Intra-arterial administration of recombinant tissue-type plasminogen activator (rt-PA) causes more intracranial bleeding than does intravenous rt-PA in a transient rat middle cerebral artery occlusion model

Male SHRs were subjected to 6 hours MCAo with 18 hours reflow using a snare ligature model. They were treated with IA saline, IA rt-PA (1, 5, 10, 30 mg/kg), or IV rt-PA (10 and 30 mg/kg) by a 10 to 60 minute infusion beginning approximately 1 minute before reflow. The rats were recovered for 24 hours after MCAo onset at which time Bleeding Score, infarct volume, and Modified Bederson Score were measured.Greater hemorrhagic transformation occurred with 10 and 30 mg/kg rt-PA administered IA than IV. The IV 10 mg/kg rt-PA dosage induced significantly less bleeding than did the 1 or 5 mg/kg IA groups. No significant increase in infarct volume was observed after IA or IV treatment. Rats treated with 30 mg/kg rt-PA by either the IA or IV route had greater neurological dysfunction compared to all other groups.Administration of rt-PA by the IA route following 6 hours of MCAo results in greater ICH and worse functional recovery than comparable dosages IV. Significantly greater bleeding was observed when the IA dose was a tenth of the IV dose. The increased bleeding did not translate in larger infarct volumes.Currently, the only approved pharmacological treatment for ischemic stroke is rt-PA via the intravenous (IV) route. However, recent experience with Intra-arterial (IA) infusion of rt-PA, alone or in combination with IV therapy or retrieval devices at the site of thrombus formation may provide a recanalization advantage over IV administration, especially in cases of high clot burden such as a thrombus located in the M1 or M2 segment of the middle cerebral artery [1-3]. IA administration of therapeutic agents within the first 3 hours of stroke symptom onset in the clinic is feasible [4,5] and is required for direct-acting fibrinolytic agents in development [6]. Although IA administration of a thrombolytic may improve the recanalization rate, such local infusion of agent may also increase the risk of intracerebral hemorrhage (ICH) [7] especially as the therapeutic window is