Coagulation Factor XII Levels and Intrinsic Thrombin Generation in Multiple Sclerosis

Ziliotto, Nicole; Baroni, Marcello; Straudi, Sofía; Manfredini, Fabio; Mari, Rosella; Menegatti, Erica; Voltan, Rebecca; Secchiero, Paola; Zamboni, Paolo; Basaglia, Nino; Marchetti, Giovanna; Bernardi, Francesco

doi:10.3389/fneur.2018.00245

Cited by 19 publications

(16 citation statements)

References 35 publications

(38 reference statements)

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“…Several recent studies have highlighted the importance of the interplay between the activation of the coagulation cascade and neuroinflammation, suggesting that coagulation factors are crucial not only for the activation of the acute hemostatic cascade, but have a broader role involving neurodegeneration and neuroinflammation (4–20).…”

Section: Introductionmentioning

confidence: 99%

A Perspective of Coagulation Dysfunction in Multiple Sclerosis and in Experimental Allergic Encephalomyelitis

Plantone¹,

Inglese

Salvetti

et al. 2019

Front. Neurol.

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A key role of both coagulation and vascular thrombosis has been reported since the first descriptions of multiple sclerosis (MS). Subsequently, the observation of a close concordance between perivascular fibrin(ogen) deposition and the occurrence of clinical signs in experimental allergic encephalomyelitis (EAE), an animal model of MS, led to numerous investigations focused on the role of thrombin and fibrin(ogen). Indeed, the activation of microglia, resident innate immune cells, occurs early after fibrinogen leakage in the pre-demyelinating lesion stage of EAE and MS. Thrombin has both neuroprotective and pro-apoptotic effects according to its concentration. After exposure to high concentrations of thrombin, astrocytes become reactive and lose their neuroprotective and supportive functions, microglia proliferate, and produce reactive oxygen species, IL-1β, and TNFα. Heparin inhibits the thrombin generation and suppresses EAE. Platelets play an important role too. Indeed, in the acute phase of the disease, they begin the inflammatory response in the central nervous system by producing of IL-1alpha and triggering and amplifying the immune response. Their depletion, on the contrary, ameliorates the course of EAE. Finally, it has been proven that the use of several anticoagulant agents can successfully improve EAE. Altogether, these studies highlight the role of the coagulation pathway in the pathophysiology of MS and suggest possible therapeutic targets that may complement existing treatments.

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Section: Introductionmentioning

confidence: 99%

A Perspective of Coagulation Dysfunction in Multiple Sclerosis and in Experimental Allergic Encephalomyelitis

Plantone¹,

Inglese

Salvetti

et al. 2019

Front. Neurol.

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“…Elevated FXII activity was found in RRMS and SPMS compared to controls, and greater activity levels were associated with higher occurrence of relapses and shorter relapse-free periods, independently from the use of immune modulatory therapy (10). Another recent study that evaluated the ratio of FXII activity and the amount of circulating protein found increase activity of FII and FX was protein levels and reduced function within the intrinsic coagulation pathway (137). Notably, intrinsic thrombin generation did not result in the detection of prothrombotic features in the evaluated PMS patients (137).…”

Section: Coagulation and Hemostasis Findings In Multiple Sclerosis Pamentioning

confidence: 99%

“…Another recent study that evaluated the ratio of FXII activity and the amount of circulating protein found increase activity of FII and FX was protein levels and reduced function within the intrinsic coagulation pathway (137). Notably, intrinsic thrombin generation did not result in the detection of prothrombotic features in the evaluated PMS patients (137). These data underline the importance of evaluating the activity of both antigen and coagulation factors.…”

