Interleukin-6 receptor blockade with subcutaneous tocilizumab improves coagulation activity in patients with COVID-19

Nisio, Marcello Di; Potere, Nicola; Candeloro, Matteo; Spacone, Antonella; Pieramati, Leonardo; Ferrandu, Giovanna; Rizzo, Giulia; Vella, Matteo La; Carlo, Silvio Di; Cibelli, Donatella; Parruti, Giustino; Levi, Marcel; Porreca, Ettore

doi:10.1016/j.ejim.2020.10.020

Cited by 30 publications

(32 citation statements)

References 24 publications

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“…IL-6 is also involved in the COVID-19-associated coagulopathy [101] as it is known to interfere with the coagulation cascade through the generation of tissue factor and thrombin [102,103], to stimulate platelet activity, and induce endothelial dysfunction [104]. With this regard, tocilizumab seems to improve the hypercoagulable state in COVID-19 patients, irrespective of prophylactic or therapeutic dose of anticoagulant therapy, and was associated with a parallel improvement in respiratory function [105]. Recently, Canzano et al provided evidence that COVID-19 coagulopathy may be supported by diffuse cell activation mediated by tissue factor produced by platelets, granulocytes, and microvesicles on the common background of endothelial dysfunction, with all of these events strongly sustained by increased levels of IL-6.…”

Section: Pathophysiological Role Of Il-6 In Covid-19related Dysregulated Cytokine Responsementioning

confidence: 99%

“…CoV-2 pandemic, IL-6 blockade using monoclonal antibodies was investigated with potential benefits described in several observational or cohort studies [105,127,131,[158][159][160][161]. However, some contrasting data from RCTs with the IL-6 R blocker tocilizumab have raised questions on the real usefulness of these drugs and posed some questions about the real role played by IL-6 in severe COVID-19 [10,139,140,142,143,162,163].…”

Section: Expert Opinionmentioning

confidence: 99%

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The role of IL-6 and IL-6 blockade in COVID-19

Potere

Batticciotto

Vecchiè³

et al. 2021

Expert Review of Clinical Immunology

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Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a dysregulated hyperinflammatory response. Areas covered: Authors review evidence on IL-6 and IL-6 blockade in coronavirus disease 2019 (COVID-19) and discuss the pathophysiological and prognostic roles of this cytokine and the clinical impact of pharmacological blockade of IL-6 . The material includes original articles and reviews published from March 2020 to March 2021 and searched on PubMed, medRxiv, and bioRxiv. Expert opinion: IL-6 is one of the most prominent pro-inflammatory cytokines. Increased levels are recorded in COVID-19 patients, especially those with severe-to-critical disease. Evidence is accumulating on the relevance of IL-6 as a prognostic marker in COVID-19. Since IL-6 is a druggable target for several inflammatory diseases, pharmacological blockers of the IL-6 signaling pathway were repurposed to blunt the abnormal SARS-CoV-2-induced cytokine release. Data are limited to few randomized controlled trials that reported encouraging, though not conclusive, results, indicating the usefulness of IL-6 blockade early in the course of the disease in patients with hyperinflammation and no or limited organ damage. Further research is warranted to explore the role of IL-6 in different COVID-19 phenotypes and identify subgroups of patients who may mostly benefit from IL-6 pathway inhibition.

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Section: Pathophysiological Role Of Il-6 In Covid-19related Dysregulated Cytokine Responsementioning

confidence: 99%

Section: Expert Opinionmentioning

confidence: 99%

The role of IL-6 and IL-6 blockade in COVID-19

Potere

Batticciotto

Vecchiè³

et al. 2021

Expert Review of Clinical Immunology

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View full text Add to dashboard Cite

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“…Other therapies to impair the interaction between pro-inflammatory and procoagulant mechanisms have been proposed, as targeting cytokines (mainly IL-6), impairing NETosis [ 124 , 125 ] or complement inhibition [ 126 ]. Several clinical studies on tocilizumab (anti-IL-6 receptor antagonist) in COVID-19 have been published, but thrombotic complications are not always addressed [ 127 ] and if so, conflicting results are found [ 128–131 ]. Of the other novel therapeutic targets for COVID-19 associated thrombosis, clinical results are lacking.…”

