Publications by authors named "David Smadja"

148 Publications

Immune Signature Linked to COVID-19 Severity: A SARS-Score for Personalized Medicine.

Front Immunol 2021 12;12:701273. Epub 2021 Jul 12.

Centre de Recherche des Cordeliers, Sorbonne Universite, Inserm, Universite de Paris, Team Inflammation, Complement and Cancer, Paris, France.

SARS-CoV-2 infection leads to a highly variable clinical evolution, ranging from asymptomatic to severe disease with acute respiratory distress syndrome, requiring intensive care units (ICU) admission. The optimal management of hospitalized patients has become a worldwide concern and identification of immune biomarkers predictive of the clinical outcome for hospitalized patients remains a major challenge. Immunophenotyping and transcriptomic analysis of hospitalized COVID-19 patients at admission allow identifying the two categories of patients. Inflammation, high neutrophil activation, dysfunctional monocytic response and a strongly impaired adaptive immune response was observed in patients who will experience the more severe form of the disease. This observation was validated in an independent cohort of patients. Using analysis on drug signature database, we identify differential therapeutics that specifically correspond to each group of patients. From this signature, we propose a score-the SARS-Score-composed of easily quantifiable biomarkers, to classify hospitalized patients upon arrival to adapt treatment according to their immune profile.
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http://dx.doi.org/10.3389/fimmu.2021.701273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312547PMC
July 2021

Platelet activation in critically ill COVID-19 patients.

Ann Intensive Care 2021 Jul 17;11(1):113. Epub 2021 Jul 17.

Department of Internal Medicine, National Reference Center for Rare Systemic Autoimmune Diseases, AP-HP, APHP.CUP, Hôpital Cochin, 75014, Paris, France.

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.
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http://dx.doi.org/10.1186/s13613-021-00899-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286043PMC
July 2021

COVID-19 is a systemic vascular hemopathy: insight for mechanistic and clinical aspects.

Angiogenesis 2021 Jun 28. Epub 2021 Jun 28.

Angiogenesis Laboratory, Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is presenting as a systemic disease associated with vascular inflammation and endothelial injury. Severe forms of SARS-CoV-2 infection induce acute respiratory distress syndrome (ARDS) and there is still an ongoing debate on whether COVID-19 ARDS and its perfusion defect differs from ARDS induced by other causes. Beside pro-inflammatory cytokines (such as interleukin-1 β [IL-1β] or IL-6), several main pathological phenomena have been seen because of endothelial cell (EC) dysfunction: hypercoagulation reflected by fibrin degradation products called D-dimers, micro- and macrothrombosis and pathological angiogenesis. Direct endothelial infection by SARS-CoV-2 is not likely to occur and ACE-2 expression by EC is a matter of debate. Indeed, endothelial damage reported in severely ill patients with COVID-19 could be more likely secondary to infection of neighboring cells and/or a consequence of inflammation. Endotheliopathy could give rise to hypercoagulation by alteration in the levels of different factors such as von Willebrand factor. Other than thrombotic events, pathological angiogenesis is among the recent findings. Overexpression of different proangiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF-2) or placental growth factors (PlGF) have been found in plasma or lung biopsies of COVID-19 patients. Finally, SARS-CoV-2 infection induces an emergency myelopoiesis associated to deregulated immunity and mobilization of endothelial progenitor cells, leading to features of acquired hematological malignancies or cardiovascular disease, which are discussed in this review. Altogether, this review will try to elucidate the pathophysiology of thrombotic complications, pathological angiogenesis and EC dysfunction, allowing better insight in new targets and antithrombotic protocols to better address vascular system dysfunction. Since treating SARS-CoV-2 infection and its potential long-term effects involves targeting the vascular compartment and/or mobilization of immature immune cells, we propose to define COVID-19 and its complications as a systemic vascular acquired hemopathy.
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http://dx.doi.org/10.1007/s10456-021-09805-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238037PMC
June 2021

Intramuscular Vaccination in Adults with Therapeutic Anticoagulation in the Era of COVID-19 Vaccines Outbreak: A Practical Review.

TH Open 2021 Apr 25;5(2):e166-e170. Epub 2021 May 25.

Hematology department and Biosurgical Research Lab (Carpentier Foundation), Assistance Publique Hôpitaux de Paris.Centre-Université de Paris (APHP-CUP), Université de Paris, Innovative Therapies in Haemostasis, INSERM, Paris, France.

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http://dx.doi.org/10.1055/s-0041-1729627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149207PMC
April 2021

Endothelial Dysfunction as a Component of Severe Acute Respiratory Syndrome Coronavirus 2-Related Multisystem Inflammatory Syndrome in Children With Shock.

Crit Care Med 2021 Jun 1. Epub 2021 Jun 1.

Department of Biological Hematology, Necker Hospital, AP-HP Centre-Universiteé de Paris, Paris, France. HITh, UMR_S 1176, INSERM, Univ. Paris-Saclay, Le Kremlin-Bicêtre, France. Emergency Department, Georges Pompidou European Hospital, AP-HP Centre Universiteé de Paris, Paris, France. Universiteé de Paris, PARCC, INSERM, Paris, France. Pediatric Intensive Care Unit, Necker Hospital, AP-HP Centre Universiteé de Paris, Paris, France. Hematology Department and Biosurgical Research Lab (Carpentier Foundation), Georges Pompidou European Hospital, AP-HP Centre Universiteé de Paris, Paris, France. Universiteé de Paris, Innovative Therapies in Hemostasis, INSERM, Paris, France. Universiteé de Paris, EA7323, Paris, France. M3C-Necker, Congenital and Pediatric Cardiology, Necker Hospital, AP-HP Centre-Universiteé de Paris, Paris, France. Department of General Pediatrics and Pediatric Infectious Diseases, Necker Hospital, AP-HP Centre-Universiteé de Paris, Paris, France. Pediatric Emergency Department, Necker Hospital, AP-HP Centre Universiteé de Paris, Paris, France. INSERM, Centre de Recherche des Cordeliers, UMRS 1138, Sorbonne Université, Université de Paris, Paris, France.

Trial Registration: NCT04420468.

