Warfarin pretreatment reduces cell death and MMP-9 activity in experimental intracerebral hemorrhage.

Abstract

Little is known about the pathophysiology of oral anticoagulation-associated intracerebral hemorrhage (OAC-ICH). We compared hematoma volume, number of terminal deoxynucleotidyl dUTP nick-end labeling (TUNEL)-positive cells (indicating cell death), MMP-9 levels, and perilesional edema formation between warfarin-treated mice and controls. Intracerebral hemorrhage was induced by an injection of collagenase into the right striatum. Twenty-four hours later, hematoma volume was measured using a photometric hemoglobin assay. Cell death was quantified using TUNEL staining. MMP-9 levels were determined by zymography, and edema formation was assessed via the wet-dry method. Warfarin increased hematoma volume by 2.6-fold. The absolute number of TUNEL-positive cells in the perihematomal zone was lower in warfarin-treated animals (300.5 ± 39.8 cells/mm2) than in controls (430.5 ± 38.9 cells/mm2; p = 0.034), despite the larger bleeding volume. MMP-9 levels were reduced in anticoagulated mice as compared to controls (p = 0.018). Perilesional edema formation was absent in warfarin mice and modestly present in controls. Our results suggest differences in the pathophysiology of OAC-ICH compared to intracerebral hemorrhage occurring under normal coagulation. A likely explanation is that thrombin, a strong inductor of apoptotic cell death and blood-brain barrier disruption, is produced to a lesser extent in OAC-ICH. In humans, however, we assume that the detrimental effects of a larger hematoma volume in OAC-ICH by far outweigh potential protective effects of thrombin deficiency.

• Authors: Frieder Schlunk, Elena Schulz, Arne Lauer, Kazim Yigitkanli, Waltraud Pfeilschifter, Helmuth Steinmetz, Eng H Lo, Christian Foerch
• Journal: Translational stroke research (Transl Stroke Res) Vol. 6 Issue 2 Pg. 133-9 (Apr 2015) ISSN: 1868-601X [Electronic] United States
• PMID: 25424451 (Publication Type: Journal Article)

Chemical References

• Anticoagulants
• Warfarin
• Matrix Metalloproteinase 8
• Matrix Metalloproteinase 9

Topics

• Animals
• Anticoagulants (therapeutic use)
• Brain Edema (prevention & control)
• Cell Death (drug effects)
• Cerebral Hemorrhage (complications, enzymology, etiology, prevention & control)
• Disease Models, Animal
• Drug Administration Schedule
• Hematoma (etiology, prevention & control)
• In Situ Nick-End Labeling
• Male
• Matrix Metalloproteinase 8 (toxicity)
• Matrix Metalloproteinase 9 (metabolism)
• Mice
• Neurologic Examination
• Statistics, Nonparametric
• Warfarin (therapeutic use)