Angiopoietin 2 Is Associated with Vascular Necroptosis Induction in Coronavirus Disease 2019 Acute Respiratory Distress Syndrome
The American Journal of Pathology, 2022
Price D., Benedetti E., Hoffman K., Gomez-Escobar L., Alvarez-Mulett S., Capili A., Sarwath H., Parkhurst C., Lafond E., Weidman K., Ravishankar A., Cheong J., Batra R., Büyüközkan M., Chetnik K., Easthausen I., Schenck E., Racanelli A., Outtz Reed H., Laurence J., Josefowicz S., Lief L., Choi M., Schmidt F., Borczuk A., Choi A., Krumsiek J., Rafii S.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Respiratory Diseases Infectious Diseases | Pathophysiology | Plasma Serum |  Olink Target 96 |
Abstract
Vascular injury is a well-established, disease modifying factor in acute respiratory distress syndrome (ARDS) pathogenesis. Recently, COVID-19-induced injury to the vascular compartment has been linked to complement activation, microvascular thrombosis, and dysregulated immune responses. We sought to assess whether aberrant vascular activation in this prothrombotic context was associated with the induction of necroptotic vascular cell death. To achieve this, proteomic analysis was performed on blood samples from COVID-19 subjects at distinct timepoints during ARDS pathogenesis (hospitalized “at risk”, N=59, “ARDS”, N=31, and “recovery”, N=12). Assessment of circulating endothelial markers in the “at risk” cohort revealed a signature of low vascular protein abundance that tracked with low platelet levels and increased mortality. This signature was replicated in the “ARDS” cohort and correlated with increased plasma angiopoietin 2 (ANGPT2) levels. COVID-19 ARDS lung autopsy immunostaining confirmed a link between vascular injury (ANGPT2) and platelet-rich microthrombi (CD61) and induction of necrotic cell death (phosphorylated mixed lineage kinase domain-like, pMLKL). Among recovery subjects, the vascular signature identified patients with poor functional outcomes. Taken together, this vascular injury signature was associated with low platelet levels and increased mortality and could be used to identify ARDS patients most likely to benefit from vascular targeted therapies.