Data Sheet 10_Unravelling the impact of SARS-CoV-2 on hemostatic and complement systems: a systems immunology perspective.pdf

The hemostatic system prevents and stops bleeding, maintaining circulatory integrity after injury. It directly interacts with the complement system, which is key to innate immunity. In coronavirus disease 2019 (COVID-19), dysregulation of the hemostatic and complement systems has been associated with several complications. To understand the essential balance between activation and regulation of these systems, a quantitative systems immunology model can be established. The dynamics of the components are examined under three distinct conditions: the disease state representing symptomatic COVID-19 state, an intervened disease state marked by reduced levels of regulators, and drug interventions including heparin, tranexamic acid, avdoralimab, garadacimab, and tocilizumab. Simulation results highlight key components affected, including thrombin, tissue plasminogen activator, plasmin, fibrin degradation products, interleukin 6 (IL-6), the IL-6 and IL-6R complex, and the terminal complement complex (C5b-9). We explored that the decreased levels of complement factor H and C1-inhibitor significantly elevate these components, whereas tissue factor pathway inhibitor and alpha-2-macroglobulin have more modest effects. Furthermore, our analysis reveals that drug interventions have a restorative impact on these factors. Notably, targeting thrombin and plasmin in the early stages of thrombosis and fibrinolysis can improve the overall system. Additionally, the regulation of C5b-9 could aid in lysing the virus and/or infected cells. In conclusion, this study explains the regulatory mechanisms of the hemostatic and complement systems and illustrates how the biopathway machinery sustains the balance between activation and inhibition. The knowledge that we have acquired could contribute to designing therapies that target the hemostatic and complement systems.

止血系统（hemostatic system）可预防并终止出血，维持损伤后循环系统的完整性。其与补体系统（complement system）存在直接相互作用，而补体系统是先天免疫的核心组成部分。在2019冠状病毒病（COVID-19）中，止血系统与补体系统的失调已与多种并发症相关联。为阐明这两类系统激活与调控间的核心平衡机制，可构建定量系统免疫学模型（quantitative systems immunology model）。研究对三种不同条件下的系统组分动态变化展开分析：一是代表有症状COVID-19的疾病状态，二是以调节因子水平降低为特征的干预后疾病状态，三是涵盖肝素、氨甲环酸、阿夫利单抗、加拉达单抗与托珠单抗的药物干预场景。仿真结果揭示了受影响的关键组分，包括凝血酶（thrombin）、组织型纤溶酶原激活剂（tissue plasminogen activator）、纤溶酶（plasmin）、纤维蛋白降解产物（fibrin degradation products）、白细胞介素6（IL-6）、IL-6与IL-6受体复合物，以及末端补体复合物（C5b-9）。研究发现，补体因子H（complement factor H）与C1抑制物（C1-inhibitor）的水平下降会显著升高上述组分的含量，而组织因子途径抑制物（tissue factor pathway inhibitor）与α2-巨球蛋白（alpha-2-macroglobulin）的调控效果则相对温和。进一步分析表明，药物干预可对上述因子产生修复性影响。值得注意的是，在血栓形成与纤溶的早期阶段靶向凝血酶与纤溶酶，可改善整体系统状态。此外，调控末端补体复合物C5b-9，可辅助裂解病毒及受感染细胞。综上，本研究阐明了止血系统与补体系统的调控机制，并展示了生物通路系统如何维持激活与抑制间的动态平衡。本研究获得的相关认知，可为靶向止血系统与补体系统的治疗方案设计提供参考。