Publications

Dexamethasone Suppresses Endotheliopathy and Endothelial-Induced Coagulopathy in COVID-19

BACKGROUND: Endotheliopathy and coagulopathy are known complications of COVID-19, with a significant association with mortality. Although dexamethasone is the standard of care for patients with severe COVID-19, its precise mode of action remains elusive. We aim to investigate the functional consequences of dexamethasone treatment on COVID-19–associated procoagulant endotheliopathy. METHODS: First, during the 7 days after hospitalization, we measured several endothelial and coagulopathy biomarkers in a prospective cohort of patients with COVID-19 with acute respiratory distress syndrome (ARDS) who were either treated or not with both dexamethasone and therapeutic UFH (unfractionated heparin). Second, we developed an in vitro thrombin generation assay on cultured human endothelial cells to measure the ability of stimulated endothelial colony-forming cells to activate coagulation in normal plasma, which is expressed as an endogenous thrombin potential (ETP). RESULTS: Among the cohort of 44 ARDS COVID-19 patients, 23 patients treated with dexamethasone and therapeutic UFH had significantly decreased von Willebrand Factor, Ang-2 (angiopoietin-2), soluble E-selectin, and d -dimer levels over 7 days. To differentiate the effect of UFH and dexamethasone on endotheliopathy, we used the thrombin generation assay and showed that endothelial colony-forming cell stimulation with dexamethasone but not UFH—in addition to a cocktail of proinflammatory cytokines (to mimic the cytokine storm of severe COVID-19)—significantly decreased ETP in comparison to proinflammatory cytokines only. Moreover, in another cohort of 331 patients with COVID-19 of varying severity, the endothelial colony-forming cell stimulation with the plasma of 87 ARDS patients showed significantly higher ETP (1260 nmol/L per minute [interquartile range, 1140–1260]) compared with 75 non-ARDS patients (1024 nmol/L per minute [interquartile range, 915–1200]; P <0.001). Finally, 94 dexamethasone-treated ARDS patients had significantly lower ETP (962.8 nmol/L per minute [interquartile range, 782.9–1112]) in contrast to 75 nondexamethasone-treated ARDS patients (1,260 nmol/L per minute [interquartile range, 1140–1359]; P <0.001). ETP could help predict in-hospital mortality in a Kaplan-Meier estimator analysis ( P =0.0002). CONCLUSIONS: Our data suggest that dexamethasone protects against COVID-19 endothelium-induced coagulopathy. These findings are in line with the decreased prevalence of venous thrombosis among hospitalized patients with COVID-19 treated with dexamethasone.

Capillary maturation is impaired in COPD patients during exercise training-induced angiogenesis

CD147 Plasma Levels in Hospitalised Patients with Covid-19 Pneumonia Predict Illness Severity and In-Hospital Mortality

Comment et chez qui faut-il surveiller les traitements anticoagulants ?

Elevated circulating stem cells level is observed one month after implantation of Carmat bioprosthetic total artificial heart

Abstract The Aeson® total artificial heart (A-TAH) has been developed as a total heart replacement for patients at risk of death from biventricular failure. We previously described endothelialization of the hybrid membrane inside A-TAH probably at the origin of acquired hemocompatibility. We aimed to quantify vasculogenic stem cells in peripheral blood of patients with long-term A-TAH implantation. Four male adult patients were included in this study. Peripheral blood mononuclear cells were collected before A-TAH implantation (T0) and after implantation at one month (T1), between two and five months (T2), and then between six and twelve months (T3). Supervised analysis of flow cytometry data confirmed the presence of the previously identified Lin − CD133 + CD45 − and Lin − CD34 + with different CD45 level intensities. Lin − CD133 + CD45 − , Lin − CD34 + CD45 − and Lin − CD34 + CD45 + were not modulated after A-TAH implantation. However, we demonstrated a significant mobilization of Lin − CD34 + CD45 dim ( p = 0.01) one month after A-TAH implantation regardless of the expression of CD133 or c-Kit. We then visualized data for the resulting clusters on a uniform manifold approximation and projection (UMAP) plot showing all single cells of the live Lin − and CD34 + events selected from down sampled files concatenated at T0 and T1. The three clusters upregulated in T1 are CD45 dim clusters, confirming our results. In conclusion, using a flow cytometry approach, we demonstrated in A-TAH-transplanted patients a significant mobilization of Lin − CD34 + CD45 dim in peripheral blood one month after A-TAH implantation.

