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Published on: June 12, 2021
Defibrotide mitigates endothelial cell injury induced by plasmas from patients with COVID-19 and related
Sonia Elhadad1, David Redmond2, Adrian Tan3
1Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, United States of America.
Insights
Defibrotide significantly inhibited microvascular endothelial cell activation in COVID-19 and thrombotic microangiopathy (TMA) models. This suggests defibrotide’s potential therapeutic role in treating COVID-19-related vascular complications.
Area of Science:
- Endothelial Biology
- Thrombosis Research
- Pharmacology
Background:
- COVID-19 is characterized by systemic thrombosis and microvascular endothelial cell (MVEC) injury.
- These features overlap with thrombotic microangiopathies (TMAs) like atypical hemolytic-uremic syndrome (aHUS) and thrombotic thrombocytopenic purpura (TTP).
- Defibrotide is approved for hematopoietic stem cell transplant (HSCT)-associated veno-occlusive disease (VOD).
Purpose of the Study:
- To investigate the effect of defibrotide on MVEC activation and injury in the context of COVID-19 and TMAs.
- To explore the molecular mechanisms underlying defibrotide's action.
Main Methods:
- Human dermal MVECs were exposed to plasmas from patients with acute TMAs or COVID-19.
- Defibrotide's effect on caspase 8 activation (a marker of endothelial cell activation and apoptosis) was assessed.
- RNA sequencing (RNAseq) was employed to identify cellular pathways affected by defibrotide.
Main Results:
- Defibrotide demonstrated significant inhibition (60.2%) of caspase 8 activation in MVEC exposed to COVID-19 plasma.
- RNAseq revealed defibrotide modulates key pathways including TNF-α, IL-17 signaling, ECM interactions, and fibrosis.
- Specific transcripts modulated by defibrotide were identified, including those involved in endothelial barrier function, inflammation suppression, and angiogenesis.
Conclusions:
- Defibrotide effectively suppresses endothelial cell activation in models relevant to COVID-19 and TMAs.
- The findings support further investigation of defibrotide for treating COVID-19-related endotheliopathies.
- Defibrotide's modulation of specific cellular pathways offers potential therapeutic targets.
Background And Objectives:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
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