Coagulation pathways in Multiple Sclerosis

Finding a common ancestry of the coagulation and innate immune systems has boosted the investigation of the coagulation cascade pathway in multiple sclerosis (MS). Interestingly, current studies point to a role of components of both the tissue factor (extrinsic) and of the contact (intrinsic) coagulation pathways. As a matter of fact tissue factor, the glycoprotein triggering the extrinsic coagulation cascade, has been detected within chronic active MS plaques, and factor XII (FXII), the initiator of the intrinsic coagulation cascade, is a key mediator of autoimmunity. The fibrinolytic proteins have been also involved, ultimately implying fibrin, the final product of the coagulation cascade, able to induce in animal models rapid microglial responses toward the vasculature and axonal damage in neuroinflammation. The anticoagulant and anti-inflammatory proteins, including the thrombin receptor-cofactor (thrombomodulin) and the protease (protein C) inactivating factor V and factor VIII, are candidate to play a protective role in MS progression. Noticeably, in vivo administration of inhibitors of thrombin or its formation reduced disease severity in experimental autoimmune encephalomyelitis. Conversely, the protein C inhibitor has been detected within chronic active plaque samples. As supported by several experimental findings, dysregulation of procoagulant/anticoagulant molecules may contribute to MS progression. The identification of specific pathophysiological roles of coagulation proteins, and of quantitative and qualitative variations in procoagulant or anticoagulant factors, could provide useful biomarkers of the disease and its forms, as recently reported for FXII, found in the CNS of individuals suffering from MS, and participating in adaptive immunity during neuroinflammation. Moreover, the specific inhibition of pro-coagulant factors or potentiation of the anticoagulant/antinflammatory system may provide a strategy to combat the disease. Whereas experimental findings support a role of the coagulation system in MS, the regulation of coagulation factors, both proteins in plasma and/or endothelium receptors, has not been investigated in detail in blood of individuals suffering from MS. With this premise, and taking into account the key role of gene variations in several procoagulant and anticoagulant genes for thrombin formation and deep vein thrombosis, the study of the functional levels and interaction between plasma and vessel proteins may provide valuable models to interpret central nervous system (CNS) vascular changes as participants in the pathophysiology of MS. The reported and actively investigated comorbidity with MS of chronic cerebrospinal venous insufficiency (CCSVI), a vascular condition with impaired venous drainage from CNS and characterized by anomalies of the main extracranial cerebrospinal veins, stimulates a number of open questions about the relationships between coagulation pathway functional levels and vessel wall expression and features. For instance, microbleedings detected in post mortem studies and advanced MRI, particularly around the venula crossing the MS plaques, merit further attention to define specific coagulation/vessel components involved. To contribute to these issues and to reveal biomarkers of the disease progression, we used transcriptomic approaches capable to characterize expression patterns of internal jugular vein walls. Fluorogenic coagulation micro-assays with the main anticoagulant proteins challenged by specific aptamers, and multiplex antigenic assays were also exploited to characterize the plasma obtained from jugular vein.