Objectives: Severe acute respiratory syndrome coronavirus 2-related multisystem inflammatory syndrome in children is frequently associated with shock; endothelial involvement may be one of the underlying mechanisms. We sought to describe endothelial dysfunction during multisystem inflammatory syndrome in children with shock and then assess the relationship between the degree of endothelial involvement and the severity of shock.

Design: Observational study.

Setting: A PICU in a tertiary hospital.

Patients: Patients aged under 18 (n = 28) with severe acute respiratory syndrome coronavirus 2-related multisystem inflammatory syndrome in children and shock, according to the Centers for Disease Control and Prevention criteria.

Interventions: None.

Measurements And Main Results: Correlations between endothelial marker levels and shock severity were assessed using Spearman coefficient. The median (interquartile range) age was 9 years (7.5-11.2 yr). Sixteen children presented with cardiogenic and distributive shock, 10 presented with cardiogenic shock only, and two presented with distributive shock only. The median left ventricular ejection fraction, troponin level, and lactate level were, respectively, 40% (35-45%), 261 ng/mL (131-390 ng/mL), and 3.2 mmol/L (2-4.2 mmol/L). Twenty-five children received inotropes and/or vasopressors; the median Vasoactive and Inotropic Score was 8 (5-28). Plasma levels of angiopoietin-2 (6,426 pg/mL [2,814-11,836 pg/mL]), sE-selectin (130,405 pg/mL [92,987-192,499 pg/mL]), von Willebrand factor antigen (344% [288-378%]), and the angiopoietin-2/angiopoietin-1 ratio (1.111 [0.472-1.524]) were elevated and significantly correlated with the Vasoactive and Inotropic Score (r = 0.45, p = 0.016; r = 0.53, p = 0.04; r = 0.46, p = 0.013; and r = 0.46, p = 0.012, respectively).

Conclusions: Endothelial dysfunction is associated with severe acute respiratory syndrome coronavirus 2-related multisystem inflammatory syndrome in children with shock and may constitute one of the underlying mechanisms.
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http://dx.doi.org/10.1097/CCM.0000000000005093DOI Listing
June 2021

Differential association between inflammatory cytokines and multiorgan dysfunction in COVID-19 patients with obesity.

PLoS One 2021 26;16(5):e0252026. Epub 2021 May 26.

INSERM UMRS 1138, Cordeliers Research Center, Team Inflammation, Complement, and Cancer, Paris, France.

To investigate the mechanisms underlying the SARS-CoV-2 infection severity observed in patients with obesity, we performed a prospective study of 51 patients evaluating the impact of multiple immune parameters during 2 weeks after admission, on vital organs' functions according to body mass index (BMI) categories. High-dimensional flow cytometric characterization of immune cell subsets was performed at admission, 30 systemic cytokines/chemokines levels were sequentially measured, thirteen endothelial markers were determined at admission and at the zenith of the cytokines. Computed tomography scans on admission were quantified for lung damage and hepatic steatosis (n = 23). Abnormal BMI (> 25) observed in 72.6% of patients, was associated with a higher rate of intensive care unit hospitalization (p = 0.044). SARS-CoV-2 RNAaemia, peripheral immune cell subsets and cytokines/chemokines were similar among BMI groups. A significant association between inflammatory cytokines and liver, renal, and endothelial dysfunctions was observed only in patients with obesity (BMI > 30). In contrast, early signs of lung damage (ground-glass opacity) correlated with Th1/M1/inflammatory cytokines only in normal weight patients. Later lesions of pulmonary consolidation correlated with BMI but were independent of cytokine levels. Our study reveals distinct physiopathological mechanisms associated with SARS-CoV-2 infection in patients with obesity that may have important clinical implications.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0252026PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153504PMC
June 2021

Optical changes and apparent emmetropization in a patient with a peripheral unilateral lens coloboma.

J AAPOS 2021 May 11. Epub 2021 May 11.

Department of Ophthalmology, Shaare Zedek Medical Center, Jerusalem, Israel, affiliated to the Hebrew University, Jerusalem, Israel.

Lens coloboma is a developmental defect resulting from abnormalities of the zonules and ciliary body. It may present as an isolated pathology or be accompanied by anomalies in different ocular structures. We report the case of a 20-year-old man referred for evaluation of anisometropic amblyopia in the right eye. Manifest refraction was -2.25 +3.00 ×35 in the right eye; corrected distance visual acuity, 20/50. Corneal topography revealed regular astigmatism of +2.46 D at 124°, and wavefront aberrometry revealed an irregular internal astigmatism of +6.27 D at 35°. Only after full pupillary dilation was a peripheral lens coloboma observed. This case demonstrates that even minor distortions of clear and normally positioned lenses may lead to amblyopia and raises the possibility that corneal changes may occur developmentally through the process of emmetropization partly to compensate for lenticular astigmatism arising from the coloboma.
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http://dx.doi.org/10.1016/j.jaapos.2021.02.006DOI Listing
May 2021

Von Willebrand factor collagen-binding capacity predicts in-hospital mortality in COVID-19 patients: insight from VWF/ADAMTS13 ratio imbalance.

Angiogenesis 2021 08 11;24(3):407-411. Epub 2021 May 11.

Université de Paris, Innovative Therapies in Haemostasis, INSERM, 75006, Paris, France.

Background: Microthrombosis is a hallmark of COVID-19. We previously described von willebrand factor (VWF) and their high molecular weight multimers (HMWMs) as potential trigger of microthrombosis.

Objectives: Investigate VWF activity with collagen-binding assay and ADAMTS13 in COVID-19.

Methods And Results: Our study enrolled 77 hospitalized COVID-19 patients including 37 suffering from a non-critical form and 40 with critical form. Plasma levels of VWF collagen-binding ability (VWF:CB) and ADAMTS13 activity (ADAMTS13:Act) were measured in the first 48 hours following admission. VWF:CB was increased in critical (631% IQR [460-704]) patients compared to non-critical patients (259% [235-330], p < 0.005). VWF:CB was significantly associated (r = 0.564, p < 0.001) with HMWMs. Moreover, median ADAMTS13:Act was lower in critical (64.8 IU/dL IQR 50.0-77.7) than non-critical patients (85.0 IU/dL IQR 75.8-94.7, p < 0.001), even if no patients displayed majors deficits. VWF:Ag-to-ADAMTS13:Act ratio was highly associated with VWF:CB (r = 0.916, p < 0.001). Moreover, VWF:CB level was highly predictive of COVID-19 in-hospital mortality as shown by the ROC curve analysis (AUC = 0.92, p < 0.0001) in which we identified a VWF:CB cut-off of 446% as providing the best predictor sensitivity-specificity balance. We confirmed this cut-off thanks to a Kaplan-Meier estimator analysis (log-rank p < 0.001) and a Cox-proportional Hazard model (HR = 49.1, 95% CI 1.81-1328.2, p = 0.021) adjusted on, BMI, C-reactive protein, and D-dimer levels.

