Inflammatory markers and auto-Abs to type I IFNs in COVID-19 convalescent plasma cohort study.

BACKGROUND: COVID-19 convalescent plasma (CCP) contains neutralising anti-SARS-CoV-2 antibodies that may be useful as COVID-19 passive immunotherapy in patients at risk of developing severe disease. Such plasma from convalescent patients may also have additional immune-modulatory properties when transfused to COVID-19 patients. METHODS: CCP (n = 766) was compared to non-convalescent control plasma (n = 166) for soluble inflammatory markers, ex-vivo inflammatory bioactivity on endothelial cells, neutralising auto-Abs to type I IFNs and reported adverse events in the recipients. FINDINGS: CCP exhibited a statistically significant increase in IL-6 and TNF-alpha levels (0.531 ± 0.04 vs 0.271 ± 0.04; (95% confidence interval [CI], 0.07371-0.4446; p = 0.0061) and 0.900 ± 0.07 vs 0.283 ± 0.07 pg/mL; (95% [CI], 0.3097-0.9202; p = 0.0000829) and lower IL-10 (0.731 ± 0.07 vs 1.22 ± 0.19 pg/mL; (95% [CI], -0.8180 to -0.1633; p = 0.0034) levels than control plasma. Neutralising auto-Abs against type I IFNs were detected in 14/766 (1.8%) CCPs and were not associated with reported adverse events when transfused. Inflammatory markers and bioactivity in CCP with or without auto-Abs, or in CCP whether or not linked to adverse events in transfused patients, did not differ to a statistically significant extent. INTERPRETATION: Overall, CCP exhibited moderately increased inflammatory markers compared to the control plasma with no discernible differences in ex-vivo bioactivity. Auto-Abs to type I IFNs detected in a small fraction of CCP were not associated with reported adverse events or differences in inflammatory markers. Additional studies, including careful clinical evaluation of patients treated with CCP, are required in order to further define the clinical relevance of these findings. FUNDING: French National Blood Service-EFS, the Association "Les Amis de Rémi" Savigneux, France, the "Fondation pour la Recherche Médicale (Medical Research Foundation)-REACTing 2020".

Derivation and Validation of a Predictive Score for Respiratory Failure Worsening Leading to Secondary Intubation in COVID-19: The CERES Score.

Predictive scores assessing the risk of respiratory failure in COVID-19 mostly focused on the prediction of early intubation. A combined assessment of clinical parameters and biomarkers of endotheliopathy could allow to predict late worsening of acute respiratory failure (ARF), subsequently warranting intubation in COVID-19. Retrospective single-center derivation (n = 92 subjects) and validation cohorts (n = 59 subjects), including severe COVID-19 patients with non-invasive respiratory support, were assessed for at least 48 h following intensive care unit (ICU) admission. We used stepwise regression to construct the COVID endothelial and respiratory failure (CERES) score in a derivation cohort, and secondly assessed its accuracy for the prediction of late ARF worsening, requiring intubation within 15 days following ICU admission in an independent validation cohort. Platelet count, fraction of inspired oxygen, and endocan measured on ICU admission were identified as the top three predictive variables for late ARF worsening and subsequently included in the CERES score. The area under the ROC curve of the CERES score to predict late ARF worsening was calculated in the derivation and validation cohorts at 0.834 and 0.780, respectively. The CERES score is a simple tool with good performances to predict respiratory failure worsening, leading to secondary intubation, in COVID-19 patients.

Plasma Markers of Neutrophil Extracellular Trap Are Linked to Survival but Not to Pulmonary Embolism in COVID-19-Related ARDS Patients.

