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

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

Translational stroke research (2014-11-27)
Frieder Schlunk, Elena Schulz, Arne Lauer, Kazim Yigitkanli, Waltraud Pfeilschifter, Helmuth Steinmetz, Eng H Lo, Christian Foerch
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.

MATERIALS
Product Number
Brand
Product Description

USP
Warfarin, United States Pharmacopeia (USP) Reference Standard
Supelco
Warfarin, analytical standard
Supelco
Warfarin, PESTANAL®, analytical standard
Warfarin sodium, European Pharmacopoeia (EP) Reference Standard
Supelco
Warfarin Sodium, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
3-(α-Acetonylbenzyl)-4-hydroxycoumarin sodium salt, ≥98%