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(Stroke. 2002;33:3012.)
© 2002 American Heart Association, Inc.

Original Contributions

Delayed Argatroban Treatment Reduces Edema in a Rat Model of Intracerebral Hemorrhage

Takuji Kitaoka, MD; Ya Hua, MD; Guohua Xi, MD; Julian T. Hoff, MD Richard F. Keep, PhD

From the Department of Neurosurgery, University of Michigan, Ann Arbor.

Correspondence to Richard F. Keep, PhD, Department of Neurosurgery, University of Michigan, R5550 Kresge I, Ann Arbor, MI 48109-0532. 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.

Key Words: antithrombins • brain edema • intracerebral hemorrhage • thrombin • rats

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