Interleukin-6 receptor blockade with subcutaneous tocilizumab improves coagulation activity in patients with COVID-19.
Interleukin-6 receptor blockade with subcutaneous tocilizumab improves coagulation activity in patients with COVID-19.
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DOI：
10.1016/j.ejim.2020.10.020
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发表时间：
2021-01
影响因子：
8
通讯作者：
Porreca E
中科院分区：
文献类型：
--
作者：
Di Nisio M;Potere N;Candeloro M;Spacone A;Pieramati L;Ferrandu G;Rizzo G;La Vella M;Di Carlo S;Cibelli D;Parruti G;Levi M;Porreca E
COVID-19中的过度炎症激活血液凝固，增加血栓形成风险。Tocilizumab阻断IL-6受体，可能改善炎症诱导的高凝状态。托珠单抗与快速和持续的凝血改善相关。这些益处与血栓预防剂量无关。许多COVID-19患者会出现炎症反应，激活血液凝固，并可能导致血栓栓塞并发症的发生。阻断COVID-19发病机制中的关键细胞因子白细胞介素-6可能改善炎症诱导的高凝状态。本研究的目的是评估皮下注射托珠单抗（一种抗白细胞介素-6受体的重组人源化单克隆抗体）对凝血参数的影响。在标准治疗基础上接受托珠单抗324 mg单次皮下给药的实验室确诊的中度至危重COVID-19肺炎和炎症过度的住院成人患者入组本分析。在托珠单抗治疗前和治疗后第1、3和7天测量凝血参数。所有患者在入院后随访35天或直至死亡。纳入70例患者（平均年龄60岁，四分位数间距52-75）。托珠单抗治疗与D-二聚体水平降低相关（-56%; 95%置信区间[CI]，-68%至-44%），纤维蛋白原（-48%; 95%CI，-60%至-35%），C-反应蛋白（-93%; 95%CI，-99%至-87%），凝血酶原时间（-4%; 95%CI，-9%至0.8%），活化凝血活酶时间（-4%; 95%CI，-8.7%至0.8%），血小板计数增加（34%; 95%CI，23%至45%）。这些变化在给药后1天发生，在第7天持续降低。在接受预防性或治疗剂量抗凝剂的患者中始终观察到凝血功能的改善，并伴随呼吸功能的快速改善。皮下注射托珠单抗与凝血参数的显著改善相关，与血栓预防剂量无关。
Hyperinflammation in COVID-19 activates blood coagulation increasing thrombotic risk. Tocilizumab blocks IL-6 receptor and may improve inflammatory-induced hypercoagulability. Tocilizumab was associated with rapid and sustained coagulation improvement. These benefits were consistent independently of thromboprophylaxis dose. Many COVID-19 patients develop a hyperinflammatory response which activates blood coagulation and may contribute to the occurrence of thromboembolic complications. Blockade of interleukin-6, a key cytokine in COVID-19 pathogenesis, may improve the hypercoagulable state induced by inflammation. The aim of this study was to evaluate the effects of subcutaneous tocilizumab, a recombinant humanized monoclonal antibody against the interleukin-6 receptor on coagulation parameters. Hospitalized adult patients with laboratory-confirmed moderate to critical COVID-19 pneumonia and hyperinflammation, who received a single 324 mg subcutaneous dose of tocilizumab on top of standard of care were enrolled in this analysis. Coagulation parameters were measured before tocilizumab and at day 1, 3, and 7 after treatment. All patients were followed-up for 35 days after admission or until death. 70 patients (mean age 60 years, interquartile range 52-75) were included. Treatment with tocilizumab was associated with a reduction in D-dimer levels (-56%; 95% confidence interval [CI], -68% to -44%), fibrinogen (-48%; 95%CI, -60% to -35%), C-reactive protein (-93%; 95%CI, -99% to -87%), prothrombin time (-4%; 95%CI,-9% to 0.8%), and activated thromboplastin time (-4%; 95%CI,-8.7% to 0.8%), and an increase in platelet count (34%; 95%CI, 23% to 45%). These changes occurred already one day after treatment with sustained reductions throughout day 7. The improvement in coagulation was consistently observed in patients receiving prophylactic or therapeutic dose anticoagulants, and was paralleled by a rapid improvement in respiratory function. Subcutaneous tocilizumab was associated with significant improvement of blood coagulation parameters independently of thromboprophylaxis dose.
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