Abstract T MP69: 12/15-LOX Inhibition or Knockout Effectively Reduces Warfarin-associated Hemorrhagic Transformation Following Experimental Stroke
Background and Purpose: A large number of patients with Atrial Fibrillation (AF) receive oral anticoagulant, most frequently Warfarin. Because of risk of increasing bleeding, these patients are not eligible for tPA treatment in case of stroke. The current study was designed to test if inhibition of the enzyme 12/15-lipoxygenase (12/15-LOX) protects against increased hemorrhage in Warfarin-treated mice subjected to experimental stroke.
Methods: Warfarin was dosed orally in drinking water, and INR values were determined 24 hours later. C57BL6J mice were subjected to transient focal ischemia (filament MCAO) with either A) 3 hours of ischemia and 21h of reperfusion or B) 2h ischemia, followed by i.v. infusion of tPA 2 hours after reperfusion and sacrifice at 24 hours. The novel 12/15-LOX inhibitor ML351 (50 mg/kg) was given by i.p. injection; at the time of reperfusion in experiment A), concomitantly with tPA in experiment B). Hemorrhage was evaluated by measuring hemoglobin in the brain parenchyma, or by measuring hemorrhage areas in brain sections. In addition, 12/15-LOX knockout mice (ALOX15(-/-)) were compared to corresponding wild-type mice in the 3h MCAO model.
Results: Reproducible INR values ranging from 2.9 - 3.5 were achieved in all mice, and Warfarin followed by MCAO led to significant hemorrhage in both models. In Experiment A), visible hemorrhage in brain sections was significantly reduced by administration of ML351, and this result was confirmed by the hemoglobin measurement. ML351 also reduced infarct size, and showed a trend toward reduced mortality. ALOX15(-/-) mice similarly developed less hemorrhage than wild-type mice. In Experiment B), the combination of tPA and Warfarin also led to severe hemorrhage, and again this was reduced in the presence of ML351.
Conclusions: We and others have previously shown inhibition of 12/15-LOX protects against experimental stroke. The current study adds an important translational value to these studies by demonstrating a significant reduction in Warfarin-associated hemorrhagic transformation, both with and without tPA. These results suggest that ML351 or a similar 12/15-LOX inhibitor could be safely given to anticoagulated patients suffering a stroke, either alone or in conjunction with tPA.
Author Disclosures: Y. Liu: None. Y. Zheng: None. H. Karatas: None. C. Foerch: Other; Modest; Patent on GFAP as a biomarker in ICH. E.H. Lo: None. K. Van Leyen: Research Grant; Significant; NIH R01NS081180, R01NS069939. Ownership Interest; Modest; Patent for ML351 has been applied for.
- © 2015 by American Heart Association, Inc.