- Components of the hemostatic pathway are known to enhance and sustain neuroinflammation in multiple sclerosis (MS), and researchers at Massachusetts General Hospital recently reviewed decades of research into these associations
- An early event in MS pathophysiology that links primary hemostasis and neuroinflammation is the disruption of the blood–brain barrier, which occurs due to vascular inflammation through endothelial dysfunction and platelet activation
- Fibrin, fibrinogen, and thrombin are also key players in immune-mediated neuroinflammation, and impairment of the fibrinolytic system might be involved in triggering central nervous system neuroinflammation and demyelination
- Potential novel biomarkers for disease monitoring and prognosis include fibrinogen or fibrin deposition detected by imaging and genetic polymorphisms that alter fibrinolytic activity
- Platelets and coagulation proteins may be therapeutic targets for limiting neuroinflammation, and immunotherapies targeting fibrin or fibrinogen have improved symptoms in mouse models of MS
Hemostasis and peripheral inflammation substantially collaborate in responding to injury and pathogen invasion, and hemostasis enhances and sustains neuroinflammation. The hemostatic pathway is now known to have a role in the pathogenesis of multiple sclerosis (MS).
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Caterina Mainero, MD, PhD, director of multiple sclerosis research at the Martinos Center for Biomedical Imaging at Massachusetts General Hospital, and colleagues have reviewed the interplay between hemostatic and thrombotic molecular pathways in the pathogenesis of neuroinflammation in MS. They selected and reviewed the most relevant articles published between 1956 and 2020 on PubMed or Scopus.
In Multiple Sclerosis, they discuss the potential for their findings to inform the development of novel diagnostic and prognostic biomarkers and new therapeutic approaches.
Hemostatic Factors and Immune-mediated Neuroinflammation
Endothelial cells and blood platelets
Disruption of the blood–brain barrier (BBB) occurs early in the development of MS plaque. Vascular inflammation through endothelial dysfunction and platelet activation is an underlying mechanism of this central event in MS pathophysiology.
Fibrin and fibrinogen
Fibrinogen is usually thought of as supporting hemostasis and tissue repair, but it also drives local inflammation. Fibrin and fibrinogen have been noted in lesions in both relapsing-remitting and progressive MS. Both animal and human data support a causative role of the fibrinogen pathway in MS pathology.
Abnormally high plasma levels of prothrombin, Factor XII and/or Factor X have been found in individuals with relapsing–remitting and secondary-progressive MS. Factor XII appears to help drive neuroinflammation independently from its coagulation properties, which suggests the possibility of a wider search for therapeutic targets.
The protein C pathway, which helps regulate coagulability, is thought to be dysfunctional in MS. The concomitant presence of tissue factor and protein C inhibitor suppressed protein C pathways and pro-inflammatory thrombin formation in active MS lesions.
The fibrinolysis system
The plasminogen activator system seems to have both harmful and beneficial roles in MS, with a balance between injury and recovery:
- Plasminogen activator activity in MS is thought to play a major role in the disturbance of the BBB and the subsequent leukocyte migration and activation that leads to myelin breakdown
- Conversely, limited availability of tissue plasminogen activators in MS lesions reduces fibrinolysis, possibly resulting in increased fibrin deposition and, in turn, axonal degeneration
Biomarkers and Therapeutic Targets
The new understanding of the components of the hemostatic pathway in MS suggests novel disease markers and therapies:
- Platelets and coagulation proteins may be targets for limiting neuroinflammation
- Immunotherapies targeting fibrin or fibrinogen have improved symptoms in mouse models of MS, and in one such study, there was no interference with the pro-coagulation properties of fibrinogen
- Genetic alterations that alter fibrinolytic activity or other molecular pathways influencing thrombotic risk, independently from hemostatic processes and the coagulation cascade, are being examined as potential prognostic biomarkers
- Fibrinogen deposition that indicates BBB alteration can be detected on MRI in the early stages of lesion development without any evidence of gadolinium contrast enhancement
- Positron emission tomography may be able to quantify local brain fibrin deposition, as neuroinflammation induces modifications in fibrin that specific radioligands can target
No large-scale study has been conducted yet for the translation of any of this basic science and advanced technology into the clinic.
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