Anticoagulation with dabigatran does not increase secondary intracerebral haemorrhage after thrombolysis in experimental cerebral ischaemia
- 1 January 2013
- journal article
- Published by Georg Thieme Verlag KG in Thrombosis and Haemostasis
- Vol. 110 (07), 153-161
- https://doi.org/10.1160/th12-12-0942
Abstract
Dabigatran etexilate (DE) has recently been introduced for stroke prevention in atrial fibrillation, but management of acute ischaemic stroke during therapy with DE is a challenge. Thrombolysis is contrain-dicated because of a presumed increased risk of intracerebral haemorrhagic complications. We studied in different ischaemia models whether DE increases secondary haemorrhage after thrombolysis. C57BL/6 mice were anticoagulated with high-dose DE or warfarin. After 2 hour (h) or 3 h transient filament MCAO, rt-PA was injected. At 24 h after MCAO, secondary haemorrhage was quantified using a macroscopic haemorrhage score and haemoglobin spectrophotometry. Post-ischaemic blood-brain-barrier (BBB) damage was assessed using Evans blue. To increase the validity of findings, the duration of anticoagulation was prolonged in mice (5 x DE over 2 days), and the effect of DE after thrombolysis was also examined in thromboembolic MCAO in rats. Pretreatment with warfarin resulted in significantly more secondary haemorrhage (mean haemorrhage score 2.6 ± 0.2) compared to non-anticoagulated animals (1.7 ± 0.3) and DE (9 mg/kg, 1.6 ± 0.3) in 2 h ischaemia. Also after a 3 h period of ischaemia, haemorrhage was more severe in animals anticoagulated with warfarin compared to 9 mg/kg DE and non-anticoagulated control. Prolonged or enteral dabigatran pretreatment led to identical results. Also, thrombolysis after thromboembolic MCAO in rats did not induce more severe bleeding in DE-treated animals. Mice pretreated with warfarin had higher BBB permeability and increased activation of matrix-metalloproteinase 9. In conclusion, DE does not increase the risk of secondary haemorrhage after thrombolysis in various rodent models of ischaemia and reperfusion. The implications of this finding for stroke patients have to be determined in the clinical setting. * The first two authors contributed equally to this work.This publication has 37 references indexed in Scilit:
- European Research Priorities for Intracerebral HaemorrhageCerebrovascular Diseases, 2011
- Apixaban versus Warfarin in Patients with Atrial FibrillationThe New England Journal of Medicine, 2011
- Rivaroxaban versus Warfarin in Nonvalvular Atrial FibrillationThe New England Journal of Medicine, 2011
- Incidence and Management of Ischemic Stroke and Intracerebral Hemorrhage in Patients on Dabigatran Etexilate TreatmentNeurocritical Care, 2011
- The new oral anticoagulantsBlood, 2010
- Dabigatran versus Warfarin in Patients with Atrial FibrillationThe New England Journal of Medicine, 2009
- Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic StrokeThe New England Journal of Medicine, 2008
- Meta-analysis: Antithrombotic Therapy to Prevent Stroke in Patients Who Have Nonvalvular Atrial FibrillationAnnals of Internal Medicine, 2007
- Guidelines for the Early Management of Adults With Ischemic StrokeCirculation, 2007
- Hospitalized Patients With Atrial Fibrillation and a High Risk of Stroke Are Not Being Provided With Adequate AnticoagulationJournal of the American College of Cardiology, 2005