Étude prospective des événements thromboemboliques veineux chez les patients hospitalisés pour COVID-19 : anomalies associées de l’hémostase et suivi clinicobiologique à 6 mois

Introduction La COVID-19 est associée à un risque élevé d’événement thromboembolique veineux (ETEV), thrombose veineuse profonde (TVP) et/ou embolie pulmonaire (EP) en particulier chez les patients hospitalisés. Objectifs Caractériser le déséquilibre de la balance hémostatique chez ces patients et décrire la prise en charge et l’évolution à 6 mois des patients avec ETEV. Méthodes Étude prospective incluant des patients consécutifs hospitalisés en réanimation ou en médecine pour COVID-19, avec : – un écho-Doppler veineux systématique à l’admission en réanimation puis 7jours plus tard en cas de négativité et en cas de symptômes de TVP en service de médecine ;– un angioscanner thoracique réalisé en cas de suspicion d’EP ;– un bilan d’hémostase réalisé à l’admission ;– le suivi des patients ayant présenté un ETEV à 1, 3 et 6 mois afin de colliger les événements thrombotiques et hémorragiques. Résultats Du 17.03 au 11.04.2020, 133 patients d’âge médian 65 ans (72 % hommes) ont été hospitalisés pour COVID-19. Trente-huit patients ont présenté un ETEV (63 % TVP, 24 % EP, 13 % TVP+EP) dont 9 sont décédés pendant l’hospitalisation, 2 ont été transférés et 26 suivis. Nos résultats montrent : – un taux de D-dimères>3300ng/mL prédictif d’un ETEV avec une VPP 66 % (IC95 % : 51–79) et VPN 80 % (IC95 % : 65–90) en réanimation ;– une discordance significative entre les activités anticoagulante/chromogénique de la protéine C (p=.002 chez les patients ETEV+) évocatrice d’une résistance acquise à la protéine C activée ;– une association entre les taux de facteur Willebrand et d’ADAMTS13 et les ETEV (p=.05 et p=.005 respectivement) d’une part et entre les taux d’ADAMTS13/D-dimères et la mortalité d’autre part ;– des anticorps antiphospholipides présents chez 88 % des patients en réanimation, non associés à la survenue d’ETEV. Les 26 patients suivis avec ETEV ont été traités par apixaban (22), rivaroxaban (2) ou tinzaparine (2) durant 3 à 6 mois. Un infarctus du myocarde et 2 saignements mineurs ont été recensés. Aucune récidive d’ETEV n’a été observée. Conclusions La fréquence élevée d’ETEV chez les patients hospitalisés pour COVID-19 est associée à un profil biologique de thrombo-inflammation, avec un déséquilibre marqué entre facteurs prothrombotiques/inhibiteurs naturels de la coagulation et de l’axe VWF/ADAMTS13. Le traitement par anticoagulant oral direct est une option thérapeutique possible pour le traitement d’un ETEV lié à une hospitalisation pour COVID-19.

Risk factors associated with COVID-19-associated pulmonary aspergillosis in ICU patients: a French multicentric retrospective cohort

OBJECTIVES: The main objective of this study was to determine the incidence of invasive pulmonary aspergillosis (IPA) in patients with coronavirus disease 2019 (COVID-19) admitted to the intensive care unit (ICU), and to describe the patient characteristics associated with IPA occurrence and to evaluate its impact on prognosis. METHODS: We conducted a retrospective cohort study including all successive COVID-19 patients, hospitalized in four ICUs, with secondary deterioration and one or more respiratory samples sent to the mycology department. We used a strengthened IPA testing strategy including seven mycological criteria. Patients were classified as probable IPA according to the European Organization for Research and Treatment of Cancer (EORTC)/Mycoses Study Group Education and Research Consortium (MSGERC) classification if immunocompromised, and according to the recent COVID-19-associated IPA classification otherwise. RESULTS: Probable IPA was diagnosed in 21 out of the 366 COVID-19 patients (5.7%) admitted to the ICU and in the 108 patients (19.4%) who underwent respiratory sampling for deterioration. No significant differences were observed between patients with and without IPA regarding age, gender, medical history and severity on admission and during hospitalization. Treatment with azithromycin for >=3 days was associated with the diagnosis of probable IPA (odds ratio 3.1, 95% confidence interval 1.1-8.5, p = 0.02). A trend was observed with high-dose dexamethasone and the occurrence of IPA. Overall mortality was higher in the IPA patients (15/21, 71.4% versus 32/87, 36.8%, p < 0.01). CONCLUSION: IPA is a relatively frequent complication in severe COVID-19 patients and is responsible for increased mortality. Azithromycin, known to have immunomodulatory properties, may contribute to increase COVID-19 patient's susceptibility to IPA.

