Systemic inflammation in critically ill patients can lead to serious consequences such as acute respiratory distress syndrome (ARDS), a condition characterized by the presence of lung inflammation, edema, and impaired gas exchange, associated with poor survival. Understanding molecular pathobiology is essential to improve critical care of these patients. To this end, we use multimodal profiles of SARS-CoV-2 infected hospitalized participants to the Biobanque Québécoise de la COVID-19 (BQC-19) to characterize endophenotypes associated with different degrees of disease severity. Proteomic, metabolomic, and genomic characterization supported a role for neutrophil-associated procoagulant activity in severe COVID-19 ARDS that is inversely correlated with sphinghosine-1 phosphate plasma levels. Fibroblast Growth Factor Receptor (FGFR) and SH2-containing transforming protein 4 (SHC4) signaling were identified as molecular features associated with endophenotype 6 (EP6). Mechanical ventilation in EP6 was associated with alterations in lipoprotein metabolism. These findings help define the molecular mechanisms related to specific severe outcomes, that can be used to identify early unfavorable clinical trajectories and treatable traits to improve the survival of critically ill patients.