Conclusion: VWF:CB levels could summarize both VWF increased levels and hyper-reactivity subsequent to ADAMTS13 overflow and, therefore, be a valuable and easy to perform clinical biomarker of microthrombosis and COVID-19 severity.
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http://dx.doi.org/10.1007/s10456-021-09789-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111656PMC
August 2021

Lupus anticoagulant single positivity at acute phase is not associated with venous thromboembolism or in-hospital mortality in COVID-19.

Arthritis Rheumatol 2021 Apr 21. Epub 2021 Apr 21.

Université de Paris, Innovative Therapies in Haemostasis, INSERM, F-75006 Paris, France, Respiratory Medicine Department and Biosurgical Research Lab (Carpentier Foundation), Assistance Publique - Hôpitaux de Paris-Centre (APHP-CUP), F-75015, Paris, France.

Introduction: Antiphospholipid antibodies (APA) clinical relevance in COVID-19 is controversial. We aimed to investigate the prevalence and prognostic value of conventional and non-conventional APA in COVID-19 patients.

Methods: This study was a multi-centric, prospective observational French cohort of patients hospitalized for COVID-19 suspicion.

Results: 249 patients were hospitalized for suspected COVID-19, including 154 with confirmed COVID-19 and 95 not confirmed. We found a significant increase in lupus anticoagulant (LA) positivity among COVID-19 positive patients (60.9% versus 23.7% in non-COVID19 patients, p<0.001), while prevalence of conventional (anti-cardiolipin and anti-beta-2-GP1, IgG and IgM isotypes) and non-conventional APA (IgA, anti-phosphatidylserine/prothrombin and anti-prothrombin IgG and IgM) were low in both groups. COVID-19 patients with LA positivity had higher levels of fibrinogen (6.0 IQR 5.0-7.0 versus 5.3 g/L IQR 4.3-6.4, p=0.028) and C-reactive protein (CRP, 115.5 IQR 66.0-204.8 versus 91.8 mg/L IQR 27.0-155.1, p=0.019). Univariate analysis did not show any association between LA positivity and higher risk of venous thromboembolism (VTE, OR 1.02, 95% CI 0.44-2.43, p=0.95) or in-hospital mortality (OR 1.80, 95% CI 0.70-5.05, p=0.24). Unadjusted and adjusted (to CRP, age and sex) Kaplan-Meier survival curves according to LA positivity confirmed the absence of association with VTE or in-hospital mortality (unadjusted: p=0.64 and p=0.26, respectively; adjusted: hazard ratio = 1.13 95% CI 0.48-2.60 and 1.80 95% CI 0.67-5.01).

Conclusions: COVID-19 patients have an increased prevalence of LA positivity associated with biological inflammation markers. However, positive LA at admission is not associated with VTE risk and/or in-hospital mortality.
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http://dx.doi.org/10.1002/art.41777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250965PMC
April 2021

A Rare Case of Acute Bilateral Endothelial Decompensation after Prophylactic Nd:YAG Laser Iridotomy Requiring Endothelial Keratoplasty.

J Curr Glaucoma Pract 2020 Sep-Dec;14(3):109-111

Department of Ophthalmology, Shaare Zedek Medical Center, Affiliated to the Hebrew University, Jerusalem, Israel.

Aim: To describe a case of acute bilateral endothelial decompensation following prophylactic Nd:YAG laser iridotomy (LI) for occludable angles.

Background: Although regarded safe, LI can occasionally be a source of various ocular complications, including corneal endothelial damage. In the herein case, we describe the first case of acute bilateral endothelial decompensation after Nd:YAG LI.

Case Description: A 63-year-old man was referred for consultation due to visual acuity deterioration in both eyes 2 weeks after undergoing an uneventful prophylactic LI for occludable angles. On examination, bilateral corneal edema with Descemet's membrane folds was observed. Direct corneal damage from the laser beam was not seen. Specular microscopy failed to count endothelial density. Anterior-segment optical coherence tomography (OCT), ultrasound biomicroscopy, and ocular biometry were performed. The patient was referred for bilateral endothelial keratoplasty.

Conclusion: Subacute endothelial dysfunction should be considered as a possible adverse event following Nd:YAG LI and patients should be advised accordingly.

Clinical Relevance: Surgeons should be aware of the potentially devastating complication of bilateral corneal decompensation following routine Nd:YAG LI, even in patients without preexisting corneal injury. Patients should be advised accordingly.

How To Cite This Article: Weill Y, Abulafia A, Smadja D, A Rare Case of Acute Bilateral Endothelial Decompensation after Prophylactic Nd:YAG Laser Iridotomy Requiring Endothelial Keratoplasty. J Curr Glaucoma Pract 2020;14(3):109-111.
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http://dx.doi.org/10.5005/jp-journals-10078-1285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028029PMC
April 2021

D-dimer at hospital admission for COVID-19 are associated with in-hospital mortality, independent of venous thromboembolism: Insights from a French multicenter cohort study.

Arch Cardiovasc Dis 2021 May 9;114(5):381-393. Epub 2021 Mar 9.

Université de Paris, PARCC, INSERM, 75015 Paris, France.

Background: Coronavirus disease 2019 (COVID-19) has been associated with coagulation disorders, in particular high concentrations of D-dimer, and increased frequency of venous thromboembolism.

Aim: To explore the association between D-dimer at admission and in-hospital mortality in patients hospitalised for COVID-19, with or without symptomatic venous thromboembolism.

Methods: From 26 February to 20 April 2020, D-dimer concentration at admission and outcomes (in-hospital mortality and venous thromboembolism) of patients hospitalised for COVID-19 in medical wards were retrospectively analysed in a multicenter study in 24 French hospitals.

