Delayed argatroban treatment reduces edema in a rat model of intracerebral hemorrhage

• Published in: Stroke (1970) Vol. 33; no. 12; pp. 3012 - 3018
• Main Authors: KITAOKA, Takuji, YA HUA, GUOHUA XI, HOFF, Julian T, KEEP, Richard F
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01-12-2002; American Heart Association, Inc
• Subjects: Animals; Antithrombins - administration & dosage; Antithrombins - adverse effects; Antithrombins - pharmacokinetics; Biological and medical sciences; Brain - blood supply; Brain - drug effects; Brain - pathology; Brain Chemistry - drug effects; Brain Edema - pathology; Brain Edema - prevention & control; Cerebral Hemorrhage - blood; Cerebral Hemorrhage - chemically induced; Cerebral Hemorrhage - pathology; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Hemoglobins - analysis; Infusions, Parenteral; Male; Medical sciences; Microinjections; Neurology; Pipecolic Acids - administration & dosage; Pipecolic Acids - adverse effects; Pipecolic Acids - pharmacokinetics; Rats; Rats, Sprague-Dawley; Stereotaxic Techniques; Time Factors; Treatment Outcome; Tropical medicine; Vascular diseases and vascular malformations of the nervous system; Water - analysis; Animal model; brain edema; thrombin; Rat; Argatroban; Cardiovascular disease; Anticoagulant; Antithrombin; Vascular disease; antithroiubins; rats; Cerebrovascular disease; Nervous system diseases; Rodentia; Antiplatelet agent; Cerebral disorder; intracerebral hemorrhage; Vertebrata; Chemotherapy; Mammalia; Treatment; Animal; Cerebral hemorrhage; Central nervous system disease; Cerebral edema
• ISSN: 0039-2499; 1524-4628
• DOI: 10.1161/01.STR.0000037673.17260.1B

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.
This study examines (1) whether argatroban, an inhibitor of both free and fibrin-bound thrombin, can reduce edema formation after intracerebral infusion of 100 micro L 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.
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.
Our data suggest that argatroban may be an effective therapy for ICH-induced edema.