Introduction: Coronavirus disease 2019 (COVID-19) can cause life-threatening acute respiratory distress syndrome (ARDS). Recent data suggest a role for neutrophil extracellular traps (NETs) in COVID-19-related lung damage partly due to microthrombus formation. Besides, pulmonary embolism (PE) is frequent in severe COVID-19 patients, suggesting that immunothrombosis could also be responsible for increased PE occurrence in these patients. Here, we evaluate whether plasma levels of NET markers measured shorty after admission of hospitalized COVID-19 patients are associated with clinical outcomes in terms of clinical worsening, survival, and PE occurrence. Patients and Methods: Ninety-six hospitalized COVID-19 patients were included, 50 with ARDS (severe disease) and 46 with moderate disease. We collected plasma early after admission and measured 3 NET markers: total DNA, myeloperoxidase (MPO)-DNA complexes, and citrullinated histone H3. Comparisons between survivors and non-survivors and patients developing PE and those not developing PE were assessed by Mann-Whitney test. Results: Analysis in the whole population of hospitalized COVID-19 patients revealed increased circulating biomarkers of NETs in patients who will die from COVID-19 and in patients who will subsequently develop PE. Restriction of our analysis in the most severe patients, i.e., the ones who enter the hospital for COVID-19-related ARDS, confirmed the link between NET biomarker levels and survival but not PE occurrence. Conclusion: Our results strongly reinforce the hypothesis that NETosis is an attractive therapeutic target to prevent COVID-19 progression but that it does not seem to be linked to PE occurrence in patients hospitalized with COVID-19.

Viscoelastometric Testing to Assess Hemostasis of COVID-19: A Systematic Review.

Infection by SARS-CoV-2 is associated with a high risk of thrombosis. The laboratory documentation of hypercoagulability and impaired fibrinolysis remains a challenge. Our aim was to assess the potential usefulness of viscoelastometric testing (VET) to predict thrombotic events in COVID-19 patients according to the literature. We also (i) analyzed the impact of anticoagulation and the methods used to neutralize heparin, (ii) analyzed whether maximal clot mechanical strength brings more information than Clauss fibrinogen, and (iii) critically scrutinized the diagnosis of hypofibrinolysis. We performed a systematic search in PubMed and Scopus databases until 31st December 2020. VET methods and parameters, and patients' features and outcomes were extracted. VET was performed for 1063 patients (893 intensive care unit (ICU) and 170 non-ICU, 44 studies). There was extensive heterogeneity concerning study design, VET device used (ROTEM, TEG, Quantra and ClotPro) and reagents (with non-systematic use of heparin neutralization), timing of assay, and definition of hypercoagulable state. Notably, only 4 out of 25 studies using ROTEM reported data with heparinase (HEPTEM). The common findings were increased clot mechanical strength mainly due to excessive fibrinogen component and impaired to absent fibrinolysis, more conspicuous in the presence of an added plasminogen activator. Only 4 studies out of the 16 that addressed the point found an association of VETs with thrombotic events. So-called functional fibrinogen assessed by VETs showed a variable correlation with Clauss fibrinogen. Abnormal VET pattern, often evidenced despite standard prophylactic anticoagulation, tended to normalize after increased dosing. VET studies reported heterogeneity, and small sample sizes do not support an association between the poorly defined prothrombotic phenotype of COVID-19 and thrombotic events.

Prévention du risque thromboembolique veineux et surveillance de l’hémostase chez les patients hospitalisés pour COVID-19 : propositions réactualisées (avril 2021). Groupe d’intérêt en hémostase périopératoire (GIHP) et groupe d’étude sur l’hémostase et la thrombose (GFHT) Prevention of venous thromboembolism and haemostasis monitoring in patients with COVID-19: Updated proposals (April 2021): From the French working group on perioperative haemostasis (GIHP) and the French study group on thrombosis and haemostasis (GFHT), in collaboration with the French society of anaesthesia and intensive care (SFAR)