Results: Among 2878 patients enrolled in the study, 1154 (40.1%) patients had D-dimer measurement at admission. Receiver operating characteristic curve analysis identified a D-dimer concentration>1128ng/mL as the best cut-off value for in-hospital mortality (area under the curve 64.9%, 95% confidence interval [CI] 60-69), with a sensitivity of 71.1% (95% CI 62-78) and a specificity of 55.6% (95% CI 52-58), which did not differ in the subgroup of patients with venous thromboembolism during hospitalisation. Among 545 (47.2%) patients with D-dimer concentration>1128ng/mL at admission, 86 (15.8%) deaths occurred during hospitalisation. After adjustment, in Cox proportional hazards and logistic regression models, D-dimer concentration>1128ng/mL at admission was also associated with a worse prognosis, with an odds ratio of 3.07 (95% CI 2.05-4.69; P<0.001) and an adjusted hazard ratio of 2.11 (95% CI 1.31-3.4; P<0.01).

Conclusions: D-dimer concentration>1128ng/mL is a relevant predictive factor for in-hospital mortality in patients hospitalised for COVID-19 in a medical ward, regardless of the occurrence of venous thromboembolism during hospitalisation.
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http://dx.doi.org/10.1016/j.acvd.2021.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942155PMC
May 2021

Placental growth factor level in plasma predicts COVID-19 severity and in-hospital mortality.

J Thromb Haemost 2021 07 17;19(7):1823-1830. Epub 2021 May 17.

Université de Paris, PARCC, INSERM U970, Paris, France.

Background: Coronavirus disease 2019 (COVID-19) is a respiratory disease associated with vascular inflammation and endothelial injury.

Objectives: To correlate circulating angiogenic markers vascular endothelial growth factor A (VEGF-A), placental growth factor (PlGF), and fibroblast growth factor 2 (FGF-2) to in-hospital mortality in COVID-19 adult patients.

Methods: Consecutive ambulatory and hospitalized patients with COVID-19 infection were enrolled. VEGF-A, PlGF, and FGF-2 were measured in each patient ≤48 h following admission.

Results: The study enrolled 237 patients with suspected COVID-19: 208 patients had a positive diagnostic for COVID-19, of whom 23 were mild outpatients and 185 patients hospitalized after admission. Levels of VEGF-A, PlGF, and FGF-2 significantly increase with the severity of the disease (P < .001). Using a logistic regression model, we found a significant association between the increase of FGF-2 or PlGF and mortality (odds ratio [OR] 1.11, 95% confidence interval [CI; 1.07-1.16], P < .001 for FGF-2 and OR 1.07 95% CI [1.04-1.10], P < .001 for PlGF) while no association were found for VEGF-A levels. Receiver operating characteristic curve analysis was performed and we identified PlGF above 30 pg/ml as the best predictor of in-hospital mortality in COVID-19 patients. Survival analysis for PlGF confirmed its interest for in-hospital mortality prediction, by using a Kaplan-Meier survival curve (P = .001) and a Cox proportional hazard model adjusted to age, body mass index, D-dimer, and C-reactive protein (3.23 95% CI [1.29-8.11], P = .001).

Conclusion: Angiogenic factor PlGF is a relevant predictive factor for in-hospital mortality in COVID-19 patients. More than a biomarker, we hypothesize that PlGF blocking strategies could be a new interesting therapeutic approach in COVID-19.
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http://dx.doi.org/10.1111/jth.15339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250221PMC
July 2021

Appropriate Use of Idarucizumab for Dabigatran Reversal According to the International Society on Thrombosis and Hemostasis and French Working Group on Perioperative Hemostasis: A French Retrospective Study.

J Cardiothorac Vasc Anesth 2021 Feb 12. Epub 2021 Feb 12.

Université de Paris, Innovative Therapies in Hemostasis, INSERM; Hematology Department and Biosurgical Research Lab, (Carpentier Foundation) Assistance Publique Hôpitaux de Paris, Centre-Université de Paris (APHP-CUP), 75015, Paris, France; F-CRIN INNOVTE, Saint-Étienne, France.

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http://dx.doi.org/10.1053/j.jvca.2021.02.029DOI Listing
February 2021

Do Endothelial Colony-forming Cells Come From Bone Marrow or Vessels/VSELs?

Stem Cell Rev Rep 2021 Aug 2;17(4):1500-1502. Epub 2021 Mar 2.

Innovative Therapies in Hemostasis, Université de Paris, INSERM, F-75006, Paris, France.

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http://dx.doi.org/10.1007/s12015-021-10140-yDOI Listing
August 2021

Interface Fluid Syndrome 2 Decades After Laser-Assisted In situ Keratomileusis.

Eye Contact Lens 2021 06;47(6):381-382

Department of Ophthalmology, Shaare Zedek Medical Center, Jerusalem, Israel, affiliated to the Hebrew University, Jerusalem, Israel.

Purpose: To report a case of late-onset interface fluid syndrome (IFS) after laser-assisted in situ keratomileusis (LASIK).

Methods: A 94-year-old man was referred for evaluation because of persistent corneal edema 10 days after Descemet Stripping Automated Endothelial Keratoplasty (DSAEK) for pseudophakic bullous keratopathy.

Results: After an uneventful DSAEK, the patient was treated with topical antibiotics and steroids. On presentation, a well positioned and oriented DSAEK graft was observed in the right eye, yet the cornea was edematous. Applanation tonometry was normal. Anterior-segment optical coherence tomography (AS-OCT) revealed a LASIK flap with a fluid cleft beneath it. Requery confirmed that LASIK was performed 21 years ago. Topical steroids were stopped, and after 2 weeks, the cornea was clear, and AS-OCT revealed complete resolution of the interface fluid.

Conclusions: Even decades later, IFS should be considered as a source of corneal edema in patients after LASIK. Monitoring these patients with AS-OCT is recommended.
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http://dx.doi.org/10.1097/ICL.0000000000000775DOI Listing
June 2021

Anticoagulation Before Hospitalization Is a Potential Protective Factor for COVID-19: Insight From a French Multicenter Cohort Study.

J Am Heart Assoc 2021 04 8;10(8):e018624. Epub 2021 Feb 8.

PARCC INSERM Université de Paris France.

