Ziliotto Nicole, Bernardi Francesco, Jakimovski Dejan, Zivadinov Robert
Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy.
Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, Buffalo Neuroimaging Analysis Center, University at Buffalo, State University of New York, Buffalo, NY, United States.
Front Neurol. 2019 Apr 24;10:409. doi: 10.3389/fneur.2019.00409. eCollection 2019.
Significant progress has been made in understanding the complex interactions between the coagulation system and inflammation and autoimmunity. Increased blood-brain-barrier (BBB) permeability, a key event in the pathophysiology of multiple sclerosis (MS), leads to the irruption into the central nervous system of blood components that include virtually all coagulation/hemostasis factors. Besides their cytotoxic deposition and role as a possible trigger of the coagulation cascade, hemostasis components cause inflammatory response and immune activation, sustaining neurodegenerative events in MS. Early studies showing the contribution of altered hemostasis in the complex pathophysiology of MS have been strengthened by recent studies using methodologies that permitted deeper investigation. Fibrin(ogen), an abundant protein in plasma, has been identified as a key contributor to neuroinflammation. Perturbed fibrinolysis was found to be a hallmark of progressive MS with abundant cortical fibrin(ogen) deposition. The immune-modulatory function of the intrinsic coagulation pathway still remains to be elucidated in MS. New molecular details in key hemostasis components participating in MS pathophysiology, and particularly involved in inflammatory and immune responses, could favor the development of novel therapeutic targets to ameliorate the evolution of MS. This review article introduces essential information on coagulation factors, inhibitors, and the fibrinolytic pathway, and highlights key aspects of their involvement in the immune system and inflammatory response. It discusses how hemostasis components are (dys)regulated in MS, and summarizes histopathological post-mortem human brain evidence, as well as cerebrospinal fluid, plasma, and serum studies of hemostasis and fibrinolytic pathways in MS. Studies of disease-modifying treatments as potential modifiers of coagulation factor levels, and case reports of autoimmunity affecting hemostasis in MS are also discussed.
在理解凝血系统与炎症及自身免疫之间的复杂相互作用方面已取得显著进展。血脑屏障（BBB）通透性增加是多发性硬化症（MS）病理生理学中的一个关键事件，会导致包括几乎所有凝血/止血因子在内的血液成分涌入中枢神经系统。除了其细胞毒性沉积以及作为凝血级联反应可能触发因素的作用外，止血成分还会引发炎症反应和免疫激活，从而在MS中维持神经退行性病变。早期研究表明止血改变在MS复杂病理生理学中发挥作用，近期使用能进行更深入研究的方法的研究进一步证实了这一点。纤维蛋白（原）是血浆中的一种丰富蛋白质，已被确定为神经炎症的关键促成因素。纤溶异常被发现是进行性MS伴有大量皮质纤维蛋白（原）沉积的一个标志。内源性凝血途径的免疫调节功能在MS中仍有待阐明。参与MS病理生理学，特别是参与炎症和免疫反应的关键止血成分的新分子细节，可能有助于开发新的治疗靶点以改善MS的病情发展。这篇综述文章介绍了有关凝血因子、抑制剂和纤溶途径的基本信息，并强调了它们参与免疫系统和炎症反应的关键方面。它讨论了止血成分在MS中是如何（失调）调节的，并总结了死后人类脑组织病理学证据，以及MS中止血和纤溶途径的脑脊液、血浆和血清研究。还讨论了作为凝血因子水平潜在调节剂的疾病修饰治疗研究以及MS中影响止血的自身免疫病例报告。
