Abstract
IntroductionMultiple sclerosis (MS) is a demyelinating disease of the central nervous system with an underlying immune-mediated and inflammatory pathogenesis. Innate immunity, in addition to the adaptive immune system, plays a relevant role in MS pathogenesis. It represents the immediate non-specific defense against infections through the intrinsic effector mechanism “immunothrombosis” linking inflammation and coagulation. Moreover, decreased cerebral blood volume (CBV), cerebral blood flow (CBF), and prolonged mean transit time (MTT) have been widely demonstrated by MRI in MS patients. We hypothesized that coagulation/complement and platelet activation during MS relapse, likely during viral infections, could be related to CBF decrease. Our specific aims are to evaluate whether there are differences in serum/plasma levels of coagulation/complement factors between relapsing-remitting (RR) MS patients (RRMS) in relapse and those in remission and healthy controls as well as to assess whether brain hemodynamic changes detected by MRI occur in relapse compared with remission. This will allow us to correlate coagulation status with perfusion and demographic/clinical features in MS patients.Materials and MethodsThis is a multi-center, prospective, controlled study. RRMS patients (1° group: 30 patients in relapse; 2° group: 30 patients in remission) and age/sex-matched controls (3° group: 30 subjects) will be enrolled in the study. Patients and controls will be tested for either coagulation/complement (C3, C4, C4a, C9, PT, aPTT, fibrinogen, factor II, VIII, and X, D-dimer, antithrombin, protein C, protein S, von-Willebrand factor), soluble markers of endothelial damage (thrombomodulin, Endothelial Protein C Receptor), antiphospholipid antibodies, lupus anticoagulant, complete blood count, viral serological assays, or microRNA microarray. Patients will undergo dynamic susceptibility contrast-enhanced MRI using a 3.0-T scanner to evaluate CBF, CBV, MTT, lesion number, and volume.Statistical AnalysisANOVA and unpaired t-tests will be used. The level of significance was set at p ≤ 0.05.DiscussionIdentifying a link between activation of coagulation/complement system and cerebral hypoperfusion could improve the identification of novel molecular and/or imaging biomarkers and targets, leading to the development of new effective therapeutic strategies in MS.Clinical Trial Registration Clinicaltrials.gov, identifier NCT04380220.
Highlights
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system with an underlying immune-mediated and inflammatory pathogenesis
We hypothesized that cerebral hypoperfusion in all forms of MS could be the result of the blood flow deceleration mostly in the venous vessel bed during brain inflammatory-thrombotic processes in the course of relapses
While many efforts have been carried out to better define the function of innate immune cells in order to modulate their potential pathogenetic role in MS with specific therapeutic action [5, 6], the coagulant component of innate immunity, which is well studied in animals, has not been sufficiently evaluated in humans
Summary
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system with an underlying immune-mediated and inflammatory pathogenesis. In addition to the adaptive immune system, plays a relevant role in MS pathogenesis It represents the immediate non-specific defense against infections through the intrinsic effector mechanism “immunothrombosis” linking inflammation and coagulation. It is hypothesized that innate immunity, which can be considered the immediate non-specific defense against any noxa patogena including infections and dangerous agents, stimulates and modulates adaptive immunity at MS onset and mediates its neurodegenerative progressive phase [5, 6] Both inflammation and coagulation are the main effector processes of innate immunity acting synergistically through mutual regulation [7,8,9,10]. It is activated by bloodborne pathogens as well as by circulating self-components that are altered, and through its action on a platform consisting of fibrin, monocytes, neutrophils, and dendritic cells lead to fibrin formation and platelet activation
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