<h4>Contexte</h4> La COVID-19 est associée à un risque thromboembolique veineux élevé, en particulier chez les patients sévères. Depuis les premières propositions GIHP/GFHT publiées en avril 2020, de nouvelles connaissances sont apparues. L’objet du présent travail était de réactualiser ces propositions. <h4>Méthodes</h4> Un groupe de travail a défini sept questions et effectué une revue critique de la littérature. Les propositions ont été formulées après consensus entre les membres du groupe de travail et les autres membres du GIHP/GFHT. <h4>Résultats</h4> Chez les patients hospitalisés non sévères et certains patients ambulatoires à risque, nous suggérons l’administration d’une thromboprophylaxie à dose standard. Chez les patients sévères, nous suggérons une thromboprophylaxie à dose intermédiaire ou thérapeutique selon le taux de D-dimères et son évolution. Sept à dix jours après l’admission, nous suggérons de revenir à une dose standard pour réduire le risque hémorragique. Chez les patients présentant un très haut risque thrombotique, ayant reçu une thromboprophylaxie à dose thérapeutique, nous suggérons un dépistage systématique de la thrombose avant la désescalade. Nous suggérons d’ajuster l’anticoagulation au poids des patients. Nous suggérons un monitorage régulier des paramètres d’hémostase, incluant les D-dimères, chez les patients sévères. Nous suggérons un monitorage de l’anticoagulation à dose intermédiaire et thérapeutique par l’activité anti-Xa. <h4>Conclusion</h4> Les propositions réactualisées suivent une approche standard de la thromboprophylaxie, visant à diminuer l’incidence des évènements thromboemboliques veineux symptomatiques. Chez les patients sévères, nous proposons une stratégie séquentielle tenant compte de la relation temporelle entre le risque thrombotique et le risque hémorragique.

Prévention du risque thromboembolique veineux et surveillance de l’hémostase chez les patients hospitalisés pour COVID-19 : propositions réactualisées (avril 2021). Groupe d’intérêt en hémostase périopératoire (GIHP) et groupe d’étude sur l’hémostase et la thrombose (GFHT)

Résumé Contexte La COVID-19 est associée à un risque thromboembolique veineux élevé, en particulier chez les patients sévères. Depuis les premières propositions GIHP/GFHT publiées en avril 2020, de nouvelles connaissances sont apparues. L’objet du présent travail était de réactualiser ces propositions. Méthodes Un groupe de travail a défini sept questions et effectué une revue critique de la littérature. Les propositions ont été formulées après consensus entre les membres du groupe de travail et les autres membres du GIHP/GFHT. Résultats Chez les patients hospitalisés non sévères et certains patients ambulatoires à risque, nous suggérons l’administration d’une thromboprophylaxie à dose standard. Chez les patients sévères, nous suggérons une thromboprophylaxie à dose intermédiaire ou thérapeutique selon le taux de D-dimères et son évolution. Sept à dix jours après l’admission, nous suggérons de revenir à une dose standard pour réduire le risque hémorragique. Chez les patients présentant un très haut risque thrombotique, ayant reçu une thromboprophylaxie à dose thérapeutique, nous suggérons un dépistage systématique de la thrombose avant la désescalade. Nous suggérons d’ajuster l’anticoagulation au poids des patients. Nous suggérons un monitorage régulier des paramètres d’hémostase, incluant les D-dimères, chez les patients sévères. Nous suggérons un monitorage de l’anticoagulation à dose intermédiaire et thérapeutique par l’activité anti-Xa. Conclusion Les propositions réactualisées suivent une approche standard de la thromboprophylaxie, visant à diminuer l’incidence des évènements thromboemboliques veineux symptomatiques. Chez les patients sévères, nous proposons une stratégie séquentielle tenant compte de la relation temporelle entre le risque thrombotique et le risque hémorragique.

Pharmacokinetics of enoxaparin in COVID-19 critically ill patients.

BACKGROUND: In intensive-care unit (ICU) patients, pathophysiological changes may affect the pharmacokinetics of enoxaparin and result in underdosing. OBJECTIVES: To develop a pharmacokinetic model of enoxaparin to predict the time-exposure profiles of various thromboprophylactic regimens in COVID-19 ICU-patients. METHODS: This was a retrospective study in ICUs of two French hospitals. Anti-Xa activities from consecutive patients with laboratory-confirmed SARS-CoV-2 infection treated with enoxaparin for the prevention or the treatment of venous thrombosis were used to develop a population pharmacokinetic model using non-linear mixed effects techniques. Monte Carlo simulations were then performed to predict enoxaparin exposure at steady-state after three days of administration. RESULTS: A total of 391 anti-Xa samples were measured in 95 patients. A one-compartment model with first-order kinetics best fitted the data. The covariate analysis showed that enoxaparin clearance (typical value 1.1 L.h-1) was related to renal function estimated by the CKD-EPI formula and volume of distribution (typical value 17.9 L) to actual body weight. Simulation of anti-Xa activities with enoxaparin 40 mg qd indicated that 64% of the patients had peak levels within the range 0.2 to 0.5 IU.mL-1 and 75% had 12-hour levels above 0.1 IU.mL-1. Administration of a total daily dose of at least 60 mg per day improved the probability of target attainment. CONCLUSION: In ICU COVID-19 patients, exposure to enoxaparin is reduced due to an increase in the volume of distribution and clearance. Consequently, enoxaparin 40 mg qd is suboptimal to attain thromboprophylactic anti-Xa levels.

