Improved Perfusion with rt-PA and Hirulog in a Rabbit Model of Embolic Stroke

Abstract

We conducted a study using diffusion-weighted (DWI) and perfusion-weighted (PWI) magnetic resonance imaging (MRI) to evaluate the efficacy of thrombolysis in an embolic stroke model with recombinant tissue plasminogen activator (rt-PA) and hirulog, a novel direct-acting antithrombin. DWI can identify areas of ischemia minutes from stroke onset, while PWI identifies regions of impaired blood flow. Right internal carotid arteries of 36 rabbits were embolized using aged heterologous thrombi. Baseline DWI and PWI scans were obtained to confirm successful embolization. Four animals with no observable DWI lesion on the initial scan were excluded; therefore, a total of 32 animals were randomized to one of three treatment groups: rt-PA (n = 11), rt-PA plus hirulog (n = 11), or placebo (n = 10). Treatment was begun 1 h after stroke induction. Intravenous doses were as follows: rt-PA, 5 mg/kg over 0.5 h with 20% of the total dose given as a bolus; hirulog, 1 mg/kg bolus followed by 5 mg/kg over 1 h. MRI was performed at 2, 3, and 5 h following embolization. Six hours after embolization, brains were harvested, examined for hemorrhage, then prepared for histologic analysis. The rt-PA decreased fibrinogen levels by 73%, and hirulog prolonged the aPTT to four times the control value. Posttreatment areas of diffusion abnormality and perfusion delay were expressed as a ratio of baseline values. Significantly improved perfusion was seen in the rt-PA plus hirulog group compared with placebo (normalized ratios of the perfusion delay areas were as follows: placebo, 1.58, 0.47-3.59; rt-PA, 1.12, 0.04-3.95; rt-PA and hirulog, 0.40, 0.02-1.08; p < 0.05). Comparison of diffusion abnormality ratios measured at 5 h showed trends favoring reduced lesion size in both groups given rt-PA (normalized ratios of diffusion abnormality areas were as follows: placebo, 3.69, 0.39-15.71; rt-PA, 2.57, 0.74-5.00; rt-PA and hirulog, 1.95, 0.33-6.80; p = 0.32). Significant cerebral hemorrhage was observed in one placebo, two rt-PA, and three rt-PA plus hirulog treated animals. One fatal systemic hemorrhage was observed in each of the rt-PA groups. We conclude that rt-PA plus hirulog improves cerebral perfusion but does not necessarily reduce cerebral injury. DWI and PWI are useful methods for monitoring thrombolysis.

Mild Hypothermia Reduces Tissue Plasminogen Activator-Related Hemorrhage and Blood Brain Barrier Disruption After Experimental Stroke

“…Sections were photographed and inspected for gross hemorrhage. Five brain sections were visually inspected for gross hemorrhage and scored by a rater blinded to treatment using methods previously published by our group (Yenari et al, 1997a(Yenari et al, , 1997b(Yenari et al, , 2006. Only cerebral hemorrhages visible to the naked eye were scored: 0, if there was no gross hemorrhage, 1 = small amount of hemorrhage (present on no more than 1 brain section), 2 = medium amount of hemorrhage (present on 2-3 sections), 3 = large amount of hemorrhage (present on > 3 sections, but no subarachnoid blood), 4 = severe hemorrhage = same as 3 but brain also has subarachnoid blood.…”

Magnetic Resonance Imaging in Experimental Models of Brain Disorders

“…Thrombolysis with recombinant tissue plasminogen activator (rt-PA) is currently the only approved treatment strategy in acute ischemic stroke (The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group, 1995). In an embolic stroke model, the combination of perfusion MRI and DW MRI has demonstrated that rt-PA administration within 1 hour after stroke improves perfusion and reduces ischemic tissue damage (Yenari et al, 1997) (Fig. 2A).…”

Intra-Arterial rtPA Treatment of Stroke Assessed by Diffusion- and Perfusion-Weighted MRI

“…2,3 DWI has very high sensitivity for detecting acute cerebral infarction, 4 and PWI can provide a rapid qualitative measure of tissue perfusion, suggesting that DWI and PWI may be suitable techniques to monitor the efficacy of thrombolytic therapy. Although this has been demonstrated in animal models, 5 few data are available on the use of DWI and PWI in patients treated with rtPA, and to the best of our knowledge there are no reports with angiographic correlation. The authors present the case of a patient who was treated with intra-arterial rtPA and who subsequently underwent DWI and PWI.…”