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

Tatiana Koudriavtseva, Annunziata Stefanile, Marco Fiorelli, Caterina Lapucci, Svetlana Lorenzano, Silvana Zannino, Laura Conti, Giovanna D'Agosto, Fulvia Pimpinelli, Enea Gino Di Domenico, Chiara Mandoj, Diana Giannarelli, Sara Donzelli, Giovanni Blandino, Marco Salvetti, Matilde Inglese, Tatiana Koudriavtseva, Annunziata Stefanile, Marco Fiorelli, Caterina Lapucci, Svetlana Lorenzano, Silvana Zannino, Laura Conti, Giovanna D'Agosto, Fulvia Pimpinelli, Enea Gino Di Domenico, Chiara Mandoj, Diana Giannarelli, Sara Donzelli, Giovanni Blandino, Marco Salvetti, Matilde Inglese

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/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 analysis: ANOVA and unpaired t-tests will be used. The level of significance was set at p ≤ 0.05.

Discussion: Identifying 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.

Keywords: cerebral hypoperfusion; coagulation; complement; infection; multiple sclerosis; platelets; relapse.

Copyright © 2020 Koudriavtseva, Stefanile, Fiorelli, Lapucci, Lorenzano, Zannino, Conti, D’Agosto, Pimpinelli, Di Domenico, Mandoj, Giannarelli, Donzelli, Blandino, Salvetti and Inglese.

Figures

Figure 1
Figure 1
Flow chart of the study protocol.
Figure 2
Figure 2
Luminex Assay Principle. The sample is added to the mixture of colored beads coated with specific antibodies that bind the analyte of interest, the biotinylated detection antibodies in turn bind the analyte, and an analyte-antibody sandwich is formed. Streptoavidin conjugated with phycoerythrin (PE) binds biotinylated detection antibodies. The analysis of the beads is carried out either in a double laser flow with the Luminex 200 instrument or inside a magnet with the Luminex MAGPIX analyzer. The signal strength of phycoerythrin is directly proportional to the concentration of the specific analyte.
Figure 3
Figure 3
Workflow of circulating miRNA profiling. For circulating miRNA profiling blood samples from patients will be processed. In particular, circulating RNA will be extracted from serum samples with a column-based extraction method. Total and small RNA quality will be assessed by Bioanalyzer. Then, total RNA will be labelled for the hybridization to Human miRNA Microarray Release 21 (Agilent) containing probes for 2549 human miRNAs. Microarray data will be subjected to bioinformatic analysis to identify a signature of miRNAs differentially expressed. Deregulated miRNAs pathway analysis and correlations analysis with clinical variables will be performed.
Figure 4
Figure 4
DSC perfusion maps and their overlap with structural masks in an MS patient. (A). AIF curve created by using global, automatic, and outside-artery technique (B). Leakage map, obtained through the leakage correction function, to minimize leakage effect both on Gadolinium and no Gadolinium enhancing lesions (C). a. CBV map; b. CBF map; c. MTT map. (D). a. NAWM (red), obtained by subtracting from white matter (WM binary) masks the different types of lesions, linearly registered to CBV map; b. thalamus (yellow), caudate (green), putamen (light blue), globus pallidus (blue), obtained by using FIRST software, linearly registered to CBV map. AIF, arterial input function; CBV, cerebral blood volume; CBF, cerebral blood flow; MTT, mean transit time; NAWM, normal appearing white matter.

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