Background & Objectives
This study aimed to assess the risk and benefit of tPA treatment under oral anticoagulation with dabigatran compared to warfarin or vehicle control in transient middle cerebral artery occlusion (tMCAO).

Methods
After pretreatment with warfarin (0.2 mg/kg/day), dabigatran (20 mg/kg/day), or vehicle (0.5% carboxymethyl cellulose sodium salt) for 7 days, tMCAO was induced for 120 min followed by reperfusion and tPA (10 mg/kg/10 ml). Clinical parameters, including cerebral infarction volume, hemorrhagic volume, and blood coagulation, were examined. At 24 h after reperfusion, markers for the neurovascular unit at the periischemic lesion were immunohistochemically examined in brain sections, and MMP-9 activity was measured by zymography.

Results
Paraparesis and intracerebral hemorrhage volume were significantly improved in the dabigatran-pretreated group than in the warfarin-pretreated group. A marked dissociation between astrocyte foot processes and the basal lamina or pericyte was observed in the warfarin-pretreated group, which was greatly improved in the dabigatran-pretreated group. Furthermore, a remarkable activation of MMP-9 in the ipsilateral warfarin-pretreated rat brain was greatly reduced in dabigatran-pretreated rats.

Conclusions
The present study reveals that the mechanism of intracerebral hemorrhage with warfarin-pretreatment plus tPA in ischemic stroke rats is the dissociation of the neurovascular unit, including the pericyte. Neurovascular protection by dabigatran, which was first shown in this study, could partly explain the reduction in hemorrhagic complication by dabigatran reported in the clinical study.