Rivaroxaban ameliorates disease course in an animal model of multiple sclerosis

Merker, Monika; Eichler, Susann; Herrmann, Alexander M.; Wiendl, Heinz; Kleinschnitz, Christoph; Göbel, Kerstin; Meuth, Sven G.

doi:10.1016/j.jneuroim.2017.08.013

Cited by 10 publications

(11 citation statements)

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“…Moreover, a close correlation between the cerebral or spinal fibrin load and the number of relapses was reported in EAE mice, and anticoagulant administration or fibrinogen depletion reversed the pathology (11,34). Furthermore, inhibition of other coagulation factors like thrombin or FXa led to an amelioration of neuroinflammation in animal models (11,19).…”

Section: Discussionmentioning

confidence: 89%

“…KK can cleave FXII to its active form, thereby initiating both the proinflammatory KKS, resulting in BK release, and the intrinsic coagulation cascade, leading to an activation of factor X (FX) and prothrombin, and thereby finally causing fibrin formation (13). There is evidence that the inhibition of active FX (FXa) and thrombin is protective in EAE (11,19). To exclude that improved EAE outcome is due to different amounts of thrombin and FXa in the plasma and CNS in Klkb1 −/− mice compared with WT controls, we determined the concentration of both.…”

Section: Significancementioning

confidence: 99%

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Plasma kallikrein modulates immune cell trafficking during neuroinflammation via PAR2 and bradykinin release

Göbel

Asaridou

Merker

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Blood–brain barrier (BBB) disruption and transendothelial trafficking of immune cells into the central nervous system (CNS) are pathophysiological hallmarks of neuroinflammatory disorders like multiple sclerosis (MS). Recent evidence suggests that the kallikrein-kinin and coagulation system might participate in this process. Here, we identify plasma kallikrein (KK) as a specific direct modulator of BBB integrity. Levels of plasma prekallikrein (PK), the precursor of KK, were markedly enhanced in active CNS lesions of MS patients. Deficiency or pharmacologic blockade of PK renders mice less susceptible to experimental autoimmune encephalomyelitis (a model of MS) and is accompanied by a remarkable reduction of BBB disruption and CNS inflammation. In vitro analysis revealed that KK modulates endothelial cell function in a protease-activated receptor-2–dependent manner, leading to an up-regulation of the cellular adhesion molecules Intercellular Adhesion Molecule 1 and Vascular Cell Adhesion Molecule 1, thereby amplifying leukocyte trafficking. Our study demonstrates that PK is an important direct regulator of BBB integrity as a result of its protease function. Therefore, KK inhibition can decrease BBB damage and cell invasion during neuroinflammation and may offer a strategy for the treatment of MS.

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Section: Discussionmentioning

confidence: 89%

Section: Significancementioning

confidence: 99%

Plasma kallikrein modulates immune cell trafficking during neuroinflammation via PAR2 and bradykinin release

Göbel

Asaridou

Merker

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…Growing evidences suggest the crosstalk between hemostasis components, inflammation, and immune system, which appear to be involved in MS pathophysiology ( 3 – 8 ). The relationship of the coagulation pathway with disease processes could be further supported by recent findings, showing that anticoagulation ameliorated clinical course of experimental autoimmune encephalomyelitis (EAE), an animal model of MS ( 9 , 10 ).…”

Section: Introductionmentioning

confidence: 82%

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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“…2 Moreover, pharmacological inhibition of the enzymatic activity of FX with rivaroxaban leads to an attenuated disease course in EAE, including a decrease in microglial activation and reduced T-cell infiltration. 5 While research has for a long time concentrated on the extrinsic part of the coagulation system, recent investigations have uncovered the important role of the blood coagulation protein Factor XII (FXII). FXII can be activated by plasma kallikrein, plasmin, or negatively charged surfaces in vitro, while in vivo activation is still under debate.…”

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confidence: 99%

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confidence: 99%