Experimental model of warfarin-associated intracerebral hemorrhage.
OBJECTIVE
Future demographic changes predict an increase in the number of patients with atrial fibrillation. As long-term anticoagulation for the prevention of ischemic strokes becomes more prevalent, the burden of warfarin-associated intracerebral hemorrhage (W-ICH) is likely to grow. However, little is known about the clinical aspects and pathophysiologic mechanisms of W-ICH. This study describes the development of a mouse model of W-ICH in which hematoma growth and outcomes can be correlated with anticoagulation parameters.


METHODS
CD-1 mice were treated with warfarin (2 mg/kg per 24 hours) added to drinking water. ICH was induced by stereotactic injection of collagenase type VII (0.075 U) into the right striatum. Hemorrhagic blood volume was quantified by means of a photometric hemoglobin assay 2 and 24 hours after hemorrhage induction. Neurologic outcomes were assessed on a 5-point scale.


RESULTS
The international normalized ratio in nonanticoagulated mice was 0.8+/-0.1. After 24 (W-24) and 30 (W-30) hours of warfarin pretreatment, international normalized ratio values increased to 3.5+/-0.9 and 7.2+/-3.4, respectively. Compared with nonanticoagulated mice, mean hemorrhagic blood volume determined 24 hours after hemorrhage induction was found to be 2.5-fold larger in W-24 mice (P=0.019) and 3.1-fold larger in W-30 mice (P<0.001, n=10 per group). Mortality at 24 hours after hemorrhage induction was 0% in nonanticoagulated mice, 10% in W-24 mice, and 30% in W-30 mice. Hematoma enlargement between 2 and 24 hours after hemorrhage induction was -1.4% for nonanticoagulated mice, 22.9% for W-24 mice, and 62.2% for W-30 mice.


CONCLUSIONS
This study characterizes the first experimental model of W-ICH. It may be helpful in gaining further insights into the pathophysiology of W-ICH and may be used for testing the efficacy of treatment strategies, such as hemostatic therapy, in this severe subtype of stroke.
Foerch
Christian
C
Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Masschusetts 02129, USA. foerch@em.uni-frankfurt.de
Arai
Ken
K
Jin
Guang
G
Park
Kyung-Pil
KP
Pallast
Stefanie
S
van Leyen
Klaus
K
Lo
Eng H
EH
D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000633:toxicity*; D001925:Brain Damage, Chronic / Q000209:etiology; D002543:Cerebral Hemorrhage / Q000139:chemically induced* / Q000150:complications / Q000503:physiopathology; D017364:Collagenases / Q000008:administration & dosage / Q000633:toxicity*; D003342:Corpus Striatum; D004195:Disease Models, Animal; D018450:Disease Progression; D006406:Hematoma / Q000139:chemically induced / Q000503:physiopathology; D007267:Injections; D019934:International Normalized Ratio; D008297:Male; D051379:Mice; D003012:Microbial Collagenase; D009069:Movement Disorders / Q000209:etiology; D014859:Warfarin / Q000008:administration & dosage / Q000633:toxicity*
D000925:Anticoagulants; D014859:Warfarin; D017364:Collagenases; C533954:collagenase VII-S, Clostridium histolyticum; D003012:Microbial Collagenase
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