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Warfarin Pretreatment Reduces Cell Death and MMP-9 Activity in Experimental Intracerebral Hemorrhage

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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.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Neurology, Johann Wolfgang Goethe University, Frankfurt am Main, Germany

    Frieder Schlunk, Elena Schulz, Arne Lauer, Waltraud Pfeilschifter, Helmuth Steinmetz & Christian Foerch

  2. Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, USA

    Frieder Schlunk, Elena Schulz, Arne Lauer, Kazim Yigitkanli & Eng H. Lo

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  1. Frieder Schlunk
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  2. Elena Schulz
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  3. Arne Lauer
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  4. Kazim Yigitkanli
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  5. Waltraud Pfeilschifter
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  7. Eng H. Lo
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  8. Christian Foerch
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Correspondence to Frieder Schlunk.

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Schlunk, F., Schulz, E., Lauer, A. et al. Warfarin Pretreatment Reduces Cell Death and MMP-9 Activity in Experimental Intracerebral Hemorrhage. Transl. Stroke Res. 6, 133–139 (2015). https://doi.org/10.1007/s12975-014-0377-3

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  • DOI: https://doi.org/10.1007/s12975-014-0377-3

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