Pretreatment with rivaroxaban attenuates stroke severity in rats by a dual antithrombotic and anti-inflammatory mechanism

Melanie Dittmeier; Peter Kraft; Michael K. Schuhmann; Felix Fluri; Christoph Kleinschnitz

doi:10.1160/TH15-08-0631

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2016; 115(04): 835-843
DOI: 10.1160/TH15-08-0631

Stroke, Systemic or Venous Thromboembolism

Schattauer GmbH

Pretreatment with rivaroxaban attenuates stroke severity in rats by a dual antithrombotic and anti-inflammatory mechanism

Melanie Dittmeier

¹Department of Neurology, University Hospital Würzburg, Würzburg, Germany

,

Peter Kraft

¹Department of Neurology, University Hospital Würzburg, Würzburg, Germany

,

Michael K. Schuhmann

¹Department of Neurology, University Hospital Würzburg, Würzburg, Germany

,

Felix Fluri^*

¹Department of Neurology, University Hospital Würzburg, Würzburg, Germany

,

Christoph Kleinschnitz^*

¹Department of Neurology, University Hospital Würzburg, Würzburg, Germany

› Institutsangaben

Abstract

Summary

Stroke outcome is more favourable in patients receiving oral anticoagulants compared with non-anticoagulated patients. The reasons for this “stroke-attenuating” property of oral anticoagulants are largely unknown. This study examined whether prestroke anticoagulation with rivaroxaban, a novel direct factor Xa inhibitor, influences stroke severity, thrombin-mediated intracerebral thrombus formation and pro-inflammatory processes in a rat model of brain ischaemia/reperfusion injury. Male Wistar rats were anticoagulated with rivaroxaban and subjected to 90 minutes of transient middle cerebral artery occlusion. Infarct size, functional outcome and the occurrence of intracranial haemorrhage (ICH) were assessed until day 7. Thrombin generation was determined by measuring the amount of thrombin/antithrombin complex. Intracerebral thrombus formation was evaluated by histology and Western blot. CD68-immunoreactivity and the expression of cytokines and adhesion molecules were investigated to assess postischaemic inflammation. The integrity of the blood–brain barrier was analysed using fluorescein isothiocyanate-dextran. Rats pretreated with rivaroxaban developed significantly smaller strokes and less severe functional deficits compared with controls. Although rivaroxaban strongly reduced thrombin-mediated thrombus formation, this was not accompanied by an increased risk of ICH. In addition, rivaroxaban dampened the inflammatory response in the ischaemic brain by downregulating ICAM-1 expression and the activation of CD68+-immune cells. In contrast, rivaroxaban had no effect on the integrity of the blood–brain barrier after stroke. Here, we identified reduced thrombo-inflammation as a major determinant of the stroke-protective property of rivaroxaban in rats. Further studies are needed to assess the therapeutic potential of novel oral anticoagulants in the acute phase after a stroke.

Keywords

tMCAO - experimental stroke - rivaroxaban - thrombin - cerebral inflammation

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Referenzen

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