Abstract
Endothelial dysfunction accompanies the microvascular thrombosis commonly observed in severe COVID-19. Constitutively, the endothelial surface is anticoagulant, a property maintained at least in part via signaling through the Tie2 receptor. During inflammation, the Tie2 antagonist angiopoietin-2 (Angpt-2) is released from endothelial cells and inhibits Tie2, promoting a prothrombotic phenotypic shift. We sought to assess whether severe COVID-19 is associated with procoagulant endothelial dysfunction and alterations in the Tie2/angiopoietin axis. Primary HUVECs treated with plasma from patients with severe COVID-19 upregulated the expression of thromboinflammatory genes, inhibited the expression of antithrombotic genes, and promoted coagulation on the endothelial surface. Pharmacologic activation of Tie2 with the small molecule AKB-9778 reversed the prothrombotic state induced by COVID-19 plasma in primary endothelial cells. Lung autopsies from patients with COVID-19 demonstrated a prothrombotic endothelial signature. Assessment of circulating endothelial markers in a cohort of 98 patients with mild, moderate, or severe COVID-19 revealed endothelial dysfunction indicative of a prothrombotic state. Angpt-2 concentrations rose with increasing disease severity, and the highest levels were associated with worse survival. These data highlight the disruption of Tie2/angiopoietin signaling and procoagulant changes in endothelial cells in severe COVID-19. Our findings provide rationale for current trials of Tie2-activating therapy with AKB-9778 in COVID-19.
Highlights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), can result in critical illness characterized by severe pulmonary disease [1], in addition to several extrapulmonary manifestations [2], and carries a significant morality rate
Patients in the highest tertile of Angpt-2 (Log-rank P = 0.023), E selectin (Log-rank P = 0.013), and P selectin (Log-rank P = 0.036) had worse survival compared with patients in the bottom 2 tertiles (Figure 5). These results suggest that Angpt-2 and other markers of endothelial dysfunction and thrombosis are strongly correlated with COVID-19 disease severity and implicate perturbation of the Tie2-angiopoietin pathway in this process
To interrogate the Ang2-Tie2 system in COVID-19–mediated endothelial dysfunction, we used an in vitro model in which primary endothelial cells were treated with COVID-19 plasma
Summary
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), can result in critical illness characterized by severe pulmonary disease [1], in addition to several extrapulmonary manifestations [2], and carries a significant morality rate. Critical COVID-19 illness is characterized by a prothrombotic coagulopathy, and higher D-dimer concentrations and activation of coagulation are associated with worse outcomes [3,4,5]. Endothelial dysfunction in COVID-19 may be mediated through circulating inflammatory cytokines [9, 10], autoantibodies [11, 12], and neutrophil extracellular traps (NETs) [13], as well as potentially via direct viral infection [14]
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