Aberdeen Cardiovascular & Diabetes Centre, School of Medicine, Medical Sciences and Nutrition, Aberdeen, UK.
Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
J Thromb Haemost. 2020 Jul;18(7):1548-1555. doi: 10.1111/jth.14872. Epub 2020 Jun 3.
The global pandemic of coronavirus disease 2019 (COVID-19) is associated with the development of acute respiratory distress syndrome (ARDS), which requires ventilation in critically ill patients. The pathophysiology of ARDS results from acute inflammation within the alveolar space and prevention of normal gas exchange. The increase in proinflammatory cytokines within the lung leads to recruitment of leukocytes, further propagating the local inflammatory response. A consistent finding in ARDS is the deposition of fibrin in the air spaces and lung parenchyma. COVID-19 patients show elevated D-dimers and fibrinogen. Fibrin deposits are found in the lungs of patients due to the dysregulation of the coagulation and fibrinolytic systems. Tissue factor (TF) is exposed on damaged alveolar endothelial cells and on the surface of leukocytes promoting fibrin deposition, while significantly elevated levels of plasminogen activator inhibitor 1 (PAI-1) from lung epithelium and endothelial cells create a hypofibrinolytic state. Prophylaxis treatment of COVID-19 patients with low molecular weight heparin (LMWH) is important to limit coagulopathy. However, to degrade pre-existing fibrin in the lung it is essential to promote local fibrinolysis. In this review, we discuss the repurposing of fibrinolytic drugs, namely tissue-type plasminogen activator (tPA), to treat COVID-19 associated ARDS. tPA is an approved intravenous thrombolytic treatment, and the nebulizer form has been shown to be effective in plastic bronchitis and is currently in Phase II clinical trial. Nebulizer plasminogen activators may provide a targeted approach in COVID-19 patients to degrade fibrin and improving oxygenation in critically ill patients.
新型冠状病毒病 2019（COVID-19）的全球大流行与急性呼吸窘迫综合征（ARDS）的发展有关，这需要重症患者进行通气。ARDS 的病理生理学是由于肺泡空间内的急性炎症和正常气体交换受阻所致。肺内促炎细胞因子的增加导致白细胞募集，进一步加剧局部炎症反应。ARDS 的一个常见发现是纤维蛋白在气腔和肺实质中的沉积。COVID-19 患者的 D-二聚体和纤维蛋白原升高。由于凝血和纤维蛋白溶解系统失调，COVID-19 患者的肺部可见纤维蛋白沉积。组织因子（TF）暴露于受损的肺泡内皮细胞和白细胞表面，促进纤维蛋白沉积，而肺上皮细胞和内皮细胞中显著升高的纤溶酶原激活物抑制剂 1（PAI-1）则导致低纤维蛋白溶解状态。COVID-19 患者预防性使用低分子量肝素（LMWH）治疗对于限制凝血功能障碍很重要。然而，要降解肺内已存在的纤维蛋白，促进局部纤维蛋白溶解至关重要。在这篇综述中，我们讨论了纤维蛋白溶解药物（即组织型纤溶酶原激活物（tPA））的再利用，以治疗与 COVID-19 相关的 ARDS。tPA 是一种已批准的静脉溶栓治疗药物，雾化形式已被证明对塑料性支气管炎有效，目前正在进行 II 期临床试验。雾化纤溶酶原激活物可能为 COVID-19 患者提供一种靶向方法，降解纤维蛋白，改善重症患者的氧合。
