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.

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.

National early warning score to predict intensive care unit transfer and mortality in COVID-19 in a French cohort.

BACKGROUND: No risk stratification tool has been validated in hospitalised patients with coronavirus disease 2019 (COVID-19), despite a high rate of intensive care requirement and in-hospital mortality. We aimed to determine whether the National Early Warning Score (NEWS) at admission can accurately predict in-hospital mortality and ICU transfer. METHODS: This was a retrospective cohort study from January 24 to April 16, 2020, at Lille University Hospital. All consecutive adult patients with laboratory-confirmed COVID-19 who were initially admitted to non-ICU wards were included. The primary outcome was a composite criterion consisting of ICU transfer or in-hospital mortality. We evaluated the prognostic performance of NEWS by calculating the area under (AUC) the receiver operating characteristic curve, the optimal threshold value of NEWS, and its association with the primary outcome. RESULTS: Of the 202 COVID-19 patients, the median age was 65 (interquartile range 52-78), 38.6% were women and 136 had at least one comorbidity. The median NEWS was 4 (2-6). A total of 65 patients were transferred to the ICU or died in the hospital. Compared with patients with favourable outcome, these patients were significantly older, had more comorbidities and higher NEWS. The AUC for NEWS was 0.68 (0.60-0.77) and the best cutoff value was 6. Adjusted odds ratio for NEWS ≥ 6 as an independent predictor was 3.78 (1.94-7.09). CONCLUSIONS: In hospitalised COVID-19 patients, NEWS was an independent predictor of ICU transfer and in-hospital death. In daily practice, NEWS ≥ 6 at admission may help to identify patients who are at risk to deteriorate.

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

[Figure: see text].

Study protocol for a multicentre, 2×2 factorial, randomised, controlled trial evaluating the interest of intravenous iron and tranexamic acid to reduce blood transfusion in hip fracture patients (the HiFIT study).

INTRODUCTION: Blood transfusion and anaemia are frequent and are associated with poor outcomes in patients with hip fracture (HF). We hypothesised that preoperative intravenous iron and tranexamic acid (TXA) may reduce the transfusion rate in these patients. METHODS AND ANALYSIS: The HiFIT study is a multicentre, 2×2 factorial, randomised, double-blinded, controlled trial evaluating the effect of iron isomaltoside (IIM) (20 mg/kg) vs placebo and of TXA (intravenously at inclusion and topically during surgery) versus placebo on transfusion rate during hospitalisation, in patients undergoing emergency surgery for HF and having a preoperative haemoglobin between 95 and 130 g/L. 780 patients are expected. The primary endpoint is the proportion of patients receiving an allogenic blood transfusion of packed red blood cells from the day of surgery until hospital discharge (or until D30 if patient is still hospitalised). Enrolment started on March 2017 in 11 French hospitals. The study was stopped between July 2017 and August 2018 (because of investigation of serious AEs with IIM in Spain) and slowed down since March 2020 (COVID-19 crisis). The expected date of final follow-up is May 2022. Analyses of the intent-to-treat and per-protocol populations are planned. ETHICS AND DISSEMINATION: The HiFIT trial protocol has been approved by the Ethics Committee of Comité de Protection des Personnes Ouest II and the French authorities (ANSM). It will be carried out according to the principles of the Declaration of Helsinki and the Good Clinical Practice guidelines. The results will be disseminated through presentation at scientific conferences and publication in peer-reviewed journals. The HiFIT trial will be the largest study evaluating iron and TXA in patients with HF. TRIAL REGISTRATION NUMBER: clinicalTrials.gov identifier: NCT02972294; EudraCT Number 2016-003087-40.

Coagulation biomarkers are independent predictors of increased oxygen requirements in COVID-19.

BACKGROUND: Hypercoagulability seems to contribute to SARS-CoV-2 pneumonia pathogenesis. However, age and metabolic syndrome are potential confounders when assessing the value of coagulation biomarkers' prediction of COVID-19 outcomes. We assessed whether coagulation biomarkers, including factor VIII (FVIII) and von Willebrand factor (VWF) levels, measured at time of admission, were predictive of COVID-19 adverse outcomes irrespective of age and major comorbidities associated with metabolic syndrome. METHODS: Blood was sampled at admission in 243 adult COVID-19 patients for analysis of coagulation biomarkers including FVIII and VWF on platelet-poor plasma. The association between baseline C-reactive protein (CRP), activated partial thromboplastin time ratio, prothrombin time ratio, D-dimers, fibrinogen, FVIII, VWF antigen (VWF:Ag), and FVIII/VWF:Ag ratio levels and adverse outcomes (increased oxygen requirements, thrombosis, and death at day 30) was assessed by regression analysis after adjustment on age, sex, body mass index (BMI), diabetes, and hypertension. RESULTS: In univariable regression analysis increased CRP (subdistribution hazard ratio [SHR], 1.68; 95% confidence interval [CI], 1.26-2.23), increased fibrinogen (SHR, 1.32; 95% CI, 1.04-1.68), and decreased FVIII/VWF:Ag ratio (SHR, 0.70; 95% CI, 0.52-0.96) levels at admission were significantly associated with the risk of increased oxygen requirement during follow-up. Leucocytes (SHR, 1.36; 95% CI, 1.04-1.76), platelets (SHR,1.71; 95% CI, 1.11-2.62), D-dimers (SHR, 2.48; 95% CI, 1.66-3.78), and FVIII (SHR, 1.78; 95% CI, 1.17-2.68) were associated with early onset of thrombosis after admission. After adjustment for age, sex, BMI, hypertension, and diabetes, these associations were not modified. CONCLUSION: Coagulation biomarkers are early and independent predictors of increased oxygen requirement in COVID-19 patients.

