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Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic with a great impact on social and economic activities, as well as public health. In most patients, the symptoms of COVID-19 are a high-grade fever and a dry cough, and spontaneously resolve within ten days. However, in severe cases, COVID-19 leads to atypical bilateral interstitial pneumonia, acute respiratory distress syndrome, and systemic thromboembolism, resulting in multiple organ failure with high mortality and morbidity. SARS-CoV-2 has immune evasion mechanisms, including inhibition of interferon signaling and suppression of T cell and B cell responses. SARS-CoV-2 infection directly and indirectly causes dysregulated immune responses, platelet hyperactivation, and endothelial dysfunction, which interact with each other and are exacerbated by cardiovascular risk factors. In this review, we summarize current knowledge on the pathogenic basis of thromboinflammation and endothelial injury in COVID-19. We highlight the distinct contributions of dysregulated immune responses, platelet hyperactivation, and endothelial dysfunction to the pathogenesis of COVID-19. In addition, we discuss potential therapeutic strategies targeting these mechanisms.
由嚴(yán)重急性呼吸系統(tǒng)綜合癥冠狀病毒 2 (SARS-CoV-2) 引起的 2019 年冠狀病毒病 (COVID-19) 已成為全球流行病，對(duì)社會(huì)和經(jīng)濟(jì)活動(dòng)以及公共衛(wèi)生產(chǎn)生重大影響。在大多數(shù)患者中，COVID-19 的癥狀是高燒和干咳，并在 10 天內(nèi)自然消退。然而，在嚴(yán)重的情況下，COVID-19會(huì)導(dǎo)致非典型雙側(cè)間質(zhì)性肺炎、急性呼吸窘迫綜合征和全身血栓栓塞，導(dǎo)致多器官功能衰竭，死亡率和發(fā)病率很高。SARS-CoV-2 具有免疫逃避機(jī)制，包括抑制干擾素信號(hào)傳導(dǎo)和抑制 T 細(xì)胞和 B 細(xì)胞反應(yīng)。SARS-CoV-2 感染直接和間接導(dǎo)致免疫反應(yīng)失調(diào)、血小板過(guò)度活化和內(nèi)皮功能障礙，它們相互作用并因心血管危險(xiǎn)因素而加劇。在這篇綜述中，我們總結(jié)了當(dāng)前關(guān)于 COVID-19 血栓炎癥和內(nèi)皮損傷的致病基礎(chǔ)的知識(shí)。我們強(qiáng)調(diào)了失調(diào)的免疫反應(yīng)、血小板過(guò)度活化和內(nèi)皮功能障礙對(duì) COVID-19 發(fā)病機(jī)制的獨(dú)特貢獻(xiàn)。此外，我們討論了針對(duì)這些機(jī)制的潛在治療策略。

 
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Based on the results of clinical trials, the current recommendation for the treatment of severely ill patients with COVID-19 receiving mechanical respiratory or circulatory supports is the use of dexamethasone. If these patients are within 24 h of admission to the ICU, dexamethasone plus tocilizumab, an IL-6 inhibitor, could be another option. For the treatment of hospitalized COVID-19 patients requiring oxygen delivery through a high-flow device or noninvasive ventilation, dexamethasone or dexamethasone plus remdesivir is recommended, while tocilizumab or baricitinib, a JAK inhibitor, can be added if rapidly worsening respiratory distress and systemic inflammation are observed in these patients. For hospitalized mild-to-moderate COVID-19 patients requiring supplemental oxygen, the use of dexamethasone and/or remdesivir is recommended. For COVID-19 inpatients without oxygen support or outpatients, there is insufficient evidence for therapeutic recommendation. Anticoagulation with prophylactic dose of heparin is recommended for hospitalized COVID-19 patients. Collectively, anti-inflammation drugs, especially targeting IL-6, is the main therapeutic option in addition to antiviral agents.

