Thromboses and COVID-19: reducing inflammation in addition to thromboprophylaxis.
Thromboses and COVID-19: reducing inflammation in addition to thromboprophylaxis.
复制标题
DOI：
10.1016/s2665-9913(21)00003-5
复制
发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Hunt BJ
中科院分区：
文献类型：
--
作者：
Mehta P;Haskard DO;Laffan MA;Chambers RC;Hunt BJ
2019冠状病毒病大流行是一个前所未有的全球卫生保健紧急情况，发展为2019冠状病毒病肺炎的患者死亡率很高。这些患者存在血栓前状态，尽管进行了血栓预防，但仍发生静脉和动脉血栓。促血栓形成机制是多因素的，免疫激活导致急性期反应，导致血浆凝血因子（特别是纤维蛋白原）升高。其他特征包括血小板高反应性、缺氧效应、嗜中性粒细胞胞外陷阱的形成和补体激活。尽管在COVID-19患者中观察到非常高的循环D-二聚体浓度，但几乎没有弥散性血管内凝血的证据，因为不存在血小板减少症和低纤维蛋白原血症，并且筛选凝血时间没有延长。已经提出了许多驱动COVID-19患者血栓形成的机制，包括内皮细胞的炎症激活。我们认为，COVID-19肺炎患者血栓形成的发病机制与白塞综合征患者相似。白塞综合征是一种多系统血管炎，最常见的特征是复发性口腔生殖器溃疡和葡萄膜炎。血管受累影响10-30%的白塞综合征患者，主要引起浅表或深静脉血栓形成。血管壁炎症，而不是高凝状态，是白塞综合征患者血栓形成的主要原因。因此，治疗指南支持免疫抑制（包括类固醇和肿瘤坏死因子阻断），并不鼓励使用抗凝治疗，主要是由于隐性肺动脉瘤出血的风险，而这在COVID-19患者中不存在。1尽管在白塞综合征患者和COVID-19患者中描述了肺栓塞，但该术语可能会产生误导，因为CT肺血管造影上看到的节段和亚节段变化可能不是由栓塞引起的，而是由局部炎症引起的免疫血栓形成或原位血栓形成引起的。这两种情况在组织学上有相似之处。在白塞氏综合征患者中，血栓紧紧粘附在血管壁上，并且COVID-19患者的一些血栓铸型已被证明符合肺动脉血管系统（表明原位解剖学来源），并且在没有明显远端栓塞源的情况下发生，例如深静脉血栓形成。2因此，肺部炎症很可能导致白塞综合征患者和COVID-19患者的血栓形成。血栓预防可将不适、不活动、住院患者的静脉血栓栓塞风险降低约50%。药物血栓预防可提高生存率，并已成为COVID-19肺炎患者的标准治疗，但血栓并发症的发生率仍然很高。我们假设，除了血栓预防外，抗炎策略可能有助于COVID-19肺炎患者减轻免疫血栓形成的负担。靶向炎症以减少血栓形成的治疗潜力在卡那单抗抗炎性血栓形成结局研究（CANTOS）中得到了证实，这是一项安慰剂对照试验，在COVID-19大流行之前发表。该试验表明，靶向白细胞介素-1 β可显著降低复发性血栓事件（如心肌梗死、卒中和
The COVID-19 pandemic is an unprece dented global health-care emergency, with high mortality in patients who develop COVID-19 pneumonia. These patients have a prothrombotic state with both venous and arterial thrombi occurring despite thromboprophylaxis. Prothrombotic mechanisms are multifactorial, with immune activation leading to an acute phase response, resulting in elevated plasma coagulation factors (particularly fibrinogen). Other features include platelet hyperreactivity, the effects of hypoxia, formation of neutro phil extracellular traps, and comple ment activation. Although very high circulating D-dimer concentrations are observed in patients with COVID-19, there is little evidence of disseminated intravascular coagulation, as thrombocytopenia and hypo fibrinogenaemia are not present and screening clotting times are not prolonged. Many mechanisms driving thromboses in patients with COVID-19 have been suggested, including inflammatory activation of endo thelial cells. We believe that the patho genesis of thrombosis in patients with COVID-19 pneumonia shares similarities with that in patients with Behçet’s syndrome. Behçet’s syndrome is a multisystem vasculitis, most commonly characterised by recurrent orogenital ulcers and uveitis. Vascular involvement affects 10–30% of people with Behçet’s syndrome, causing mainly superficial or deep venous thrombosis. Vascular wall inflammation, rather than a hypercoagulable state, is the main cause of thromboses in patients with Behçet’s syndrome. Hence, treatment guidelines endorse immunosuppression (including steroids and tumour necrosis factor blockade) and discourage the use of anticoagulation, mainly due to the perceived risk of bleeding from covert pulmonary arterial aneurysms, which is not present in patients with COVID-19. 1 Although pulmonary emboli are described in patients with Behçet’s syndrome and patients with COVID-19, this term could be misleading, as segmental and subsegmental changes seen on CT pulmonary angiograms might not be caused by emboli but by immunothrombosis or in-situ thrombosis due to local inflammation. There are histological similarities in the two conditions. In patients with Behçet’s syndrome, thrombi are tightly adherent to the vessel wall, and some thrombus casts in patients with COVID-19 have been shown to conform to the pulmonary artery vasculature (suggesting in-situ anatomical origin) and to occur without an overt distal embolic source, such as deep venous thrombosis. 2 Therefore, pulmonary inflammation is likely to drive thrombosis in both patients with Behçet’s syndrome and patients with COVID-19.Thromboprophylaxis reduces the risk of venous thromboembolism for unwell, immobile, hospitalised patients by approximately 50%. Pharma co logical thromboprophylaxis improves survival and has become stan dard of care in patients with COVID-19 pneumonia, but throm botic compli ca tions still occur at high rates. We hypothesise that an anti-inflam matory strategy, in addition to thromboprophylaxis, might be beneficial in patients with COVID-19 pneumonia to reduce the burden of immunothrombosis. The therapeutic potential of targeting inflammation to reduce thromboses was shown by the Canakinumab Antiinflammatory Thrombosis Outcomes Study (CANTOS), 3 a placebo-controlled trial that was published before the COVID-19 pandemic. This trial showed that targeting interleukin-1β significantly reduced the frequency of recurrent thrombotic events (eg, myocardial infarction, stroke, and