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Thrombolysis with recombinant tissue plasminogen activator under dabigatran anticoagulation in experimental stroke
Author(s) -
Pfeilschifter Waltraud,
Bohmann Ferdinand,
Baumgarten Peter,
Mittelbronn Michel,
Pfeilschifter Josef,
LindhoffLast Edelgard,
Steinmetz Helmuth,
Foerch Christian
Publication year - 2012
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.23558
Subject(s) - medicine , thrombolysis , dabigatran , warfarin , stroke (engine) , tissue plasminogen activator , contraindication , plasminogen activator , anesthesia , atrial fibrillation , cardiology , myocardial infarction , pathology , mechanical engineering , alternative medicine , engineering
Abstract Objective: Anticoagulation with dabigatran etexilate (DE) has a favorable risk‐to‐benefit profile for the prevention of ischemic events in patients with atrial fibrillation compared to warfarin. Whereas warfarin constitutes a strong contraindication for thrombolysis, it is unclear whether patients anticoagulated with DE can be thrombolysed. We compared the risk of thrombolysis‐associated hemorrhagic transformation (HT) after pretreatment with DE or warfarin in a mouse model of ischemic stroke. Methods: Thirty‐nine C57BL/6 mice were pretreated orally with 75mg/kg DE, 112.5mg/kg DE, 2mg/kg warfarin, or saline. We performed right middle cerebral artery occlusion for 3 hours, administered recombinant tissue plasminogen activator (rt‐PA) directly before reperfusion, and assessed neurological deficit and HT blood volume after 24 hours. Results: Warfarin anticoagulation increased HT secondary to rt‐PA treatment as compared to nonanticoagulated controls (6.9 ± 5.5μl vs 0.8 ± 0.6μl, p < 0.05). In contrast, the rate of HT after pretreatment with 75mg/kg DE, which led to plasma levels comparable to the highest plasma levels observed in participants of the RE‐LY trial, did not differ significantly from controls (1.6 ± 0.8; p > 0.05 vs control). However, a high‐dose group receiving 112.5mg/kg DE showed a considerable extent of HT (9.2 ± 5.6μl, p < 0.01). Interpretation: Our experimental data suggest that the risk of thrombolysis‐associated HT may not be increased under DE pretreatment with standard doses leading to plasma levels of up to 400ng/ml, a concentration that was not exceeded in the majority of DE trial patients. At higher DE plasma levels, however, the risk of severe HT rises considerably, emphasizing the need for a readily available assay of DE anticoagulant activity. ANN NEUROL 2012