Abstract
BackgroundTissue type plasminogen activator is the only approved thrombolytic agent for the treatment of ischemic stroke. However, it carries the disadvantage of a 10-fold increase in symptomatic and asymptomatic intracranial hemorrhage. A safer thrombolytic agent may improve patient prognosis and increase patient participation in thrombolytic treatment. A novel direct-acting thrombolytic agent, Δ(K2-K5) plasmin, promising an improved safety profile was examined for safety in the snare ligature model of stroke in the rat.MethodsMale spontaneously hypertensive rats were subjected to 6 hours middle cerebral artery occlusion followed by 18 hours reflow. Beginning 1 minute before reflow, they were dosed with saline, vehicle, Δ(K2-K5) plasmin (0.15, 0.5, 1.5, and 5 mg/kg) or recombinant tissue-type plasminogen activator (10 and 30 mg/kg) by local intra-arterial infusion lasting 10 to 60 minutes. The rats were assessed for bleeding score, infarct volume, modified Bederson score and general behavioral score. In a parallel study, temporal progression of infarct volume was determined. In an in vitro study, whole blood clots from humans, canines and rats were exposed to Δ(K2-K5). Clot lysis was monitored by absorbance at 280 nm.ResultsThe main focus of this study was intracranial hemorrhage safety. Δ(K2-K5) plasmin treatment at the highest dose caused no more intracranial hemorrhage than the lowest dose of recombinant tissue type plasminogen activator, but showed at least a 5-fold superior safety margin. Secondary results include: temporal infarct volume progression shows that the greatest expansion of infarct volume occurs within 2–3 hours of middle cerebral artery occlusion in the spontaneously hypertensive rat. A spike in infarct volume was observed at 6 hours ischemia with reflow. Δ(K2-K5) plasmin tended to reduce infarct volume and improve behavior compared to controls. In vitro data suggests that Δ(K2-K5) plasmin is equally effective at lysing clots from humans, canines and rats.ConclusionsThe superior intracranial hemorrhage safety profile of the direct-acting thrombolytic Δ(K2-K5) plasmin compared with recombinant tissue type plasminogen activator makes this agent a good candidate for clinical evaluation in the treatment of acute ischemic stroke.
Highlights
Tissue type plasminogen activator is the only approved thrombolytic agent for the treatment of ischemic stroke
Clots from humans, canines and rats showed nearly identical lysis kinetics when exposed to Δ(K2-K5) plasmin (Figure 4)
Ten were excluded from the study based on the a priori exclusion criteria including: breakage of the Middle cerebral artery (MCA) (2), excessive surgical bleeding (3), lack of right side weakness (1), missing brain sections (2), high preischemia plasma glucose concentration (1), and nonrecovery from anesthesia (1)
Summary
Tissue type plasminogen activator is the only approved thrombolytic agent for the treatment of ischemic stroke. It carries the disadvantage of a 10-fold increase in symptomatic and asymptomatic intracranial hemorrhage. A novel thrombolytic agent that effectively lyses clots while significantly reducing the risk of hemorrhage may improve overall prognosis and potentially allow more patients with stroke to be treated. Δ(K2-K5) plasmin is rapidly neutralized by endogenous inhibitors after IV administration, accounting for its hemorrhagic safety profile This attribute requires Δ(K2-K5) plasmin to be administered by a catheter advanced to the immediate proximity of the thrombus [5,6,7]. Δ(K2-K5) plasmin shows remarkable hemostatic safety in a rabbit fibrinolytic hemorrhage model [4,6,7,8], suggesting that, like native plasmin, Δ(K2-K5) plasmin poses significantly less systemic hemorrhagic risk than rt-PA
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