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.

Keywords: coagulation; coagulation inhibitors; extrinsic pathway; fibrinolytic pathway; intrinsic pathway; multiple sclerosis.

Figure 1

Change in neurovascular interface is involved in inflammatory, immune and neurodegenerative responses in multiple sclerosis. Disruption or increased permeability of blood-brain barrier cause the leakage of hemostasis components into the brain parenchyma, which triggers the coagulation cascade. In turn, hemostasis components foster the inflammatory response and the immune activation, sustaining neurodegenerative events in MS. NAWM, normal-appearing white matter; ROS, reactive oxygen species.

Figure 2

Schematic representation of the coagulation cascade and fibrinolytic pathway after blood-brain barrier damage. The coagulation cascade is activated (1) when the TF binds to its ligand, (activated) factor (F)VII, thus forming, together with membranes, a mature active binary complex (TF:FVIIa). The TF:FVIIa complex allows to cleave and activate on one side FIX and on another FX (2). TF:FVIIa:FXa is able to activate the cofactor FVIII (3) which forms a complex with the FIXa (FIXa:FVIIIa) providing a feedback loop for FX activation. The assembly FXa:FVa, converts prothrombin (FII) into thrombin (FIIa) (4). The initial amount of thrombin exerts its proteolytic action on FXI, FV, FVIII, and other substrates (5). Then the massive thrombin generation reaches a sufficient concentration to convert fibrinogen (FI) into fibrin monomers (6). The organized three-dimensional assembly of monomers in protofibrils and fibrin fibers produces the blood clot. Cross-linking stabilization of fibrin clot requires FXIII activated (FXIIIa) by thrombin activity. Coagulation complexes depend on lipids, exemplified by the platelet membrane. The dissolution of the fibrin fibers is mediated by the fibrinolytic system (7). Tissue-type plasminogen activator (tPA) converts plasminogen into plasmin which cleaves fibrin to soluble degradation products among those the D-dimers.

Figure 3

The eclectic nature of Factor XII: the crossroad between coagulation, inflammation, and immunity. a, activated; BK, bradykinin; F, factor; HK, high molecular weight kininogen; KAL, kallikrein; PK, prekallikrein; uPAR, urokinase plasminogen activator receptor; Th17, T helper 17 lymphocytes.

Figure 4

Schematic representation of vWF multimer size regulation by ADAMTS13. von Willebrand Factor (vWF) is stored in the Weibel-Palade bodies of endothelial cells or in the α-granules of platelets and it is released in an ultra-large form, a long multimeric string. The vWF serves as an adhesion surface to which platelets adhere and aggregate, and form a plug. The regulation of platelets adhesion depends upon cleavage of vWF in different size of multimeric string by ADAMTS13.