Hypotheses behind the very rare cases of thrombosis with thrombocytopenia syndrome after SARS-CoV-2 vaccination.

As of 4 April 2021, a total of 169 cases of cerebral venous sinus thrombosis (CVST) and 53 cases of splanchnic vein thrombosis were reported to EudraVigilance among around 34 million people vaccinated in the European Economic Area and United Kingdom with COVID-19 Vaccine AstraZeneca, a chimpanzee adenoviral vector (ChAdOx1) encoding the spike protein antigen of the SARS-CoV-2 virus. The first report of the European Medicines Agency gathering data on 20 million people vaccinated with Vaxzevria® in the UK and the EEA concluded that the number of post-vaccination cases with thromboembolic events as a whole reported to EudraVigilance in relation to the number of people vaccinated was lower than the estimated rate of such events in the general population. However, the EMA's Pharmacovigilance Risk Assessment Committee concluded that unusual thromboses with low blood platelets should be listed as very rare side effects of Vaxzevria®, pointing to a possible link. The same issue was identified with the COVID-19 Vaccine Janssen (Ad26.COV2.S). Currently, there is still a sharp contrast between the clinical or experimental data reported in the literature on COVID-19 and the scarcity of data on the unusual thrombotic events observed after the vaccination with these vaccines. Different hypotheses might support these observations and should trigger further in vitro and ex vivo investigations. Specialized studies were needed to fully understand the potential relationship between vaccination and possible risk factors in order to implement risk minimization strategies.

Impact of High-Dose Prophylactic Anticoagulation in Critically Ill Patients With COVID-19 Pneumonia.

BACKGROUND: Because of the high risk of thrombotic complications (TCs) during SARS-CoV-2 infection, several scientific societies have proposed to increase the dose of preventive anticoagulation, although arguments in favor of this strategy are inconsistent. RESEARCH QUESTION: What is the incidence of TC in critically ill patients with COVID-19 and what is the relationship between the dose of anticoagulant therapy and the incidence of TC? STUDY DESIGN AND METHODS: All consecutive patients referred to eight French ICUs for COVID-19 were included in this observational study. Clinical and laboratory data were collected from ICU admission to day 14, including anticoagulation status and thrombotic and hemorrhagic events. The effect of high-dose prophylactic anticoagulation (either at intermediate or equivalent to therapeutic dose), defined using a standardized protocol of classification, was assessed using a time-varying exposure model using inverse probability of treatment weight. RESULTS: Of 538 patients included, 104 patients experienced a total of 122 TCs with an incidence of 22.7% (95% CI, 19.2%-26.3%). Pulmonary embolism accounted for 52% of the recorded TCs. High-dose prophylactic anticoagulation was associated with a significant reduced risk of TC (hazard ratio, 0.81; 95% CI, 0.66-0.99) without increasing the risk of bleeding (HR, 1.11; 95% CI, 0.70-1.75). INTERPRETATION: High-dose prophylactic anticoagulation is associated with a reduction in thrombotic complications in critically ill patients with COVID-19 without an increased risk of hemorrhage. Randomized controlled trials comparing prophylaxis with higher doses of anticoagulants are needed to confirm these results. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT04405869; URL: www.clinicaltrials.gov.

Vascular Endothelial Damage in the Pathogenesis of Organ Injury in Severe COVID-19.

[Figure: see text].