Nader Yatim1,2, Jeremy Boussier1, David M Smadja3,4,5, Benjamin Terrier6,7,8, Richard Chocron9,10, Jérôme Hadjadj2,11, Aurélien Philippe3,4,5, Nicolas Gendron3,4,5, Laura Barnabei11, Bruno Charbit12, Tali-Anne Szwebel2, Nicolas Carlier13, Frédéric Pène14,15, Célia Azoulay2, Lina Khider5,16, Tristan Mirault16,9, Jean-Luc Diehl5,13,17, Coralie L Guerin3, Frédéric Rieux-Laucat11, Darragh Duffy1,12, Solen Kernéis18,19,20. 1. Translational Immunology Lab, Department of Immunology, Institut Pasteur, 75015, Paris, France. 2. Department of Internal Medicine, National Reference Center for Rare Systemic Autoimmune Diseases, AP-HP, APHP.CUP, Hôpital Cochin, 75014, Paris, France. 3. Innovative Therapies in Haemostasis, INSERM, Université de Paris, 75006, Paris, France. 4. Hematology Department, APHP-CUP, 75015, Paris, France. 5. Biosurgical Research Lab (Carpentier Foundation), Georges Pompidou European Hospital, 75015, Paris, France. 6. Department of Internal Medicine, National Reference Center for Rare Systemic Autoimmune Diseases, AP-HP, APHP.CUP, Hôpital Cochin, 75014, Paris, France. benjamin.terrier@aphp.fr. 7. Université de Paris, INSERM, U970, PARCC, Paris, France. benjamin.terrier@aphp.fr. 8. Department of Internal Medicine, Hôpital Cochin, 27, Rue du Faubourg Saint-Jacques, 75679, Paris Cedex 14, France. benjamin.terrier@aphp.fr. 9. Université de Paris, INSERM, U970, PARCC, Paris, France. 10. Emergency Department, APHP-CUP, 75015, Paris, France. 11. Imagine Institute Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM, UMR 1163, Université de Paris, 75015, Paris, France. 12. Cytometry and Biomarkers UTechS, CRT, Institut Pasteur, 75015, Paris, France. 13. Department of Pulmonology, APHP-CUP, Hôpital Cochin, 75014, Paris, France. 14. Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, 75006, Paris, France. 15. Service de Médecine Intensive and Réanimation, APHP-CUP, Hôpital Cochin, 75014, Paris, France. 16. Vascular Medicine Department, APHP-CUP, Université de Paris, 75015, Paris, France. 17. Intensive Care Unit, APHP-CUP, 75015, Paris, France. 18. Equipe Mobile d'Infectiologie, APHP-CUP, Hôpital Cochin, 75014, Paris, France. 19. Epidemiology and Modelling of Antibiotic Evasion (EMAE), Institut Pasteur, 75015, Paris, France. 20. Université de Paris, INSERM, IAME, Université de Paris, 75006, Paris, France.
Abstract
BACKGROUND: Microvascular, arterial and venous thrombotic events have been largely described during severe coronavirus disease 19 (COVID-19). 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 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. An unbiased gene set enrichment analysis revealed that critically ill patients had increased expression of genes related to platelet activation. Hierarchical clustering identified ITG2AB, GP1BB, PPBP and SELPLG to be upregulated in a grade-dependent manner. ROC curve analysis for the prediction of intubation was significant for SELPLG and PPBP (AUC = 0.8, p = 0.046 for both). An optimal cutoff value for PBPP was predictive of intubation with 100% NPV and 45% PPV, and for SELPLG with 100% NPV and 50% PPV. CONCLUSION: We provide evidence that platelets contribute to COVID-19 severity. Plasma sP-selectin level was associated with severity and in-hospital mortality. Transcriptional analysis identified PPBP/CXCL7 and SELPLG as biomarkers for intubation. These findings provide additional evidence for platelet activation in driving critical COVID-19. Specific studies evaluating the performance of these biomarkers are required.
BACKGROUND: Microvascular, arterial and venous thrombotic events have been largely described during severe coronavirus disease 19 (COVID-19). 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 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. An unbiased gene set enrichment analysis revealed that critically illpatients had increased expression of genes related to platelet activation. Hierarchical clustering identified ITG2AB, GP1BB, PPBP and SELPLG to be upregulated in a grade-dependent manner. ROC curve analysis for the prediction of intubation was significant for SELPLG and PPBP (AUC = 0.8, p = 0.046 for both). An optimal cutoff value for PBPP was predictive of intubation with 100% NPV and 45% PPV, and for SELPLG with 100% NPV and 50% PPV. CONCLUSION: We provide evidence that platelets contribute to COVID-19 severity. Plasma sP-selectin level was associated with severity and in-hospital mortality. Transcriptional analysis identified PPBP/CXCL7 and SELPLG as biomarkers for intubation. These findings provide additional evidence for platelet activation in driving critical COVID-19. Specific studies evaluating the performance of these biomarkers are required.
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