Clinico-Biological Features and Clonal Hematopoiesis in Patients with Severe COVID-19.

Advanced age or preexisting comorbidities have been characterized as risk factors for severe coronavirus disease 2019 (COVID-19) cases requiring hospitalization and intensive care. In recent years, clonal hematopoiesis (CH) of indeterminate potential (CHIP) has emerged as a risk factor for chronic inflammatory background and subsequent aging-associated diseases. The purpose of this study was to identify biological factors (particularly leukocyte subtypes and inflammatory markers) associated with a risk of clinical deterioration (i.e., orotracheal intubation (OTI)) and to determine whether CH was likely to influence clinical and biological behavior in patients with severe COVID-19 requiring hospitalization. Here, we describe clinical and biological features, including the screening of CHIP mutants in a well-annotated cohort of 122 hospitalized patients with a laboratory-confirmed diagnosis of COVID-19 (55% requiring OTI). We showed that elevated white blood cell counts, especially neutrophils and high C-reactive protein (CRP) levels at admission, were associated with an increased requirement of OTI. We noticed a high prevalence of CH (25%, 38%, 56%, and 82% of patients aged <60 years, 60-70 years, 70-80 years, and >80 years) compared to a retrospective cohort of patients free of hematological malignancy explored with the same pipelines (10%, 21%, 37%, and 44%). However, the existence of CH did not significantly impact clinical outcome, including OTI or death, and did not correlate with other laboratory findings.

Prevention of thrombotic risk in hospitalized patients with COVID-19 and hemostasis monitoring.

COVID-19 is an infection induced by the SARS-CoV-2 coronavirus, and severe forms can lead to acute respiratory distress syndrome (ARDS) requiring intensive care unit (ICU) management. Severe forms are associated with coagulation changes, mainly characterized by an increase in D-dimer and fibrinogen levels, with a higher risk of thrombosis, particularly pulmonary embolism. The impact of obesity in severe COVID-19 has also been highlighted.In this context, standard doses of low molecular weight heparin (LMWH) may be inadequate in ICU patients, with obesity, major inflammation, and hypercoagulability. We therefore urgently developed proposals on the prevention of thromboembolism and monitoring of hemostasis in hospitalized patients with COVID-19.Four levels of thromboembolic risk were defined according to the severity of COVID-19 reflected by oxygen requirement and treatment, the body mass index, and other risk factors. Monitoring of hemostasis (including fibrinogen and D-dimer levels) every 48 h is proposed. Standard doses of LMWH (e.g., enoxaparin 4000 IU/24 h SC) are proposed in case of intermediate thrombotic risk (BMI < 30 kg/m2, no other risk factors and no ARDS). In all obese patients (high thrombotic risk), adjusted prophylaxis with intermediate doses of LMWH (e.g., enoxaparin 4000 IU/12 h SC or 6000 IU/12 h SC if weight > 120 kg), or unfractionated heparin (UFH) if renal insufficiency (200 IU/kg/24 h, IV), is proposed. The thrombotic risk was defined as very high in obese patients with ARDS and added risk factors for thromboembolism, and also in case of extracorporeal membrane oxygenation (ECMO), unexplained catheter thrombosis, dialysis filter thrombosis, or marked inflammatory syndrome and/or hypercoagulability (e.g., fibrinogen > 8 g/l and/or D-dimers > 3 µg/ml). In ICU patients, it is sometimes difficult to confirm a diagnosis of thrombosis, and curative anticoagulant treatment may also be discussed on a probabilistic basis. In all these situations, therapeutic doses of LMWH, or UFH in case of renal insufficiency with monitoring of anti-Xa activity, are proposed.In conclusion, intensification of heparin treatment should be considered in the context of COVID-19 on the basis of clinical and biological criteria of severity, especially in severely ill ventilated patients, for whom the diagnosis of pulmonary embolism cannot be easily confirmed.