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      Thrombin generation correlates with disease duration in multiple sclerosis (MS): Novel insights into the MS-associated prothrombotic state

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          Abstract

          Background

          Thrombin is well recognised for its role in the coagulation cascade but it also plays a role in inflammation, with enhanced thrombin generation observed in several inflammatory disorders. Although patients with multiple sclerosis (MS) have a higher incidence of thrombotic disease, thrombin generation has not been studied to date.

          Objectives

          The aim of this study was to characterise calibrated automated thrombography parameters in patients with relapsing–remitting MS (RRMS) and primary progressive MS (PPMS) in comparison to healthy controls (HCs).

          Methods

          Calibrated automated thrombography was performed on platelet poor plasma from 15 patients with RRMS, 15 with PPMS and 19 HCs.

          Results

          We found that patients with RRMS generate thrombin at a significantly faster rate than the less inflammatory subtype, PPMS or HCs. In addition, the speed of thrombin generation was significantly correlated with time from clinical diagnosis in both subtypes. However, in RRMS the rate of thrombin generation was increased with increased time from clinical diagnosis, while in PPMS the rate of thrombin generation decreased with increased time from clinical diagnosis.

          Conclusions

          These data likely reflect the differential active proinflammatory states in each MS subtype and provide novel mechanistic insights into the clinically relevant prothrombotic state observed in these patients.

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          Most cited references13

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          New Multiple Sclerosis Phenotypic Classification

          Background: In 1996, the clinical course of multiple sclerosis (MS) was characterized as relapsing-remitting, primary progressive, secondary progressive or progressive relapsing. Since then, an increased understanding of MS and its pathology prompted a re-examination of these clinical phenotypes. Main recommendations of the 2013 revisions are provided herein. Summary: Clinically isolated syndrome has been added, and progressive relapsing MS has been eliminated, from the clinical course descriptions. All forms of MS should be further subcategorized as either active or non-active. Active MS is defined as the occurrence of clinical relapse or the presence of new T2 or gadolinium-enhancing lesions over a specified period of time, preferably at least one year. An additional subcategory for patients with progressive MS differentiates between those who have shown signs of disability progression over a given time period and those who have remained stable. The term ‘worsening' is recommended to describe patients whose disease is advancing for any reason, whereas ‘disease progression' should be reserved for those with progressive disease who are truly progressing (as opposed to worsening from a relapse). The term ‘benign' should be used with caution as the course of MS can worsen at any time, even after many years of apparent stability. Key Messages: Newer characterizations of MS phenotypes include a consideration of disease activity (based on the clinical relapse rate and imaging findings) and disease progression. Accurate clinical course descriptions are useful for communication, prognostication, clinical trial design and to guide everyday clinical decision-making. © 2014 S. Karger AG, Basel
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            Evidence of platelet activation in multiple sclerosis

            Objective A fatality in one multiple sclerosis (MS) patient due to acute idiopathic thrombocytopenic purpura (ITP) and a near fatality in another stimulated our interest in platelet function abnormalities in MS. Previously, we presented evidence of platelet activation in a small cohort of treatment-naive MS patients. Methods In this report, 92 normal controls and 33 stable, untreated MS patients were studied. Platelet counts, measures of platelet activation [plasma platelet microparticles (PMP), P-selectin expression (CD62p), circulating platelet microaggragtes (PAg)], as well as platelet-associated IgG/IgM, were carried out. In addition, plasma protein S activity was measured. Results Compared to controls, PMP were significantly elevated in MS (p < 0.001) and CD62p expression was also markedly elevated (p < 0.001). Both are markers of platelet activation. Platelet-associated IgM, but not IgG, was marginally elevated in MS (p = 0.01). Protein S in MS patients did not differ significantly from normal values. Conclusion Platelets are significantly activated in MS patients. The mechanisms underlying this activation and its significance to MS are unknown. Additional study of platelet activation and function in MS patients is warranted.
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              Novel aspects of fibrin(ogen) fragments during inflammation.

