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

Abstract

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.

• Authors: Shigenobu Sawada, Yoko Ono, Yusuke Egashira, Toshinori Takagi, Kazuhiro Tsuruma, Masamitsu Shimazawa, Toru Iwama, Hideaki Hara
• Journal: Current neurovascular research (Curr Neurovasc Res) Vol. 14 Issue 2 Pg. 96-103 ( 2017) ISSN: 1875-5739 [Electronic] United Arab Emirates
• PMID: 27993122 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright© Bentham Science Publishers; For any queries, please email at [email protected].

Chemical References

• Anticoagulants
• Factor Xa Inhibitors
• Isothiocyanates
• isothiocyanic acid
• Warfarin
• Rivaroxaban

Topics

• Animals
• Anticoagulants (therapeutic use)
• Blood-Brain Barrier (drug effects, physiopathology)
• Cells, Cultured
• Cerebral Hemorrhage (complications, drug therapy, mortality, pathology)
• Disease Models, Animal
• Electric Impedance
• Endothelial Cells (drug effects)
• Factor Xa Inhibitors (therapeutic use)
• Hematoma (drug therapy, etiology)
• Isothiocyanates (pharmacokinetics)
• Mice
• Neurologic Examination
• Permeability (drug effects)
• Rivaroxaban (therapeutic use)
• Treatment Outcome
• Warfarin (therapeutic use)