Background Coronavirus disease 2019 (COVID-19) is a respiratory disease associated with thrombotic outcomes with coagulation and endothelial disorders. Based on that, several anticoagulation guidelines have been proposed. We aimed to determine whether anticoagulation therapy modifies the risk of developing severe COVID-19. Methods and Results Patients with COVID-19 initially admitted in medical wards of 24 French hospitals were included prospectively from February 26 to April 20, 2020. We used a Poisson regression model, Cox proportional hazard model, and matched propensity score to assess the effect of anticoagulation on outcomes (intensive care unit admission or in-hospital mortality). The study enrolled 2878 patients with COVID-19, among whom 382 (13.2%) were treated with oral anticoagulation therapy before hospitalization. After adjustment, anticoagulation therapy before hospitalization was associated with a better prognosis with an adjusted hazard ratio of 0.70 (95% CI, 0.55-0.88). Analyses performed using propensity score matching confirmed that anticoagulation therapy before hospitalization was associated with a better prognosis, with an adjusted hazard ratio of 0.43 (95% CI, 0.29-0.63) for intensive care unit admission and adjusted hazard ratio of 0.76 (95% CI, 0.61-0.98) for composite criteria intensive care unit admission or death. In contrast, therapeutic or prophylactic low- or high-dose anticoagulation started during hospitalization were not associated with any of the outcomes. Conclusions Anticoagulation therapy used before hospitalization in medical wards was associated with a better prognosis in contrast with anticoagulation initiated during hospitalization. Anticoagulation therapy introduced in early disease could better prevent COVID-19-associated coagulopathy and endotheliopathy, and lead to a better prognosis.
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http://dx.doi.org/10.1161/JAHA.120.018624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174166PMC
April 2021

Influence of Reading on Smartphone Screens on Visual Optical Quality Metrics and Tear Film Stability.

Cornea 2021 Jan 18. Epub 2021 Jan 18.

Department of Ophthalmology, Shaare Zedek Medical Center, Jerusalem, Israel; Affiliated with the Hebrew University of Jerusalem; and iSEARCH, Innovation Shaarezedek Eye Advanced Research Center Hub, Jerusalem, Israel.

Purpose: To evaluate the impact of a prolonged reading session on a smartphone screen on optical quality metrics and tear film stability.

Methods: This prospective study was conducted in 41 healthy volunteers who were asked to read an article on a smartphone screen for 20 minutes. The following tests were performed before the reading task in this consecutive order and repeated after the reading task in the same order: automated noninvasive tear break-up time, optical quality assessment including Objective Scatter Index (OSI), modulation transfer function, Strehl ratio, and tear film dynamic analysis as follows: vision break-up time (VBUT) as a function of OSI changes within 20 seconds, using a double-pass aberrometer imaging system, and fluorescein tear break-up time (FBUT) measured using the slit lamp.

Results: All break-up time-related parameters (noninvasive tear break-up time, FBUT and VBUT) were significantly reduced after the reading task (P < 0.01). The OSI was significantly worsened after the reading task (P = 0.01), whereas all the other optical quality metrics (modulation transfer function and Strehl ratio) slightly deteriorated, were not statistically significant. A significant correlation was found between the shortening of the FBUT, VBUT, and the worsening of the OSI (r = -0.33, P < 0.05).

Conclusions: A reading session on a smartphone screen in healthy subjects was found to significantly affect the tear film stability and objectively worsen the retinal image quality.
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http://dx.doi.org/10.1097/ICO.0000000000002656DOI Listing
January 2021

Circulating Von Willebrand factor and high molecular weight multimers as markers of endothelial injury predict COVID-19 in-hospital mortality.

Angiogenesis 2021 08 15;24(3):505-517. Epub 2021 Jan 15.

Université de Paris, Institut Cochin, INSERM, 75014 Paris, France, Hematology Department Assistance Publique Hôpitaux de Paris. Centre-Université de Paris (APHP-CUP), Cochin Hospital, 75014, Paris, France.

Background: Coronavirus disease 2019 (COVID-19) is a respiratory disease associated with endotheliitis and microthrombosis.

Objectives: To correlate endothelial dysfunction to in-hospital mortality in a bi-centric cohort of COVID-19 adult patients.

Methods: Consecutive ambulatory and hospitalized patients with laboratory-confirmed COVID-19 were enrolled. A panel of endothelial biomarkers and von Willebrand factor (VWF) multimers were measured in each patient ≤ 48 h following admission.

Results: Study enrolled 208 COVID-19 patients of whom 23 were mild outpatients and 189 patients hospitalized after admission. Most of endothelial biomarkers tested were found increased in the 89 critical patients transferred to intensive care unit. However, only von Willebrand factor antigen (VWF:Ag) scaled according to clinical severity, with levels significantly higher in critical patients (median 507%, IQR 428-596) compared to non-critical patients (288%, 230-350, p < 0.0001) or COVID-19 outpatients (144%, 133-198, p = 0.007). Moreover, VWF high molecular weight multimers (HMWM) were significantly higher in critical patients (median ratio 1.18, IQR 0.86-1.09) compared to non-critical patients (0.96, 1.04-1.39, p < 0.001). Among all endothelial biomarkers measured, ROC curve analysis identified a VWF:Ag cut-off of 423% as the best predictor for in-hospital mortality. The accuracy of VWF:Ag was further confirmed in a Kaplan-Meier estimator analysis and a Cox proportional Hazard model adjusted on age, BMI, C-reactive protein and D-dimer levels.

Conclusion: VWF:Ag is a relevant predictive factor for in-hospital mortality in COVID-19 patients. More than a biomarker, we hypothesize that VWF, including excess of HMWM forms, drives microthrombosis in COVID-19.
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http://dx.doi.org/10.1007/s10456-020-09762-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809553PMC
August 2021

Dabigatran Level Before Reversal Can Predict Hemostatic Effectiveness of Idarucizumab in a Real-World Setting.

Front Med (Lausanne) 2020 16;7:599626. Epub 2020 Dec 16.

Université de Paris, Innovative Therapies in Haemostasis, INSERM, Paris, France.

