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

Parsons, Martin; O’Connell, Karen; Allen, Seamus; Egan, Karl; Szklanna, Paulina B.; McGuigan, Christopher; Áinle, Fionnuala Ní; Maguire, Patricia B.

doi:10.1177/2055217317747624

Cited by 11 publications

(10 citation statements)

References 26 publications

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“…Overall, the lower FXII:ratio and longer TG time parameters suggested that in part of MS patients (i) FXII could be less active per antigen unit and (ii) FXII response to contact activation and its support to the intrinsic coagulation pathway could be reduced. Interestingly, it has been recently reported that in TG, triggered by extrinsic activation, time parameters were shorter in MS patients ( 23 ), which does not conflict with our data because extrinsic TG does not explore FXII contribution. Noteworthy, both the intrinsic TG, first reported in our study, and the extrinsic TG ( 23 ) tightly depend on activation and activity of coagulation factors in the common pathway, essential to generate thrombin.…”

Section: Discussionsupporting

confidence: 52%

“…Interestingly, it has been recently reported that in TG, triggered by extrinsic activation, time parameters were shorter in MS patients ( 23 ), which does not conflict with our data because extrinsic TG does not explore FXII contribution. Noteworthy, both the intrinsic TG, first reported in our study, and the extrinsic TG ( 23 ) tightly depend on activation and activity of coagulation factors in the common pathway, essential to generate thrombin. Although indirectly, our study does not support the presence of a prothrombotic state in the MS patients under study.…”

Section: Discussionsupporting

confidence: 52%

“…Local and systemic thrombotic events has been described in MS potentially in relation to the overstimulation of innate immunity for both its inflammatory and coagulant components ( 22 ). Recently, the hypercoagulability and potentially prothrombotic state in MS patients has been investigated by TG, triggered by extrinsic activation ( 23 ).…”

Section: Introductionmentioning

confidence: 99%

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Coagulation Factor XII Levels and Intrinsic Thrombin Generation in Multiple Sclerosis

et al. 2018

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BackgroundFactor XII (FXII) activation initiates the intrinsic (contact) coagulation pathway. It has been recently suggested that FXII could act as an autoimmunity mediator in multiple sclerosis (MS). FXII depositions nearby dentritic cells were detected in the central nervous system of MS patients and increased FXII activity has been reported in plasma of relapsing remitting and secondary progressive MS patients. FXII inhibition has been proposed to treat MS.ObjectiveTo investigate in MS patients multiple FXII-related variables, including the circulating amount of protein, its pro-coagulant function, and their variation over time. To explore kinetic activation features of FXII in thrombin generation (TG).MethodsIn plasma from 74 MS patients and 49 healthy subjects (HS), FXII procoagulant activity (FXII:c) and FXII protein (FXII:Ag) levels were assessed. Their ratio (FXII:ratio) values were derived. Intrinsic TG was evaluated by different triggers.ResultsHigher FXII:Ag levels (p = 0.003) and lower FXII:ratio (p < 0.001) were detected in MS patients compared with HS. FXII variables were highly correlated over four time points, which supports investigation of FXII contribution to disease phenotype and progression. A significant difference over time was detected for FXII:c (p = 0.031). In patients selected for the lowest FXII:ratio, TG triggered by ellagic acid showed a trend in lower endogenous thrombin potential (ETP) in MS patients compared with HS (p = 0.042). Intrinsic triggering of TG by nucleic acid addition produced longer time parameters in patients than in HS and substantially increased ETP in MS patients (p = 0.004) and TG peak height in HS (p = 0.008). Coherently, lower FXII:ratio and longer lag time (p = 0.02) and time to peak (p = 0.007) point out a reduced response of FXII to activation in part of MS patients.ConclusionIn MS patients, factor-specific and modified global assays suggest the presence of increased FXII protein level and reduced function within the intrinsic coagulation pathway. These novel findings support further investigation by multiple approaches of FXII contribution to disease phenotype and progression.

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Section: Discussionsupporting

confidence: 52%

Section: Discussionsupporting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

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Coagulation Factor XII Levels and Intrinsic Thrombin Generation in Multiple Sclerosis

et al. 2018

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“…Interestingly, relapse free time negatively correlated with level of either prothrombin, factor XII, or factor X indicating disease exacerbation as a condition characterized by increased coagulation activity (9). Similarly, the speed of thrombin generation was found faster in relapsing-remitting than in primary progressive MS or healthy controls and correlated with time from clinical diagnosis likely reflecting the differential active proinflammatory state in each MS subtype (72). Dermatan sulfate and heparin inhibit the generation of thrombin activity and both have been demonstrated to be effective therapeutic agent for EAE (73–75).…”

Section: Thrombinmentioning

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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“…Of note, relapse-free time negatively correlated with levels of prothrombin, factor XII, or factor X, indicating that disease exacerbation is characterized by increased coagulation activity (31). Interestingly, the speed of thrombin generation was higher in relapsing-remitting than in primary progressive MS or healthy controls and correlated with time from clinical diagnosis, likely suggesting a differential active proinflammatory state in each MS subtype (32). By the proteomics approach, some serum proteins such as antithrombin, ceruloplasmin, clusterin, apolipoprotein E, and complement C3 were differently expressed in RRMS patients compared to controls (33).…”

Section: Introductionmentioning

confidence: 98%

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

et al. 2020

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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

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

Cited by 11 publications

References 26 publications

Coagulation Factor XII Levels and Intrinsic Thrombin Generation in Multiple Sclerosis

Coagulation Factor XII Levels and Intrinsic Thrombin Generation in Multiple Sclerosis

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

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

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