Molecular Neuroinflammation and Neuronal Plasticity Research Laboratory, Hospital Universitario Santa Cristina, IIS Hospital Universitario de La Princesa, 28009, Madrid, Spain.
Laboratory of Diabetes and Vascular Pathology, IIS-Fundación Jiménez Díaz, 28040, Madrid, Spain.
Cardiovasc Diabetol. 2024 Feb 20;23(1):75. doi: 10.1186/s12933-023-02097-8.
Early since the onset of the COVID-19 pandemic, the medical and scientific community were aware of extra respiratory actions of SARS-CoV-2 infection. Endothelitis, hypercoagulation, and hypofibrinolysis were identified in COVID-19 patients as subsequent responses of endothelial dysfunction. Activation of the endothelial barrier may increase the severity of the disease and contribute to long-COVID syndrome and post-COVID sequelae. Besides, it may cause alterations in primary, secondary, and tertiary hemostasis. Importantly, these responses have been highly decisive in the evolution of infected patients also diagnosed with diabetes mellitus (DM), who showed previous endothelial dysfunction. In this review, we provide an overview of the potential triggers of endothelial activation related to COVID-19 and COVID-19 under diabetic milieu. Several mechanisms are induced by both the viral particle itself and by the subsequent immune-defensive response (i.e., NF-κB/NLRP3 inflammasome pathway, vasoactive peptides, cytokine storm, NETosis, activation of the complement system). Alterations in coagulation mediators such as factor VIII, fibrin, tissue factor, the von Willebrand factor: ADAMST-13 ratio, and the kallikrein-kinin or plasminogen-plasmin systems have been reported. Moreover, an imbalance of thrombotic and thrombolytic (tPA, PAI-I, fibrinogen) factors favors hypercoagulation and hypofibrinolysis. In the context of DM, these mechanisms can be exacerbated leading to higher loss of hemostasis. However, a series of therapeutic strategies targeting the activated endothelium such as specific antibodies or inhibitors against thrombin, key cytokines, factor X, complement system, the kallikrein-kinin system or NETosis, might represent new opportunities to address this hypercoagulable state present in COVID-19 and DM. Antidiabetics may also ameliorate endothelial dysfunction, inflammation, and platelet aggregation. By improving the microvascular pathology in COVID-19 and post-COVID subjects, the associated comorbidities and the risk of mortality could be reduced.
自 COVID-19 大流行早期以来，医学和科学界已经意识到 SARS-CoV-2 感染的额外呼吸道作用。COVID-19 患者中发现了内皮炎、高凝和低纤维蛋白溶解，这是内皮功能障碍的后续反应。内皮屏障的激活可能会加重疾病的严重程度，并导致长 COVID 综合征和 COVID-19 后遗症。此外，它可能导致原发性、继发性和三级止血的改变。重要的是，这些反应在感染患者中也被高度决定，这些患者还被诊断患有糖尿病（DM），他们先前存在内皮功能障碍。在这篇综述中，我们提供了 COVID-19 与糖尿病环境下 COVID-19 相关的内皮激活潜在触发因素的概述。病毒颗粒本身和随后的免疫防御反应（即 NF-κB/NLRP3 炎性小体途径、血管活性肽、细胞因子风暴、NETosis、补体系统激活）会引发多种机制。已经报道了凝血介质的改变，如因子 VIII、纤维蛋白、组织因子、血管性血友病因子：ADAMST-13 比值、激肽释放酶-激肽系统或纤溶酶原-纤溶酶系统。此外，血栓形成和溶栓（tPA、PAI-I、纤维蛋白原）因子的失衡有利于高凝和低纤维蛋白溶解。在 DM 的情况下，这些机制可能会加剧，导致止血功能更高的丧失。然而，针对激活的内皮的一系列治疗策略，如针对凝血酶、关键细胞因子、因子 X、补体系统、激肽释放酶-激肽系统或 NETosis 的特异性抗体或抑制剂，可能代表解决 COVID-19 和 DM 中存在的这种高凝状态的新机会。抗糖尿病药物也可能改善内皮功能障碍、炎症和血小板聚集。通过改善 COVID-19 和 COVID-19 后患者的微血管病理学，可以降低相关并发症和死亡率的风险。