Section: Coagulation and Hemostasis Findings In Multiple Sclerosis Pamentioning

confidence: 99%

Coagulation Pathways in Neurological Diseases: Multiple Sclerosis

et al. 2019

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Significant progress has been made in understanding the complex interactions between the coagulation system and inflammation and autoimmunity. Increased blood-brain-barrier (BBB) permeability, a key event in the pathophysiology of multiple sclerosis (MS), leads to the irruption into the central nervous system of blood components that include virtually all coagulation/hemostasis factors. Besides their cytotoxic deposition and role as a possible trigger of the coagulation cascade, hemostasis components cause inflammatory response and immune activation, sustaining neurodegenerative events in MS. Early studies showing the contribution of altered hemostasis in the complex pathophysiology of MS have been strengthened by recent studies using methodologies that permitted deeper investigation. Fibrin(ogen), an abundant protein in plasma, has been identified as a key contributor to neuroinflammation. Perturbed fibrinolysis was found to be a hallmark of progressive MS with abundant cortical fibrin(ogen) deposition. The immune-modulatory function of the intrinsic coagulation pathway still remains to be elucidated in MS. New molecular details in key hemostasis components participating in MS pathophysiology, and particularly involved in inflammatory and immune responses, could favor the development of novel therapeutic targets to ameliorate the evolution of MS. This review article introduces essential information on coagulation factors, inhibitors, and the fibrinolytic pathway, and highlights key aspects of their involvement in the immune system and inflammatory response. It discusses how hemostasis components are (dys)regulated in MS, and summarizes histopathological post-mortem human brain evidence, as well as cerebrospinal fluid, plasma, and serum studies of hemostasis and fibrinolytic pathways in MS. Studies of disease-modifying treatments as potential modifiers of coagulation factor levels, and case reports of autoimmunity affecting hemostasis in MS are also discussed.

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“…MS patients from the 2nd population, enrolled in the RAGTIME study, provided blood sampling at four time points: T0) baseline point, prior to the first rehabilitative session; T1) intermediate point, after six training sessions; T2) end of treatment, 12 completed rehabilitative sessions, 1 month after T0; T3) follow-up, after 3 months from the end of training program (30)(Ziliotto et al 2018 ).…”

Section: Methodsmentioning

confidence: 99%

Changes in expression profiles of internal jugular vein wall and plasma protein levels in multiple sclerosis

Marchetti

Ziliotto

Meneghetti

et al. 2018

Mol Med

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BackgroundMultiple sclerosis (MS) is an inflammatory, demyelinating and degenerative disorder of the central nervous system (CNS). Several observations support interactions between vascular and neurodegenerative mechanisms in multiple sclerosis (MS). To investigate the contribution of the extracranial venous compartment, we analysed expression profiles of internal jugular vein (IJV), which drains blood from CNS, and related plasma protein levels.MethodsWe studied a group of MS patients (n = 19), screened by echo-color Doppler and magnetic resonance venography, who underwent surgical reconstruction of IJV for chronic cerebrospinal venous insufficiency (CCSVI). Microarray-based transcriptome analysis was conducted on specimens of IJV wall from MS patients and from subjects undergoing carotid endarterectomy, as controls. Protein levels were determined by multiplex assay in: i) jugular and peripheral plasma from 17 MS/CCSVI patients; ii) peripheral plasma from 60 progressive MS patients, after repeated sampling and iii) healthy individuals.ResultsOf the differentially expressed genes (≥ 2 fold-change, multiple testing correction, P < 0.05), the immune-related CD86 (8.5 fold-change, P = 0.002) emerged among the up regulated genes (N = 409). Several genes encoding HOX transcription factors and histones potentially regulated by blood flow, were overexpressed. Smooth muscle contraction and cell adhesion processes emerged among down regulated genes (N = 515), including the neuronal cell adhesion L1CAM as top scorer (5 fold-change, P = 5 × 10− 4).Repeated measurements in jugular/peripheral plasma and overtime in peripheral plasma showed conserved individual plasma patterns for immune-inflammatory (CCL13, CCL18) and adhesion (NCAM1, VAP1, SELL) proteins, despite significant variations overtime (SELL P < 0.0001). Both age and MS disease phenotypes were determinants of VAP1 plasma levels.Data supported cerebral related-mechanisms regulating ANGPT1 levels, which were remarkably lower in jugular plasma and correlated in repeated assays but not between jugular/peripheral compartments.ConclusionsThis study provides for the first time expression patterns of the IJV wall, suggesting signatures of altered vascular mRNA profiles in MS disease also independently from CCSVI. The combined transcriptome-protein analysis provides intriguing links between IJV wall transcript alteration and plasma protein expression, thus highlighting proteins of interest for MS pathophysiology.Electronic supplementary materialThe online version of this article (10.1186/s10020-018-0043-4) contains supplementary material, which is available to authorized users.

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Coagulation Factor XII Levels and Intrinsic Thrombin Generation in Multiple Sclerosis

Cited by 19 publications

References 35 publications

A Perspective of Coagulation Dysfunction in Multiple Sclerosis and in Experimental Allergic Encephalomyelitis

A Perspective of Coagulation Dysfunction in Multiple Sclerosis and in Experimental Allergic Encephalomyelitis

Coagulation Pathways in Neurological Diseases: Multiple Sclerosis

Changes in expression profiles of internal jugular vein wall and plasma protein levels in multiple sclerosis

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