Idarucizumab has been included in guidelines for the management of bleeding or surgical procedure in dabigatran-treated patients without need for biological monitoring. The aim of the study was to assess the prognostic value of dabigatran plasma level before reversal to test the hemostatic efficacy of idarucizumab. The secondary objectives were (i) to analyze plasma dabigatran level according to the risk of rebound and (ii) to evaluate the incidence of post-reversal non-favorable clinical outcomes (including thromboembolism, bleeding, antithrombotic, and death) and antithrombotic resumption. This was an observational multicentric cohort study, which included all French patients who required idarucizumab for dabigatran reversal. Between May 2016 and April 2019, 87 patients from 21 French centers were enrolled. Patients received idarucizumab for overt bleeding ( = 61), urgent procedures ( = 24), or overdose without bleeding ( = 2). Among patients with major bleeding ( = 57), treatment with idarucizumab was considered effective in 44 (77.2%) of them. Patients who did not achieve effective hemostasis after reversal had a significantly higher mean level of plasma dabigatran at baseline (524.5 ± 386 vs. 252.8 ng/mL ± 235, = 0.033). Furthermore, patients who did not achieve effective hemostasis after reversal had less favorable outcomes during follow-up (46.2 vs. 81.8%, = 0.027). ROC curve identified a cutoff of 264 ng/mL for dabigatran level at admission to be predictive of ineffective hemostasis. No plasma dabigatran rebound was observed after reversal in patients with dabigatran plasma level < 264 ng/mL at baseline. This retrospective study shows that dabigatran level before reversal could predict hemostatic effectiveness and dabigatran plasma rebound after idarucizumab injection.
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http://dx.doi.org/10.3389/fmed.2020.599626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772865PMC
December 2020

No impact of cancer and plague-relevant polymorphisms on COVID-19.

Oncoimmunology 2020 12 8;9(1):1857112. Epub 2020 Dec 8.

Equipe Labellisée Par La Ligue Contre Le Cancer, Université De Paris, Sorbonne Université, INSERM U1138, Centre De Recherche Des Cordeliers, Paris, France.

Formyl peptide receptor 1 (FPR1) is a pattern-recognition receptor that detects bacterial as well as endogenous danger-associated molecular patterns to trigger innate immune responses by myeloid cells. A single nucleotide polymorphism, rs867228 (allelic frequency 19-20%), in the gene coding for FPR1 accelerates the manifestation of multiple carcinomas, likely due to reduced anticancer immunosurveillance secondary to a defect in antigen presentation by dendritic cells. Another polymorphism in , rs5030880 (allelic frequency 12-13%), has been involved in the resistance to plague, correlating with the fact that FPR1 is the receptor for . Driven by the reported preclinical effects of FPR1 on lung inflammation and fibrosis, we investigated whether rs867228 or rs5030880 would affect the severity of coronavirus disease-19 (COVID-19). Data obtained on patients from two different hospitals in Paris refute the hypothesis that rs867228 or rs5030880 would affect the severity of COVID-19.
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http://dx.doi.org/10.1080/2162402X.2020.1857112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734042PMC
December 2020

Predictive Factor for COVID-19 Worsening: Insights for High-Sensitivity Troponin and D-Dimer and Correlation With Right Ventricular Afterload.

Front Med (Lausanne) 2020 12;7:586307. Epub 2020 Nov 12.

Innovative Therapies in Haemostasis, INSERM, Université de Paris, Paris, France.

Coronavirus disease 2019 (COVID-19) has been associated with cardiovascular complications and coagulation disorders. To explore clinical and biological parameters of COVID-19 patients with hospitalization criteria that could predict referral to intensive care unit (ICU). Analyzing the clinical and biological profiles of COVID-19 patients at admission. Among 99 consecutive patients that fulfilled criteria for hospitalization, 48 were hospitalized in the medicine department, 21 were first admitted to the medicine ward department and referred later to ICU, and 30 were directly admitted to ICU from the emergency department. At admission, patients requiring ICU were more likely to have lymphopenia, decreased SpO, a D-dimer level above 1,000 ng/mL, and a higher high-sensitivity cardiac troponin (Hs-cTnI) level. A receiver operating characteristic curve analysis identified Hs-cTnI above 9.75 pg/mL as the best predictive criteria for ICU referral [area under the curve (AUC), 86.4; 95% CI, 76.6-96.2]. This cutoff for Hs-cTnI was confirmed in univariate [odds ratio (OR), 22.8; 95% CI, 6.0-116.2] and multivariate analysis after adjustment for D-dimer level (adjusted OR, 20.85; 95% CI, 4.76-128.4). Transthoracic echocardiography parameters subsequently measured in 72 patients showed an increased right ventricular (RV) afterload correlated with Hs-cTnI ( = 0.42, = 0.010) and D-dimer ( = 0.18, = 0.047). Hs-cTnI appears to be the best relevant predictive factor for referring COVID-19 patients to ICU. This result associated with the correlation of D-dimer with RV dilatation probably reflects a myocardial injury due to an increased RV wall tension. This reinforces the hypothesis of a COVID-19-associated microvascular thrombosis inducing a higher RV afterload.
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http://dx.doi.org/10.3389/fmed.2020.586307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689153PMC
November 2020

Multidimensional Proteomic Approach of Endothelial Progenitors Demonstrate Expression of KDR Restricted to CD19 Cells.

Stem Cell Rev Rep 2021 04 17;17(2):639-651. Epub 2020 Nov 17.

Innovative Therapies in Haemostasis, INSERM, Université de Paris, F-75006, Paris, France.

