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

Abstract

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.

Rivaroxaban does not influence hemorrhagic transformation in a diabetes ischemic stroke and endovascular thrombectomy model

“…Furthermore, Rivaroxaban may have little effect on MMP-9 expression. This study also reveals that Rivaroxaban does not increase occludin degradation and has no effect on BBB stability in diabetes post-experimental ET, which is similar to normal experimental stroke models 55 .…”

Risk–Benefit Profile of Direct-Acting Oral Anticoagulants in Established Therapeutic Indications: An Overview of Systematic Reviews and Observational Studies

“…The latest meta-analysis of observational studies on dabigatran (not included in our analysis) corroborated these findings by pooling seven cohort studies (HR 0.44, 95 % CI 0.34–0.59, I 2  = 64 % for dabigatran 150 mg) [77]. The mechanism behind a reduced ICH risk is still largely unknown, although in vivo studies pointed out that the potential anti-inflammatory properties of dabigatran may partially explain the observed clinical benefit [78, 79]. …”

Rivaroxaban improves vascular response in LPS-induced acute inflammation in experimental models

“…Clinical studies with NOACS have shown that these drugs reduce the incidence of cardiovascular events including coronary and peripheral artery disease, cerebral ischemia, thrombosis, thromboembolic events, and atherosclerosis [12,13]. In addition to this, experimental studies proposed a series of vascular protective properties of NOAC via inhibition of FXa [14][15][16][17][18][19][20][21][22][23][24][25][26]. These include potential anti-inflammatory effects [15,[19][20][21]23,24,27], that might perhaps impact vascular function and pathology [14,25].…”