Imbalance between procoagulant factors and natural coagulation inhibitors contributes to hypercoagulability in the critically ill COVID-19 patient: clinical implications.

OBJECTIVE: Coronavirus Disease-2019 (COVID-19) predisposes patients to thrombosis which underlying mechanisms are still incompletely understood. We sought to investigate the balance between procoagulant factors and natural coagulation inhibitors in the critically ill COVID-19 patient and to evaluate the usefulness of hemostasis parameters to identify patients at risk of venous thromboembolic event (VTE). PATIENTS AND METHODS: We conducted an observational study recording VTEs defined as deep vein thrombosis or pulmonary embolism using lower limb ultrasound (92% of the patients), computed tomography pulmonary angiography (6%) and both tests (2%). We developed a comprehensive analysis of hemostasis. RESULTS: Ninety-two consecutive mechanically ventilated COVID-19 patients (age, 62 years [53-69] (median [25th-75th percentiles]); M/F sex ratio, 2.5; body-mass index, 28 kg/m2 [25-32]; past hypertension (52%) and diabetes mellitus (30%)) admitted to the Intensive Care Unit (ICU) from 03/11/2020 to 5/05/2020, were included. When tested, patients were receiving prophylactic (74%) or therapeutic (26%) anticoagulation. Forty patients (43%) were diagnosed with VTE. Patients displayed inflammatory and prothrombotic profile including markedly elevated plasma fibrinogen (7.7 g/L [6.1-8.6]), D-dimer (3,360 ng/mL [1668-7575]), factor V (166 IU/dL [136-195]) and factor VIII activities (294 IU/dL [223-362]). We evidenced significant discrepant protein C anticoagulant and chromogenic activities, combined with slightly decreased protein S activity. Plasma D-dimer >3,300 ng/mL predicted VTE presence with 78% (95%-confidence interval (95% CI), 62-89) sensitivity, 69% (95% CI, 55-81) specificity, 66% (95% CI, 51-79) positive predictive value and 80% (95% CI, 65-90) negative predictive value [area under the ROC curve, 0.779 (95%CI, 0.681-0.859), p=0.0001]. CONCLUSIONS: Mechanically ventilated COVID-19 patients present with an imbalance between markedly increased factor V/VIII activity and overwhelmed protein C/S pathway. Plasma D-dimer may be a useful biomarker at the bedside for suspicion of VTE.

Unusual arterial thrombotic events in Covid-19 patients.

INTRODUCTION: COVID-19 infection is commonly complicated with pro-thrombotic state and endothelial dysfunction. While several studies reported a high incidence of venous thromboembolic events. The occurrence of arterial thromboses are yet rarely described and could be underestimated. OBJECTIVES: To describe the clinical and biological characteristics of COVID-19 patients presenting with an associated arterial thromboembolic event. MATERIAL AND METHODS: We performed a retrospective multicentric study in 3 centers between France and Italy. All patients with a confirmed SARS-CoV-2 infection and arterial thromboembolic events were included in the analysis. RESULTS: From March 8th to April 25th 2020, we identified 20 patients (24 events) with arterial thromboembolic events over 209 admitted patients (9.6%) with severe COVID-19 infection. Arterial thrombotic events included acute coronary occlusions (n = 9), stroke (n = 6), limb ischemia (n = 3), splenic infarcts (n = 3), aortic thrombosis (n = 2) and occlusive mesenteric ischemia (n = 1). At the time of the event, 10/20 (50%) of patients received thromboprohylaxis, 2/20 (10%) were receiving treatment dose anticoagulation and 5/20 (25%) were receiving antiplatelet therapy. CONCLUSION: Our observations suggest that serious arterial thrombotic events might occur in Covid-19 patients. However, the exact incidence of such events and the best way to prevent them yet remains to be investigated.