Endothelial progenitor cells (EPCs) are involved in vasculogenesis and cardiovascular diseases. However, the phenotype of circulating EPCs remains elusive but they are more often described as CD34KDR. The aim of the study was to extensively characterize circulating potential vasculogenic stem cell candidates in two populations of patients with cardiovascular disease by powerful multidimensional single cell complementary cytometric approaches (mass, imaging and flow). We identified cellular candidates in one patient before and after bioprosthetic total artificial heart implantation and results were confirmed in healthy peripheral and cord blood by mass cytometry. We also quantified cellular candidates in 10 patients with different COVID-19 severity. Both C-TAH implantation and COVID-19 at critical stage induce a redistribution of circulating CD34 and CD19 sub-populations in peripheral blood. After C-TAH implantation, circulating CD34 progenitor cells expressed c-Kit stem marker while specific subsets CD34CD133CD45c-KitKDR were mobilized. KDR was only expressed by CD19 B-lymphocytes and CD14 monocytes subpopulations in circulation. We confirmed by mass cytometry this KDR expression on CD19 in healthy peripheral and cord blood, also with a VE-cadherin expression, confirming absence of endothelial lineage marker on CD34 subtypes. In COVID-19, a significant mobilization of CD34c-KitKDR cells was observed between moderate and critical COVID-19 patients regardless CD133 or CD45 expression. In order to better evaluate EPC phenotype, we performed imaging flow cytometry measurements of immature CD34KDR cells in cord blood and showed that, after elimination of non-circular events, those cells were all CD19. During COVID-19, a significant mobilization of CD19KDR per million of CD45 cells was observed between moderate and critical COVID-19 patients regardless of CD34 expression. CD34c-Kit cells are mobilized in both cardiovascular disease described here. KDR cells in peripheral blood are CD19 positive cells and are not classic vasculogenic stem and/or progenitor cells. A better evaluation of c-Kit and KDR expressing cells will lead to the redefinition of circulating endothelial progenitors.Graphical abstract Central illustration figure. Multidimensional proteomic approach of endothelial progenitors demonstrate expression of KDR restricted to CD19 cells. Endothelial progenitor cells (EPCs) are involved in cardiovascular diseases, however their phenotype remains elusive. We elucidated here EPCs phenotype by a deep characterization by multidimensional single cell complementary cytometric approaches after Bioprosthetic total artificial heart implantation and during COVID-19. We showed a redistribution of circulating CD34 and CD19 sub-populations in both situations. None of the immature cell population expresses KDR. Mobilized CD34 expressed c-Kit. Imaging flow cytometry demonstrated that CD34KDR cells, after elimination of non-circular events, are all CD19. Our results suggest a new definition of circulating EPCs and emphasize involvement of CD19 cells in cardiovascular disease.
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http://dx.doi.org/10.1007/s12015-020-10062-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670993PMC
April 2021

Prevalence and characteristics of pulmonary embolism in 1042 COVID-19 patients with respiratory symptoms: A nested case-control study.

Thromb Res 2021 01 7;197:94-99. Epub 2020 Nov 7.

Université de Paris, France; Groupe Hospitalier Paris Saint-Joseph, F-75014 Paris, France; Department of Vascular Medicine, France; INSERM CRESS UMR 1153, F-75005 Paris, France.

Introduction: Coronavirus disease 2019 (COVID-19) has been associated with cardiovascular complications and coagulation disorders. Previous studies reported pulmonary embolism (PE) in severe COVID-19 patients. Aim of the study was to estimate the prevalence of symptomatic PE in COVID-19 patients and to identify the clinical, radiological or biological characteristics associated with PE.

Patients/methods: We conducted a retrospective nested case-control study in 2 French hospitals. Controls were matched in a 1:2 ratio on the basis of age, sex and center. PE patients with COVID-19 were compared to patients in whom PE was ruled out (CTPA controls) and in whom PE has not been investigated (CT controls).

Results: PE was suspected in 269 patients among 1042 COVID-19 patients, and confirmed in 59 patients (5.6%). Half of PE was diagnosed at COVID-19 diagnosis. PE patients did not differ from CT and CTPA controls for thrombosis risk factors. PE patients more often required invasive ventilation compared to CTPA controls (odds ratio (OR) 2.79; 95% confidence interval (CI) 1.33-5.84) and to CT controls (OR 8.07; 95% CI 2.70-23.82). PE patients exhibited more extensive parenchymal lesions (>50%) than CT controls (OR 3.90; 95% CI 1.54-9.94). D-dimer levels were 5.1 (95% CI 1.90-13.76) times higher in PE patients than CTPA controls.

Conclusions: Our results suggest a PE prevalence in COVID-19 patients close to 5% in the whole population and to 20% of the clinically suspected population. PE seems to be associated with more extensive lung damage and to require more frequently invasive ventilation.
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http://dx.doi.org/10.1016/j.thromres.2020.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648521PMC
January 2021

Interleukin-8 Receptors CXCR1 and CXCR2 Are Not Expressed by Endothelial Colony-forming Cells.

Stem Cell Rev Rep 2021 Apr 13;17(2):628-638. Epub 2020 Nov 13.

Innovative Therapies in Haemostasis, INSERM, Université de Paris, F-75006 , Paris, France.

Endothelial colony-forming cells (ECFCs) are human vasculogenic cells described as potential cell therapy product and good candidates for being a vascular liquid biopsy. Since interleukin-8 (IL-8) is a main actor in senescence, its ability to interact with ECFCs has been explored. However, expression of CXCR1 and CXCR2, the two cellular receptors for IL-8, by ECFCs remain controversial as several teams published contradictory reports. Using complementary technical approaches, we have investigated the presence of these receptors on ECFCs isolated from cord blood. First, CXCR1 and CXCR2 were not detected on several clones of cord blood- endothelial colony-forming cell using different antibodies available, in contrast to well-known positive cells. We then compared the RT-PCR primers used in different papers to search for the presence of CXCR1 and CXCR2 mRNA and found that several primer pairs used could lead to non-specific DNA amplification. Last, we confirmed those results by RNA sequencing. CXCR1 and CXCR2 were not detected in ECFCs in contrary to human-induced pluripotent stem cell-derived endothelial cells (h-iECs). In conclusion, using three different approaches, we confirmed that CXCR1 and CXCR2 were not expressed at mRNA or protein level by ECFCs. Thus, IL-8 secretion by ECFCs, its effects in angiogenesis and their involvement in senescent process need to be reanalyzed according to this absence of CXCR-1 and - 2 in ECFCs.Graphical Abstract.
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http://dx.doi.org/10.1007/s12015-020-10081-yDOI Listing
April 2021

Human Aortic Valve Interstitial Cells Display Proangiogenic Properties During Calcific Aortic Valve Disease.

Arterioscler Thromb Vasc Biol 2021 01 5;41(1):415-429. Epub 2020 Nov 5.

Université de Paris, Innovative Therapies in Haemostasis, INSERM, France (N.G., A.B., E.R., S.I., S.L., A. Cras, N.N., J.R., P.G., D.M.S.).

