promote angiogenesis; and RGS5, which regulates caspase activation and apoptosis.</p><p><b>CONCLUSION: </b>Our data, in the context of a recent clinical trial in severe COVID-19, suggest benefits to further exploration of defibrotide and these pathways in COVID-19 and related endotheliopathies.</p> |
| DOI | 10.1016/j.thromres.2023.03.009 |
| Alternate Journal | Thromb Res |
| PubMed ID | 37001283 |
| PubMed Central ID | PMC10033153 |