Section: Treatmentmentioning

confidence: 99%

Prophylaxis and treatment of COVID-19 related venous thromboembolism

Kaptein

Stals

Huisman

et al. 2021

Postgraduate Medicine

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COVID-19 pneumonia has been associated with high rates of thrombo-embolic complications, mostly venous thromboembolism (VTE), which is thought to be a combination of conventional VTE and in situ immunothrombosis in the pulmonary vascular tree. The incidence of thrombotic complications is dependent on setting (intensive care unit (ICU) versus general ward) and the threshold for performing diagnostic tests (screening versus diagnostic algorithms triggered by symptoms). Since these thrombotic complications are associated with in-hospital mortality, all current guidelines and consensus papers propose pharmacological thromboprophylaxis in all hospitalized patients with COVID-19. Several trials are ongoing to study the optimal intensity of anticoagulation for this purpose. As for the management of thrombotic complications, treatment regimens from non-COVID-19 guidelines can be adapted, with choice of anticoagulant drug class dependent on the situation. Parenteral anticoagulation is preferred for patients on ICUs or with impending clinical deterioration, while oral treatment can be started in stable patients. This review describes current knowledge on incidence and pathophysiology of COVID-19 associated VTE and provides an overview of guideline recommendations on thromboprophylaxis and treatment of established VTE in COVID-19 patients.

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“…Although a relationship between corticosteroid therapy and VTE has been previously described, early interventions aimed at reducing inflammation, such as dexamethasone, might help to prevent this hypercoagulable state [37]. In fact, treatment to counteract inflammation and cytokine storm syndrome has been related with lower mortality and with an improvement of inflammatory-induced hypercoagulability in COVID-19 patients [37][38][39]. This is important because we have observed that PE was diagnosed mostly between 2-4 weeks after onset of symptoms, which means that PE occurs during or immediately after the systemic hyperinflammation stage, consistent with the thromboinflammation term [39][40][41].…”

Section: Discussionmentioning

confidence: 99%

“…In fact, treatment to counteract inflammation and cytokine storm syndrome has been related with lower mortality and with an improvement of inflammatory-induced hypercoagulability in COVID-19 patients [37][38][39]. This is important because we have observed that PE was diagnosed mostly between 2-4 weeks after onset of symptoms, which means that PE occurs during or immediately after the systemic hyperinflammation stage, consistent with the thromboinflammation term [39][40][41]. Indeed, inflammatory parameters, such as C-reactive protein or ferritin, were higher during these weeks in PE patients than in non-PE patients, though non-statistically significant.…”

Section: Discussionmentioning

confidence: 99%

Blood test dynamics in hospitalized COVID-19 patients: Potential utility of D-dimer for pulmonary embolism diagnosis

et al. 2020

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Background A higher incidence of thrombotic events, mainly pulmonary embolism (PE), has been reported in hospitalized patients with COVID-19. The main objective was to assess clinical and laboratory differences in hospitalized COVID-19 patients according to occurrence of PE. Methods This retrospective study included all consecutive patients hospitalized with COVID-19 who underwent a computed tomography (CT) angiography for PE clinical suspicion. Clinical data and median blood test results distributed into weekly periods from COVID-19 symptoms onset, were compared between PE and non-PE patients. Results Ninety-two patients were included, 29 (32%) had PE. PE patients were younger (63.9 (SD 13.7) vs 69.9 (SD 12.5) years). Clinical symptoms and COVID-19 CT features were similar in both groups. PE was diagnosed after a mean of 20.0 (SD 8.6) days from the onset of COVID-19 symptoms. Corticosteroid boluses were more frequently used in PE patients (62% vs. 43%). No patients met ISTH DIC criteria. Any parameter was statistically significant or clinically relevant except for D-Dimer when comparing both groups. Median values [IQR] of D-dimer in PE vs non-PE patients were: week 2 (2010.7 [770.1–11208.9] vs 626.0 [374.0–2382.2]; p = 0.004); week 3 (3893.1 [1388.2–6694.0] vs 1184.4 [461.8–2447.8]; p = 0.003); and week 4 (2736.3 [1202.1–8514.1] vs 1129.1 [542.5–2834.6]; p = 0.01). Median fold-increase of D-dimer between week 1 and 2 differed between groups (6.64 [3.02–23.05] vs 1.57 [0.64–2.71], p = 0.003); ROC curve AUC was 0.879 (p = 0.003) with a sensitivity and specificity for PE of 86% and 80%, respectively. Conclusions Among hospitalized COVID-19 patients, D-dimer levels are higher at weeks 2, 3 and 4 after COVID-19 symptom onset in patients who develop PE. This difference is more pronounced when the fold increase between weeks 1 and 2 is compared.

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Interleukin-6 receptor blockade with subcutaneous tocilizumab improves coagulation activity in patients with COVID-19

Cited by 30 publications

References 24 publications

The role of IL-6 and IL-6 blockade in COVID-19

The role of IL-6 and IL-6 blockade in COVID-19

Prophylaxis and treatment of COVID-19 related venous thromboembolism

Blood test dynamics in hospitalized COVID-19 patients: Potential utility of D-dimer for pulmonary embolism diagnosis

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