Rivaroxaban and apixaban reduce hemorrhagic transformation after thrombolysis by protection of neurovascular unit in rat.

Abstract

BACKGROUND AND PURPOSE:

This study aimed to assess the risk and benefit of tissue-type plasminogen activator treatment after oral anticoagulation with rivaroxaban or apixaban compared with warfarin or placebo.

METHODS:

Pretreatment with warfarin (0.2 mg/kg per day), rivaroxaban (2 mg/kg per day), apixaban (10 mg/kg per day), or vehicle (0.5% carboxymethyl cellulose sodium salt) was performed for 7 days. Transient middle cerebral artery occlusion was then induced for 120 minutes, followed by reperfusion with tissue-type plasminogen activator (10 mg/kg per 10 mL). Clinical parameters, including cerebral infarction volume, hemorrhagic volume, and blood coagulation, were examined. Twenty-four hours after reperfusion, markers for the neurovascular unit at the peri-ischemic lesion were immunohistochemically examined in brain sections, and matrix metalloproteinase-9 activity was measured by zymography.

RESULTS:

The paraparesis score was significantly improved in the rivaroxaban-pretreated group compared with the warfarin-pretreated group. Intracerebral hemorrhage was observed in the warfarin-pretreated group, and this was reduced in the rivaroxaban and apixaban-pretreated groups compared with the vehicle group. Marked dissociation of astrocyte foot processes and the basal lamina or pericytes was observed in the warfarin-pretreated group, and this was improved in the rivaroxaban and apixaban-pretreated groups. Furthermore, activation of matrix metalloproteinase-9 in the ipsilateral warfarin-pretreated brain was greatly reduced in rivaroxaban- and apixaban-pretreated rats.

CONCLUSIONS:

This study shows a lower risk of intracerebral hemorrhage after tissue-type plasminogen activator treatment in rats with ischemic stroke that are pretreated with rivaroxaban and apixaban compared with pretreatment with warfarin. Reducing neurovascular dissociation by rivaroxaban and apixaban compared with warfarin could partly explain a reduction in hemorrhagic complications reported in clinical studies.

• Authors: Syoichiro Kono, Toru Yamashita, Kentaro Deguchi, Yoshio Omote, Taijun Yunoki, Kota Sato, Tomoko Kurata, Nozomi Hishikawa, Koji Abe
• Journal: Stroke (Stroke) Vol. 45 Issue 8 Pg. 2404-10 (Aug 2014) ISSN: 1524-4628 [Electronic] United States
• PMID: 24984746 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 American Heart Association, Inc.

Chemical References

• Anticoagulants
• Fibrinolytic Agents
• Morpholines
• Pyrazoles
• Pyridones
• Thiophenes
• apixaban
• Rivaroxaban
• Tissue Plasminogen Activator

Topics

• Animals
• Anticoagulants (pharmacology, therapeutic use)
• Blood Coagulation (drug effects)
• Brain (drug effects)
• Brain Ischemia (drug therapy)
• Fibrinolytic Agents (adverse effects, therapeutic use)
• Intracranial Hemorrhages (etiology, prevention & control)
• Male
• Morpholines (pharmacology, therapeutic use)
• Pyrazoles (pharmacology, therapeutic use)
• Pyridones (pharmacology, therapeutic use)
• Rats
• Rats, Wistar
• Rivaroxaban
• Stroke (drug therapy)
• Thiophenes (pharmacology, therapeutic use)
• Thrombolytic Therapy (adverse effects)
• Tissue Plasminogen Activator (adverse effects, therapeutic use)