Coagulation/Complement Activation and Cerebral Hypoperfusion in Relapsing-Remitting Multiple Sclerosis

Abstract

Introduction: Multiple 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 Methods: This is a multi-center, prospective, controlled study. RRMS patients (1°group: 30 patients in relapse; 2°group: 30 patients in remission) and age/sexmatched 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

Cerebrospinal fluid cells immune landscape in multiple sclerosis

“…Indeed, this field is the subject of increasing attention from researchers. Koudriavtseva and colleagues have undertaken a multicenter, prospective, controlled study to determine the exact links between activation of the coagulation/complement system and cerebral hypoperfusion in RRMS cases [56]. It has been suggested that interfering with the coagulation system might provide a novel therapeutic target in the treatment of MS and demyelinating diseases.…”

Tissue factor as a potential coagulative/vascular marker in relapsing-remitting multiple sclerosis

“…As already reported in our previous work describing this study protocol (7), among the causes of neuroinflammation, there are recurrent and chronic infections accompanied by local innate immunity activation and consequent adaptive immune response, which in turn induces immune-thrombotic events. Indeed, coagulation is activated during viral infections and plays multiple functions in the host immune system (10).…”

“…In our previous work ( 6 ), we described in detail the possible role of coagulation/complement and platelet activation in the context of multiple sclerosis activity. Briefly, endothelial cell dysfunction, increased coagulation activity during disease exacerbation, excessive platelet activation, evidence of oxidative stress, perivascular fibrin(ogen) deposition, higher plasma levels of prothrombin and factor X (FX), complement activation, vascular occlusion within demyelinating lesions, altered blood-brain barrier (BBB) permeability, and hypoxia-like tissue injury have all been reported in people with multiple sclerosis ( 6 , 7 ).…”

Vascular Dementia and Crosstalk Between the Complement and Coagulation Systems

“…Coagulation can be activated by vascular injury caused by hypoxia and inflammation ( 101 ). Follow-up studies of the Rotterdam study in the 1990's found that dementia risk increased with elevated levels of serum fibrinogen, thrombin-antithrombin complex, D-dimer, and tissue-type plasminogen activator ( 102 , 103 ).…”

“…Over and under activation of the complement and coagulation systems have been recognised to play a part in various diseases such as Alzheimer's disease, multiple sclerosis, atypical haemolytic uremic syndrome, and antiphospholipid syndrome ( 94 , 101 ). Therefore, the potential role of these systems in VaD should be considered.…”