title: 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.affiliation: Department of Neurology, Johann Wolfgang Goethe University, Frankfurt am Main, Germany, fschlunk@gmail.com.
authors.forename: Frieder
authors.initials: F
authors.lastname: Schlunk
authors.forename: Elena
authors.initials: E
authors.lastname: Schulz
authors.forename: Arne
authors.initials: A
authors.lastname: Lauer
authors.forename: Kazim
authors.initials: K
authors.lastname: Yigitkanli
authors.forename: Waltraud
authors.initials: W
authors.lastname: Pfeilschifter
authors.forename: Helmuth
authors.initials: H
authors.lastname: Steinmetz
authors.forename: Eng H
authors.initials: EH
authors.lastname: Lo
authors.forename: Christian
authors.initials: C
authors.lastname: Foerch
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use*; D001929:Brain Edema / Q000517:prevention & control; D016923:Cell Death / Q000187:drug effects; D002543:Cerebral Hemorrhage / Q000150:complications / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D006406:Hematoma / Q000209:etiology / Q000517:prevention & control; D020287:In Situ Nick-End Labeling; D008297:Male; D020784:Matrix Metalloproteinase 8 / Q000633:toxicity; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D009460:Neurologic Examination; D018709:Statistics, Nonparametric; D014859:Warfarin / Q000627:therapeutic use*
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D020784:Matrix Metalloproteinase 8; D020780:Matrix Metalloproteinase 9