Recommandations de bonne pratique pour la prise en charge de la maladie veineuse thromboembolique chez l’adulte. Version courte

Platelet activation in critically ill COVID-19 patients

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.

[Acute megakaryoblastic leukemia (AML-7) in a woman of 95 years].

Acute leukemia of megakaryocyte lineage (AML-7) is a rare entity defined by a blastic proliferation of which a part (>or= 50%) is represented by megakaryoblasts. We report the case of a 95 year old woman presenting a AML-7 secondary to a myelodysplastic syndrome (MDS), that represents an unusual form of MDS acutisation.

Plasma ratio of angiopoietin-2 to angiopoietin-1 is a biomarker of vascular impairment in chronic obstructive pulmonary disease patients

Egfl7 Represses the Vasculogenic Potential of Human Endothelial Progenitor Cells

Interleukin-8 release by endothelial colony-forming cells isolated from idiopathic pulmonary fibrosis patients might contribute to their pathogenicity

Dysfonction endothéliale et défaut de réponse au réentraînement à l’effort dans la BPCO–Mobilisation des progéniteurs endothéliaux circulants

Increase of angiogenic and angiostatic mediators in patients with idiopathic pulmonary fibrosis

HIF-Prolyl Hydroxylase 2 Inhibition Enhances the Efficiency of Mesenchymal Stem Cell-Based Therapies for the Treatment of Critical Limb Ischemia

Abstract Upregulation of hypoxia-inducible transcription factor-1α (HIF-1α), through prolyl-hydroxylase domain protein (PHD) inhibition, can be thought of as a master switch that coordinates the expression of a wide repertoire of genes involved in regulating vascular growth and remodeling. We aimed to unravel the effect of specific PHD2 isoform silencing in cell-based strategies designed to promote therapeutic revascularization in patients with critical limb ischemia (CLI). PHD2 mRNA levels were upregulated whereas that of HIF-1α were downregulated in blood cells from patients with CLI. We therefore assessed the putative beneficial effects of PHD2 silencing on human bone marrow-derived mesenchymal stem cells (hBM-MSC)-based therapy. PHD2 silencing enhanced hBM-MSC therapeutic effect in an experimental model of CLI in Nude mice, through an upregulation of HIF-1α and its target gene, VEGF-A. In addition, PHD2-transfected hBM-MSC displayed higher protection against apoptosis in vitro and increased rate of survival in the ischemic tissue, as assessed by Fluorescence Molecular Tomography. Cotransfection with HIF-1α or VEGF-A short interfering RNAs fully abrogated the beneficial effect of PHD2 silencing on the proangiogenic capacity of hBM-MSC. We finally investigated the effect of PHD2 inhibition on the revascularization potential of ischemic targeted tissues in the diabetic pathological context. Inhibition of PHD-2 with shRNAs increased postischemic neovascularization in diabetic mice with CLI. This increase was associated with an upregulation of proangiogenic and proarteriogenic factors and was blunted by concomitant silencing of HIF-1α. In conclusion, silencing of PHD2, by the transient upregulation of HIF-1α and its target gene VEGF-A, might improve the efficiency of hBM-MSC-based therapies. Stem Cells 2014;32:231–243

Cirrhotic Patients Exhibit Remarkable Vascular Regenerative Profile One Month after Liver Transplantation

0130 : Endoglin is a new partner involved in platelet – endothelium interactions: role in microvessel stability?

Intermediate-dose prophylactic anticoagulation with low molecular weight heparin is safe after bioprosthetic artificial heart implantation

Human Endothelial Colony Forming Cells Express Intracellular CD133 that Modulates their Vasculogenic Properties