Platelet activation in critically ill COVID-19 patients

Nader Yatim,Frédéric Pène,Célia Azoulay,Jérôme Hadjadj,Aurélien Philippe,Solen Kernéis,Laura Barnabei,Jean‐Luc Diehl ,Darragh Duffy,David Smadja ,Jérémy Boussier ,Tristan Mirault,Coralie L Guerin,Bruno Charbit,Richard Chocron,Nicolas Gendron,Nicolas Carlier,Lina Khider,Tali‐Anne Szwebel ,Frédéric Rieux‐Laucat ,Benjamin Terrier

doi:10.1186/s13613-021-00899-1

Abstract

BackgroundMicrovascular, arterial and venous thrombotic events have been largely described during severe coronavirus disease 19 (COVID-19). However, mechanisms underlying hemostasis dysregulation remain unclear.MethodsWe explored two independent cross-sectional cohorts to identify soluble markers and gene-expression signatures that discriminated COVID-19 severity and outcomes.ResultsWe 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.ConclusionWe 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.

Highlights

Microvascular, arterial and venous thrombotic events have been largely described during severe coro‐ navirus disease 19 (COVID-19)
In particular increased D-dimer, fibrinogen and von Willebrand factor levels were found to be associated with critical illness, whereas only minor changes were noted in prothrombin time and platelet counts [8,9,10,11]
Data used for the analysis of soluble P-selectin’s ability to predict admission to intensive care unit (ICU) were extracted from a noninterventional study that was conducted at European Georges Pompidou Hospital (Paris, France) and partially described in [25] (Cohort 1)

Summary

Introduction

Microvascular, arterial and venous thrombotic events have been largely described during severe coro‐ navirus disease 19 (COVID-19). Severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) is the causative agent of the coronavirus disease 2019 (COVID-19) pandemic [1]. Severe disease is characterized by an acute respiratory distress syndrome (ARDS), respiratory failure and death in about 1% of cases [2, 3]. Most important risk factors for severe disease include age, overweight, diabetes, hypertension and history of cardiovascular disease [4, 5]. Severe and critical patients were shown to develop arterial and venous thrombotic complications, such as pulmonary embolism, stroke and myocardial infarction [6, 7].

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