              Coagulation is fundamental for the confinement of infection and/or the inflammatory response to a limited area. Under pathological inflammatory conditions such as arthritis, multiple sclerosis or sepsis, an uncontrolled activation of the coagulation system contributes to inflammation, microvascular failure and organ dysfunction. Coagulation is initiated by the activation of thrombin, which, in turn, triggers fibrin formation by the release of fibrinopeptides. Fibrin is cleaved by plasmin, resulting in clot lysis and an accompanied generation of fibrin fragments such as D and E fragments. Various coagulation factors, including fibrinogen and/or fibrin [fibrin(ogen)] and also fibrin degradation products, modulate the inflammatory response by affecting leukocyte migration and cytokine production. Fibrin fragments are mostly proinflammatory, however, Bβ15-42 in particular possesses potential antiinflammatory effects. Bβ15-42 inhibits Rho-kinase activation by dissociating Fyn from Rho and, hence prevents stress-induced loss of endothelial barrier function and also leukocyte migration. This article summarizes the state-of-the-art in inflammatory modulation by fibrin(ogen) and fibrin fragments. However, further research is required to gain better understanding of the entire role fibrin fragments play during inflammation and, possibly, disease development.
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                Author and article information

                Journal
                Mult Scler J Exp Transl Clin
                Mult Scler J Exp Transl Clin
                MSO
                spmso
                Multiple Sclerosis Journal - Experimental, Translational and Clinical
                SAGE Publications (Sage UK: London, England )
                2055-2173
                26 December 2017
                Oct-Dec 2017
                : 3
                : 4
                : 2055217317747624
                Affiliations
                UCD Conway Institute, Ringgold 8797, universityUniversity College Dublin; , Ireland
                School of Biomolecular and Biomedical Science, Ringgold 8797, universityUniversity College Dublin; , Ireland
                School of Medicine and Medical Science, Ringgold 8797, universityUniversity College Dublin; , Ireland
                Department of Neurology, St Vincent’s University Hospital, Ireland
                UCD Conway Institute, Ringgold 8797, universityUniversity College Dublin; , Ireland
                School of Biomolecular and Biomedical Science, Ringgold 8797, universityUniversity College Dublin; , Ireland
                UCD Conway Institute, Ringgold 8797, universityUniversity College Dublin; , Ireland
                School of Medicine and Medical Science, University College Dublin, Ireland
                UCD Conway Institute, Ringgold 8797, universityUniversity College Dublin; , Ireland
                School of Biomolecular and Biomedical Science, Ringgold 8797, universityUniversity College Dublin; , Ireland
                School of Medicine and Medical Science, Ringgold 8797, universityUniversity College Dublin; , Ireland
                Department of Neurology, St Vincent’s University Hospital, Ireland
                UCD Conway Institute, Ringgold 8797, universityUniversity College Dublin; , Ireland
                School of Medicine and Medical Science, Ringgold 8797, universityUniversity College Dublin; , Ireland
                Department of Haematology, Rotunda Hospital, Ireland
                Department of Haematology, Mater Misericordiae University Hospital, Ireland
                UCD Conway Institute, Ringgold 8797, universityUniversity College Dublin; , Ireland
                School of Biomolecular and Biomedical Science, Ringgold 8797, universityUniversity College Dublin; , Ireland
                Author notes
                [*]UCD Conway Institute SPHERE Research Group, School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin 4, Ireland. patricia.maguire@ 123456ucd.ie
                Author information
                http://orcid.org/0000-0002-0362-3778
                Article
                10.1177_2055217317747624
                10.1177/2055217317747624
                5753921
                399bc049-6b5c-4088-8fab-cc342cfbf2ff
                © The Author(s) 2017

                Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                : 30 May 2017
                : 8 November 2017
                : 12 November 2017
                Categories
                Original Research Paper
                Custom metadata
                October-December 2017

                multiple sclerosis,relapsing–remitting,progressive,thrombin generation,calibrated automated thrombography,platelet-poor plasma

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