Abstract

The review highlights the mechanism of development of hypercoagulation and thrombosis in severe forms of COVID-19. The introduction of the SARS-CoV-2 virus into the host organism is carried out by the interaction of the spike protein S with the angiotensin-converting enzyme ACE-2, which is located in type 2 alveocytes, vascular endothelium, kidneys, liver, and other organs. In the event of a serious condition in patients with COVID-19, both nonspecific and adaptive immunity are activated. Stimulation of the complement system with the appearance of C3a, C3b, and C5a fragments and the membrane attack complex (MAC) creates conditions for the development of hypercoagulability. The involvement of the renin-angiotensin-aldosterone system in this process and the appearance of angiotensin 2 (Ang-2) further increase the intensity of hypercoagulability. When the SARS-CoV-2 virus enters cells, the protective reaction of the adaptive immune system can turn into a pathological one (a cytokine storm develops), characterized by a high level of pro-inflammatory cytokines (IL-1α, IL-6, IL-8, TNF-α, IL-17, etc.) and chemokines (CCL-2, CCL-11, etc.), which ultimately leads to the development of thromboangiopathy or otherwise immunothrombosis in seriously ill patients with COVID-19. Patients with more severe lesions may develop a condition similar to DIC. At the same time, patients with COVID-19 have mild thrombocytopenia and elevated levels of fibrinogen, D dimer, and fibrinogen degradation products (FDP), which indicates intense thrombus formation, as well as short PT and APTT, due to a largely increased level of FVIII. In COVID-19, along with the classical one, an alternative pathway (bypassing thrombin) of regulation of the hemostasis system and thrombus formation appears, mainly associated with the influence of the spike protein S (PS, PROS1) of the SARS-CoV-2 virus and papain-like protease (PROS1). Protein S directly affects the conversion of fibrinogen to fibrin, as well as the activation of individual plasma coagulation factors. The alternative pathway of blood coagulation is also due to the activation of the complement system via the lectin pathway with the inclusion of metalloproteinases MASP-1, -2, and -3. In addition, the S protein activates tPA, which may be accompanied by hyperfibrinolysis. In seriously ill patients with COVID-19, platelets play an important role in the occurrence of thromboembolic complications. During the release reaction, platelets are released from the cytoplasm into the blood α-granules and dense granules containing inflammatory cytokines and chemokines, which enhances the cytokine storm and, consequently, thrombus formation. By acting on the spike protein S, platelets enhance an alternative way of regulating the hemostasis system and thrombus formation.

中文翻译：

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重症 COVID-19 患者的血小板激活和血栓栓塞形成机制。止血系统活动的替代机制

摘要

该综述强调了严重的 COVID-19 中高凝状态和血栓形成的发生机制。SARS-CoV-2病毒进入宿主生物体是通过刺突蛋白S与血管紧张素转换酶ACE-2的相互作用进行的，ACE-2位于2型肺泡细胞、血管内皮、肾脏、肝脏、和其他器官。如果 COVID-19 患者病情严重，非特异性免疫和适应性免疫都会被激活。C3a、C3b 和 C5a 片段以及膜攻击复合物 (MAC) 的出现对补体系统的刺激为高凝状态的发展创造了条件。肾素-血管紧张素-醛固酮系统参与这一过程以及血管紧张素2 (Ang-2) 的出现进一步增加了高凝状态的强度。当 SARS-CoV-2 病毒进入细胞时，适应性免疫系统的保护性反应可能转变为病理性反应（形成细胞因子风暴），其特征是高水平的促炎细胞因子（IL-1α、IL-6） 、IL-8、TNF-α、IL-17 等）和趋化因子（CCL-2、CCL-11 等），最终导致 COVID-19 重症患者发生血栓血管病或其他免疫血栓形成。病变较严重的患者可能会出现类似于 DIC 的病症。同时，COVID-19患者出现轻度血小板减少，纤维蛋白原、D二聚体和纤维蛋白原降解产物（FDP）水平升高，这表明血栓形成严重，并且由于水平大幅升高，PT和APTT也较短。 FVIII。在COVID-19中，除了经典途径之外，还出现了调节止血系统和血栓形成的另一种途径（绕过凝血酶），主要与SARS-CoV的刺突蛋白S（PS，PROS1）的影响有关。 2病毒和木瓜蛋白酶样蛋白酶(PROS1)。Protein S 直接影响纤维蛋白原向纤维蛋白的转化，以及单个血浆凝血因子的激活。凝血的替代途径也是由于通过包含金属蛋白酶 MASP-1、-2 和 -3 的凝集素途径激活补体系统。此外，S蛋白激活tPA，这可能伴有纤溶亢进。在COVID-19重症患者中，血小板在血栓栓塞并发症的发生中发挥着重要作用。在释放反应过程中，血小板从细胞质释放到血液中的α颗粒和含有炎性细胞因子和趋化因子的致密颗粒中，从而增强细胞因子风暴，从而增强血栓形成。通过作用于刺突蛋白 S，血小板增强了调节止血系统和血栓形成的另一种方式。