on October 17, 2002
Published online before print October 17, 2002, doi: 10.1161/01.STR.0000037673.17260.1B
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Submitted on June 10, 2002
From the Department of Neurosurgery, University of Michigan, Ann Arbor. * To whom correspondence should be addressed. E-mail: rkeep{at}umich.edu.
Background and Purpose—Studies indicate that thrombin plays an important role in intracerebral hemorrhage (ICH)-induced edema formation. Although thrombin is produced as the blood clots, it may be bound to fibrin and only gradually released from the clot. The time window for administration of a thrombin inhibitor to reduce ICH-induced edema is unknown. Whether this time window extends beyond the period when a thrombin inhibitor might exacerbate rebleeding is also unknown. Methods—This study examines (1) whether argatroban, an inhibitor of both free and fibrin-bound thrombin, can reduce edema formation after intracerebral infusion of 100 µL of blood in the rat; (2) the therapeutic time window for argatroban; and (3) whether argatroban promotes rebleeding in a model in which ICH was induced by intracerebral injection of collagenase. Results—Intracerebral infusion of blood caused a marked increase in perihematomal water content. Intracerebral injection of argatroban 3 hours after ICH caused a significant reduction in edema measured at 48 hours (80.9±1.0% versus 82.6±0.8%; P<0.01). The systemic administration of high-dose argatroban (0.9 mg/h) starting 6 hours after ICH also significantly reduced edema (80.3±1.1% versus 82.0±1.3% in vehicle controls; P<0.05). There was no protection when the onset of argatroban administration was delayed to 24 hours after ICH or if a lower dose of argatroban (0.3 mg/h) was used. Argatroban did not increase collagenase-induced hematoma volume when given into the clot after 3 hours or given systemically at 6 hours. Conclusions—Our data suggest that argatroban may be an effective therapy for ICH-induced edema.
Accepted on July 3, 2002
Delayed Argatroban Treatment Reduces Edema in a Rat Model of Intracerebral Hemorrhage
Takuji Kitaoka MD;
Key words: antithrombins • brain edema • intracerebral hemorrhage • thrombin • rats
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