Coagulation Pathways in Neurological Diseases: Multiple Sclerosis

Abstract

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.

Increased Pro-Thrombotic Platelet Activity Associated with Thrombin/PAR1-Dependent Pathway Disorder in Patients with Secondary Progressive Multiple Sclerosis

“…It should be noted that the mutual cellular interactions between platelets, immune cells and endothelium are closely related to activation of all types of these cells, which can have serious consequences for maintaining the tightness of BBB and further development of local neuroinflammatory response and demyelination. BBB permeability disorder is crucial for vascular consequences leading to the development of both cardiovascular diseases and MS development [ 57 , 58 ].…”

Relationships Among Circulating Levels of Hemostasis Inhibitors, Chemokines, Adhesion Molecules, and MRI Characteristics in Multiple Sclerosis

“…This novel hemostasis inhibitors–immunity link is further supported by the positive correlation between PAI1 and CCL18 levels, previously found higher in MS patients than HI ( 10 , 14 ). As a matter of fact, increased CCL18 gene expression has been found in the rim of chronic active MS lesions ( 27 ), and increased PAI1 protein in MS lesions has been associated with impaired fibrin clearance ( 12 , 13 ), which would contribute to the chronic inflammation [reviewed in ( 4 )].…”

“…In multiple sclerosis (MS) pathogenesis, blood–brain barrier (BBB) disruption and vascular changes interact in a vicious cycle with altered immune trafficking and the inflammatory processes, supported by adhesion molecules and chemokines ( 1 – 3 ). Several studies also suggested the cross talk of immunity and inflammation with hemostasis, potentially reflected in MS pathogenesis and progression of neurodegeneration ( 4 ).…”

Dabigatran Suppresses PAR-1/SphK/S1P Activation of Astrocytes in Experimental Autoimmune Encephalomyelitis Model

“…Coagulation pathways have been demonstrated to be associated with inflammation and autoimmunity, regulating hemostasis and contributing to the pathogenesis of MS (Ziliotto et al, 2019 ). In this study, LPS and thrombin were applied to induce the activation of astrocytes.…”