From mechanistic points of view, it remains unclear whether dysregulated immune response is the primary pathogenic mechanism in severe COVID-19, although in the acute phase of severely ill patients with COVID-19, anti-inflammation agents are effective. In a retrospective observational study, persistent endotheliopathy with increased levels of factor VIII, VWF, and thrombomodulin, compared with healthy subjects, was observed in convalescent COVID-19 patients, independent of ongoing acute phase response or NETosis [215,216]. The hypercoagulable state observed in severe COVID-19 patients was associated with elevated levels of factor VIII and VWF, suggesting the involvement of endothelial cells [110]. In addition, the elevated levels of VWF were also observed in mild COVID-19 patients [95]. Together with milder thrombocytopenia in severe COVID-19 compared with severe SARS and MERS, these findings suggest that endothelial dysfunction might be the main contributor to the pathogenesis of COVID-19. On the other hand, systemic endothelial dysfunction without detectable viral RNAs in the bloodstream or in the endothelium suggests important roles of thromboinflammation in the pathogenic mechanisms of COVID-19 [217]. The vicious cycle of interaction between thromboinflammation and endothelial injury might contribute to disease severity. Contribution of each pathogenic mechanism to COVID-19 might differ among patients, depending on their background characteristics and the stages of disease progression. In fact, pre-existing cardiovascular risk factors increase the incidence of thromboembolic events in COVID-19 [35,36,37,38].

Activation of the kallikrein–kinin system due to endothelial dysfunction has been implicated in the pathophysiology of COVID-19 [125]. ACE2 internalization and/or factor XII activation might be involved in this process. However, it remains unclear which of the two mechanisms mainly contribute to activation of the kallikrein–kinin system in COVID-19. It was reported that systemic factor XIIa levels were not elevated in patients with long COVID-19 syndrome, compared with healthy subjects, while factor VIII and VWF levels were higher in these patients, suggesting that ACE2 internalization might be the main contributor to activation of the kallikrein–kinin system in COVID-19 [215]. ACE2 decoys and bradykinin inhibitors could be therapeutic candidates for COVID-19 that target endothelial dysfunction, in addition to statin and nitric oxide.

In summary, therapeutic strategies targeting thromboinflammation and endothelial injury in COVID-19 have been in development by repurposing currently available drugs, in addition to vaccines or antiviral drugs [218]. Considering the multifactorial pathogenic nature of COVID-19, combinatorial treatment might be necessary to improve clinical outcomes, including mortality. Further studies that clarify the pathogenic basis of COVID-19 might provide new insights in determining the optimal timing and combinations of drug administration as well as creating novel therapeutic strategies.

根據(jù)臨床試驗(yàn)結(jié)果，目前對(duì)接受機(jī)械呼吸或循環(huán)支持的 COVID-19 重癥患者的治療建議是使用地塞米松。如果這些患者在入住 ICU 后 24 小時(shí)內(nèi)，地塞米松加托珠單抗（一種 IL-6 抑制劑）可能是另一種選擇。對(duì)于需要通過(guò)高流量設(shè)備或無(wú)創(chuàng)通氣供氧的住院 COVID-19 患者的治療，推薦地塞米松或地塞米松加瑞德西韋，而如果呼吸窘迫和全身炎癥迅速惡化，則可以添加托珠單抗或 JAK 抑制劑巴瑞替尼在這些患者中觀察到。對(duì)于需要補(bǔ)充氧氣的住院輕中度 COVID-19 患者，建議使用地塞米松和/或瑞德西韋。對(duì)于沒(méi)有氧氣支持的 COVID-19 住院患者或門(mén)診患者，治療建議的證據(jù)不足。對(duì)于住院的 COVID-19 患者，推薦使用預(yù)防性劑量的肝素進(jìn)行抗凝。總的來(lái)說(shuō)，抗炎藥物，尤其是針對(duì) IL-6 的藥物，是除抗病毒藥物之外的主要治療選擇。

