Dysregulated primary hemostasis in critically ill COVID-19 patients

Abstract Background: Microvascular thrombosis, as well as arterial and venous thrombotic events, have been largely described during severe Coronavirus disease 19 (COVID-19). Therapeutic anticoagulation has been proposed in critical patients, however mechanisms underlying hemostasis dysregulation remain unclear. Methods: We explored two independent cross-sectional cohorts to identify soluble markers and gene-expression signatures that discriminated COVID-19 severity and outcomes. Results: We found that elevated soluble (s) P-selectin at admission was associated with disease severity. Elevated sP-selectin was predictive of intubation and death (ROC AUC = 0.67, p = 0.028 and AUC = 0.74, p = 0.0047, respectively). An optimal cutoff value of 150 NC (normalized concentration) was predictive of intubation with 66% negative predictive value (NPV) and 61% positive predictive value (PPV), and of death with 90% NPV and 55% PPV. Next, an unbiased gene set enrichment analysis revealed that critically ill patients had increased expression of genes related to primary hemostasis. Hierarchical clustering identified ITG2AB , GP1BB , PPBP and SELPLG to be upregulated in a grade-dependent manner. ROC curve analysis for the prediction of mechanical ventilation was significant for SELPLG and PPBP (AUC = 0.8, p = 0.046 for both markers). An optimal cutoff value for PBPP was predictive of mechanical ventilation with 100% NPV and 45% PPV, and for SELPLG was predictive of mechanical ventilation with 100% NPV and 50% PPV. Conclusion: We provide evidence that platelets contribute to disease severity with the identification of sP-selectin as a biomarker for poor outcome. Transcriptional analysis identified PPBP and SELPLG RNA count as biomarkers for mechanical ventilation. These findings provide rationale for novel therapeutic approaches with antiplatelet agents.