Objective: The study's aim was to analyze the capacity of human valve interstitial cells (VICs) to participate in aortic valve angiogenesis. Approach and Results: VICs were isolated from human aortic valves obtained after surgery for calcific aortic valve disease and from normal aortic valves unsuitable for grafting (control VICs). We examined VIC in vitro and in vivo potential to differentiate in endothelial and perivascular lineages. VIC paracrine effect was also examined on human endothelial colony-forming cells. A pathological VIC (VIC) mesenchymal-like phenotype was confirmed by CD90/CD73/CD44 expression and multipotent-like differentiation ability. When VIC were cocultured with endothelial colony-forming cells, they formed microvessels by differentiating into perivascular cells both in vivo and in vitro. VIC and control VIC conditioned media were compared using serial ELISA regarding quantification of endothelial and angiogenic factors. Higher expression of VEGF (vascular endothelial growth factor)-A was observed at the protein level in VIC-conditioned media and confirmed at the mRNA level in VIC compared with control VIC. Conditioned media from VIC induced in vitro a significant increase in endothelial colony-forming cell proliferation, migration, and sprouting compared with conditioned media from control VIC. These effects were inhibited by blocking VEGF-A with blocking antibody or siRNA approach, confirming VIC involvement in angiogenesis by a VEGF-A dependent mechanism.

Conclusions: We provide here the first proof of an angiogenic potential of human VICs isolated from patients with calcific aortic valve disease. These results point to a novel function of VIC in valve vascularization during calcific aortic valve disease, with a perivascular differentiation ability and a VEGF-A paracrine effect. Targeting perivascular differentiation and VEGF-A to slow calcific aortic valve disease progression warrants further investigation.
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http://dx.doi.org/10.1161/ATVBAHA.120.314287DOI Listing
January 2021

COPD is deleterious for pericytes: implications during training-induced angiogenesis in skeletal muscle.

Am J Physiol Heart Circ Physiol 2020 11 28;319(5):H1142-H1151. Epub 2020 Sep 28.

PhyMedExp, INSERM-CNRS-Montpellier University, CHU Montpellier, Montpellier, France.

Improvements in skeletal muscle endurance and oxygen uptake are blunted in patients with chronic obstructive pulmonary disease (COPD), possibly because of a limitation in the muscle capillary oxygen supply. Pericytes are critical for capillary blood flow adaptation during angiogenesis but may be impaired by COPD systemic effects, which are mediated by circulating factors. This study compared the pericyte coverage of muscle capillaries in response to 10 wk of exercise training in patients with COPD and sedentary healthy subjects (SHS). Fourteen patients with COPD were compared with seven matched SHS. SHS trained at moderate intensity corresponding to an individualized moderate-intensity patient with COPD trained at the same relative (%V̇o: COPD-RI) or absolute (mL·min·kg: COPD-AI) intensity as SHS. Capillary-to-fiber ratio (C/F) and NG2 pericyte coverage were assessed from muscle biopsies, before and after 5 and 10 wk of training. We also tested in vitro the effect of COPD and SHS serum on pericyte morphology and mesenchymal stem cell (MSC) differentiation into pericytes. SHS showed greater improvement in aerobic capacity (V̇o) than both patients with COPD-RI and patients with COPD-AI (Group × Time: = 0.004). Despite a preserved increase in the C/F ratio, NG2 pericyte coverage did not increase in patients with COPD in response to training, contrary to SHS (Group × Time: = 0.011). Conversely to SHS serum, COPD serum altered pericyte morphology ( < 0.001) and drastically reduced MSC differentiation into pericytes ( < 0.001). Both functional capacities and pericyte coverage responses to exercise training are blunted in patients with COPD. We also provide direct evidence of the deleterious effect of COPD circulating factors on pericyte morphology and differentiation. This work confirms the previously reported impairment in the functional response to exercise training of patients with COPD compared with SHS. Moreover, it shows for the first time that pericyte coverage of the skeletal capillaries is drastically reduced in patients with COPD compared with SHS during training-induced angiogenesis. Finally, it provides experimental evidence that circulating factors are involved in the impaired pericyte coverage of patients with COPD.
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http://dx.doi.org/10.1152/ajpheart.00306.2020DOI Listing
November 2020

Autoantibodies against type I IFNs in patients with life-threatening COVID-19.

Science 2020 10 24;370(6515). Epub 2020 Sep 24.

St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-ω (IFN-ω) (13 patients), against the 13 types of IFN-α (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.
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http://dx.doi.org/10.1126/science.abd4585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857397PMC
October 2020

Endothelial Colony-Forming Cells from Idiopathic Pulmonary Fibrosis Patients Have a High Procoagulant Potential.

Stem Cell Rev Rep 2021 Apr 24;17(2):694-699. Epub 2020 Sep 24.

Université de Paris, Innovative Therapies in Haemostasis, INSERM, 75006 Paris, AP-HP, Georges Pompidou European Hospital, F-75006 Paris, France, Service d'Hématologie et Laboratoire de Recherches Biochirugicales (Fondation Carpentier), 75015, Paris, France.

Idiopathic pulmonary fibrosis (IPF) is a severe, progressive and irreversible lung disease constantly associated with a major vascular remodeling process. Endothelial colony-forming cells (ECFCs) are human vasculogenic cells proposed as a cell therapy product or liquid biopsy in vascular disorders. Since the link between IPF and thrombosis has been largely proposed, the aim of our study was to explore hypercoagulability states in ECFCs from patients with IPF. We performed Thrombin generation assay (TGA) in cord blood (CB)-ECFCs, peripheral blood (PB)-ECFCs and IPF-ECFCs. Endogenous thrombin potential and peak were higher in IPF-ECFCs compared to CB-ECFCs and PB-ECFCs. As thrombin generation in ECFCs was increased, we evaluated anticoagulant proteins expressed on ECFCs membrane and identified thrombomodulin and EPCR. We found a significant decrease of both anticoagulant proteins at membrane using flow cytometry. This study is the first to examine ECFC thrombin generation in IPF. This new finding strongly argues for a role of ECFC in IPF pathophysiology and thrombotic related disorders in IPF. Graphical Abstract.
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http://dx.doi.org/10.1007/s12015-020-10043-4DOI Listing
April 2021
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