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從機(jī)制的角度來(lái)看，免疫反應(yīng)失調(diào)是否是重癥 COVID-19 的主要致病機(jī)制尚不清楚，盡管在 COVID-19 重癥患者的急性期，抗炎藥是有效的。在回顧性觀察研究，持續(xù)性內(nèi)皮盲具有增加的因子VIII，VWF，和血栓調(diào)節(jié)蛋白的水平，與健康受試者相比，在恢復(fù)期COVID-19的患者，正在進(jìn)行獨(dú)立急性期反應(yīng)的或NETosis [觀察215，216 ]。在重癥 COVID-19 患者中觀察到的高凝狀態(tài)與因子 VIII 和 VWF 水平升高有關(guān)，表明內(nèi)皮細(xì)胞的參與 [ 110]]。此外，在輕度 COVID-19 患者中也觀察到 VWF 水平升高 [ 95 ]。與嚴(yán)重的 SARS 和 MERS 相比，嚴(yán)重的 COVID-19 患者血小板減少癥較輕，這些發(fā)現(xiàn)表明內(nèi)皮功能障礙可能是 COVID-19 發(fā)病機(jī)制的主要因素。另一方面，在血流或內(nèi)皮中沒(méi)有檢測(cè)到病毒 RNA 的全身性內(nèi)皮功能障礙表明血栓炎癥在 COVID-19 的致病機(jī)制中起著重要作用 [ 217]]。血栓炎癥和內(nèi)皮損傷之間相互作用的惡性循環(huán)可能會(huì)導(dǎo)致疾病的嚴(yán)重程度。根據(jù)患者的背景特征和疾病進(jìn)展階段，每種致病機(jī)制對(duì) COVID-19 的貢獻(xiàn)可能因患者而異。事實(shí)上，預(yù)先存在的心血管疾病的危險(xiǎn)因素增加的血栓栓塞事件在COVID-19 [發(fā)病35，36，37，38 ]。

細(xì)胞轉(zhuǎn)瓶2L

由于內(nèi)皮功能障礙導(dǎo)致激肽釋放酶-激肽系統(tǒng)的激活與 COVID-19 的病理生理學(xué)有關(guān) [ 125 ]。ACE2 內(nèi)化和/或因子 XII 激活可能參與此過(guò)程。然而，目前尚不清楚這兩種機(jī)制中的哪一種主要有助于激活 COVID-19 中激肽釋放酶-激肽系統(tǒng)。據(jù)報(bào)道，與健康受試者相比，長(zhǎng)期 COVID-19 綜合征患者的全身性因子 XIIa 水平?jīng)]有升高，而這些患者的因子 VIII 和 VWF 水平更高，表明 ACE2 內(nèi)化可能是激活COVID-19 中的激肽釋放酶-激肽系統(tǒng) [ 215]]。除了他汀類藥物和一氧化氮外，ACE2 誘餌和緩激肽抑制劑可能是針對(duì)內(nèi)皮功能障礙的 COVID-19 的治療候選藥物。

總而言之，除了疫苗或抗病毒藥物外，通過(guò)重新利用當(dāng)前可用的藥物，已經(jīng)開(kāi)發(fā)出針對(duì) COVID-19 中血栓炎癥和內(nèi)皮損傷的治療策略 [ 218 ]。考慮到 COVID-19 的多因素致病性質(zhì)，可能需要聯(lián)合治療來(lái)改善臨床結(jié)果，包括死亡率。闡明 COVID-19 致病基礎(chǔ)的進(jìn)一步研究可能為確定最佳給藥時(shí)機(jī)和組合以及創(chuàng)造新的治療策略提供新的見(jiàn)解。

 關(guān)鍵詞：COVID-19; endothelial injury; inflammation; platelet activation; SARS-CoV-2; therapeutics; thrombosis
          COVID-19；內(nèi)皮損傷；炎癥; 血小板活化；SARS-CoV-2；療法；血栓形成