Extension of the therapeutic window for recombinant tissue plasminogen activator with argatroban in a rat model of embolic stroke

Background and Purpose-Argatroban, a specific thrombin inhibitor, has been shown to reduce ischemic lesion size after focal cerebral ischemia in rats. In addition, recombinant tissue Plasminogen activator (rtPA) has been show n to reduce ischemic lesion size in both rats and humans if given within 3 hours of symptom onset. We tested the hypothesis that the administration of argatroban with rtPA could extend the treatment window of stroke to 4 hour s without increasing gross cerebral hemorrhage rates or reducing efficacy. Methods-Male Wistar rats were subjected to middle cerebral artery (MCA) occ lusion by a single fibrin-rich clot. After embolization, rats were administ ered argatroban at the following dose levels: 2.08, 6.25, and 18.75 mug (.) kg(-1) (.) min(-1). In a second experiment, rats received argatroban (6.25 mug (.) kg(-1) (.) min(-1)) or argatroban in combination with rtPA 4 hours after MCA occlusion. Tissue sections were then analyzed for lesion volume, gross hemorrhage and fibrin deposition. Results-The 6.25 mug (.) kg(-1 .) min(-1) dose demonstrated a significant r eduction (P < 0.05) in lesion volume after 48 hours (27.2 +/- 6.3%) compare d with controls (35.3 +/- 3.7%). A significant reduction (P < 0.05) in lesi on volume was observed in the argatroban-plus-rtPA group (17.1 +/- 10.4%) c ompared with controls (35.3 3.7%). No increase in hemorrhagic transformatio n was observed. Fibrin deposition in the ipsilateral cortical microvasculat ure was significantly decreased in the 4-hour combination argatroban-plus-r tPA group compared with the controls (P < 0.05). Conclusions-This study demonstrates that the combination of argatroban and rtPA extends the window of opportunity for treatment of stroke to 4 hours w ithout increasing hemorrhagic transformation.