In Models of Intracerebral Hemorrhage, Rivaroxaban is Superior to Warfarin to Limit Blood Brain Barrier Disruption and Hematoma Expansion

Dec 21, 2016Current neurovascular research

Rivaroxaban better than Warfarin at reducing brain barrier damage and bleeding growth in brain hemorrhage models

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Abstract

Rivaroxaban reduced hematoma volume and improved survival rates compared to warfarin in an experimental model of intracerebral hemorrhage.

Hematoma volume and neurological deficits were significantly lower in mice pretreated with rivaroxaban than those pretreated with warfarin.
Rivaroxaban did not increase hematoma volume relative to the vehicle group.
Survival rates were improved in the rivaroxaban group seven days after intracerebral hemorrhage induction compared to the warfarin group.
Evans blue extravasation, indicating blood-brain barrier disruption, was significantly reduced in the rivaroxaban group compared to the warfarin group.
Rivaroxaban significantly mitigated the thrombin-induced increase in membrane permeability in human brain endothelial cells, while warfarin did not.

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BACKGROUND: Intracerebral hemorrhage (ICH) during oral anticoagulation therapy with an oral vitamin K epoxidase reductase such as warfarin is a life-threatening complication. However, whether direct oral anticoagulants (DOACs) are associated with larger hematoma volume and higher mortality rates remains controversial. We evaluated the hematoma volume and pathophysiology of ICH during anticoagulation with warfarin or rivaroxaban, an orally active direct factor Xa inhibitor.

METHOD: Mice were orally pretreated with rivaroxaban (10 or 30 mg/kg), warfarin (4 mg/kg), or vehicle. ICH was induced by intrastriatal collagenase-injection. Hematoma volume and neurological deficits 24 h after ICH induction were significantly decreased in the rivaroxaban-pretreated group in comparison with the warfarin-pretreated group. Rivaroxaban did not increase the hematoma volume relative to that observed for vehicle, and improved survival rate 7 days after ICH induction compared with warfarin.

RESULT: We evaluated blood-brain barrier (BBB) permeability 6 h after ICH induction using Evans blue spectrophotometry. Evans blue extravasation was significantly reduced in the rivaroxaban group compared with the warfarin group. To investigate the mechanism underlying hematoma expansion and BBB permeability, we focused on thrombin, a clot-derived factor and one of the major contributors to ICH-induced brain injury. To investigate the effects of anticoagulant agents on thrombin-induced injuries, human brain endothelial cells were used in membrane permeability assays. Rivaroxaban, but not warfarin, significantly mitigated the thrombin-induced increase in membrane permeability.

CONCLUSION: These findings indicate that rivaroxaban decreases BBB disruption after ICH, and limits early hematoma expansion in these experimental models compared with warfarin. Our study suggests that rivaroxaban has advantages over warfarin with respect to ICH, an important complication during long-term anticoagulation therapy.

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In Models of Intracerebral Hemorrhage, Rivaroxaban is Superior to Warfarin to Limit Blood Brain Barrier Disruption and Hematoma Expansion

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