Tissue Factor's Role in the Pathogenesis of Hypercoagulability in COVID-19

新出现的证据表明，新的SARS-CoV-2感染与高发病率有关， 血栓性并发症COVID-19患者的血栓并发症被发现危及生命。 D-二聚体升高和弥散性血管内凝血（DIC）是高血压患者死亡率的强预测因子。 新冠肺炎住院患者。这与凝血功能障碍在高脂血症发病机制中的主要影响相一致。 COVID-19，抗凝治疗被证明可以提高重症COVID-19患者的生存率。 尽管凝血异常与COVID-19的关联是显而易见的，但其潜在机制 这些异常是未知的。许多疾病，包括病毒感染，诱导组织因子（TF） 在单核细胞/巨噬细胞和内皮细胞中表达，并将TF+细胞外囊泡（EV）释放到 流通我们最近的研究表明，鞘磷脂代谢的改变极大地影响TF 通过控制TF加密和解密以及TF+ EV的生成来控制活动。我们假设 与SARS-CoV-2感染相关的高凝状态源于TF活性增加， TF+ EV在感染后进入循环。我们进一步假设刺突蛋白诱导的 酸性鞘磷脂酶（ASMase）的激活通过TF解密增加TF活性， 生产TF+ EV。我们认为ASMase功能性抑制剂的治疗将减弱 与SARS-CoV-2感染相关的凝血病。该提案的总体目标是获得一个证明， 上述假设的概念。我们的目标是：（i）确定SARS-CoV-2尖峰的机制 蛋白增加TF活性并产生TF+ EV;（ii）确定SARS-CoV-2的刺突蛋白在 在hACE 2转基因小鼠中激活TF诱导的凝血病和微血管血栓形成， 确定ASMase功能抑制剂是否减弱SARS-CoV-2诱导的凝血病。在 建议的研究，我们将使用SARS-CoV-2刺突蛋白假病毒和真实的SARS-CoV-2 细胞模型系统和鼠模型系统中的感染。我们提议的研究将确定潜在的 SARS-CoV 2感染诱导高凝状态和血栓形成的机制。他们还将 为开发新的、有针对性的和安全的干预措施治疗高凝状态提供线索， 新冠肺炎患者，这可能有助于降低死亡率。我们有超过三十年的经验 开展TF工作，并拥有完成拟议研究所需的所有工具、资源和技术专长 成功地

Emerging evidence indicates that the novel SARS-CoV-2 infection is associated with a high incidence of thrombotic complications. Thrombotic complications in COVID-19 patients are found to be life-threatening. Elevated D-dimers and disseminated intravascular coagulation (DIC) are strong predictors of mortality in hospitalized COVID-19 patients. Consistent with the major influence of coagulopathy in the pathogenesis of COVID-19, anticoagulant treatments were shown to improve the survival of critically ill COVID-19 patients. Although the association of coagulation abnormalities with COVID-19 is evident, the underlying mechanism for these abnormalities is unknown. Many diseases, including viral infections, induce tissue factor (TF) expression in monocytes/macrophages and endothelial cells and release TF+ extracellular vesicles (EVs) into circulation. Our recent studies suggest that alterations in sphingomyelin metabolism greatly influence TF activity by controlling TF encryption and decryption, and generation of TF+ EVs. We hypothesize that hypercoagulability associated with SARS-CoV-2 infection stems from increased TF activity and the release of TF+ EVs into the circulation following the infection. We further hypothesize that spike protein-induced activation of acid sphingomyelinase (ASMase) is responsible for increased TF activity via TF decryption and generation of TF+ EVs. We propose that treatment with ASMase functional inhibitors will attenuate coagulopathy associated with SARS-CoV-2 infection. The overall goal of the proposal is to obtain a proof of concept to the above hypothesis. Our aims are: (i) determine the mechanism by which the SARS-CoV-2 spike protein increases TF activity and generates TF+ EVs; (ii) define the role of SARS-CoV-2’s spike protein on activation of TF-induced coagulopathy and microvascular thrombosis in hACE2 transgenic mice and determine whether ASMase functional inhibitors attenuate SARS-CoV-2-induced coagulopathy. In the proposed studies, we will use both SARS-CoV-2 spike protein pseudovirus and authentic SARS-CoV-2 infections in cell model systems and a murine model system. Our proposed studies will identify potential mechanisms by which SARS-CoV2 infection induces hypercoagulability and thrombosis. They will also provide clues for the development of novel, targeted, and safe interventions to treat hypercoagulability in COVID-19 patients, which could help to reduce mortality. We have more than thirty years of experience working on TF and have all the tools and resources, and technical expertise to complete the proposed studies successfully.