Microplasmin and Tissue Plasminogen Activator: Comparison of Therapeutic Effects in Rat Stroke Model at Multiparametric MR Imaging

Abstract

Purpose:To prospectively compare therapeutic and hemorrhagic effects of microplasmin and tissue plasminogen activator (tPA) in stroke therapy by using multiparametric magnetic resonance (MR) imaging in a photothrombotic rat stroke model. Materials and Methods:The animal experiment complied with institutional regulations for laboratory animals. Stroke was induced in rats with photothrombotic occlusion of middle cerebral artery (MCA). T2-weighted, perfusion-weighted (PW), and diffusion-weighted (DW) MR imaging was performed 1 hour and 24 hours after occlusion. On the basis of PW and DW images at 1 hour, 49 rats with cortex and subcortex involvement and with perfusion-diffusion mismatch were randomly assigned into one of four groups: control group, group treated with 7.5 mg microplasmin, group treated with 10 mg/kg microplasmin, or group treated with 10 mg/kg tPA. Agents were intravenously injected 1.5 hours after occlusion. Infarct size and hemorrhagic transformation were assessed with MR imaging and histomorphologic findings. Neurologic deficit was scored. Measurements were statistically analyzed. Results:There were 13 rats in the control group, 13 in the 7.5 mg/kg microplasmin group, nine in the 10 mg/kg microplasmin group, and 14 in the 10 mg/kg tPA group. Despite similar baseline perfusion-diffusion mismatch, histochemically defined total infarct volume was reduced from 25% Ϯ 5 (standard deviation) in control group to 21% Ϯ 2, 20% Ϯ 4, and 20% Ϯ 5 in 7.5 mg/kg microplasmin, 10 mg/kg microplasmin, and tPA groups, respectively, as similarly shown on T2-weighted, DW, and PW images at 24 hours (P Ͻ .05). Cerebral hemorrhage rate at 24 hours was higher in tPA group than in the other three groups. Bederson score of neurologic deficits was significantly reduced in treated groups compared with that in control group. Conclusion:Perfusion-diffusion mismatch appeared useful in selecting candidates for thrombolytic therapy. Multiparametric MR imaging allowed noninvasive assessment of effects of microplasmin and tPA in rats; microplasmin had a significantly lower hemorrhagic rate. Note: This copy is for your personal, non-commercial use only. To order presentation-ready copies for distribution to your colleagues or clients, use the Radiology Reprints form at the end of this article. Tissue plasminogen activator (tPA) has shown therapeutic effects for the treatment of acute ischemic stroke in both animals (1,2) and patients (3,4). Results of some studies (5-7) indicate that tPA may increase the risk of hemorrhagic transformation, especially in cases of blood-brain barrier perturbation before tPA administration (5,6) and in cases of delayed (4 -6 hours) tPA treatment (5,8). In patients who received tPA, the incidence of symptomatic hemorrhage showed a 10-fold increase compared with that in a placebo group (3,9); however, there is still controversy about the adverse effects of tPA (10,11). Therefore, efforts have been made to develop new thrombolytic agents that may improve the benefit-to-risk ratio in the management of strok...

Molecular Mechanisms of Apoptosis in Cerebral Ischemia: Multiple Neuroprotective Opportunities

“…As microplasmin attacks fibrin directly, whereas both tPA and desmoteplase act on fibrin through plasminogen. Furthermore, microplasmin showed significantly lower rate of hemorrhage as compared to tPA [320]. It is currently undergoing phase II trials.…”

Direct fibrinolytic agents: biochemical attributes, preclinical foundation and clinical potential

“…A phase I/II dose selection and safety trial is underway in patients with recent (category I or IIa) lower extremity ischemia [71 (NCT 00418483)] caused by non-embolic thrombosis (> 10 cm in length) of an infrainguinal graft or native In vitro retracted clots: greater lytic activity than t-PA after catheter injection [39] Distal abdominal aorta thrombosis (rabbit): equivalent to t-PA with unimpeded blood flow in aorta, superior in thrombolysis and flow restoration with impeded flow (limited plasminogen supply) [16] Arteriovenous graft thrombosis (porcine): superior thrombolysis than with t-PA [38] Middle cerebral artery thrombo-occlusion: effective thrombolysis [54] Ear-puncture bleeding model (rabbit): hemostatic safety at suprathrombolytic dosages, as compared with bleeding caused by t-PA at any therapeutic dosage [16,55,57]. No effect with systemic heparin aspirin [56] Mini-plasmin Femoral artery thrombosis (canine): greater efficacy than t-PA [58] Middle cerebral artery ligation (mouse, hamster): reduced ischemic injury after systemic administration [59] Micro-plasmin Extracorporeal loop thrombus (rabbit): equivalent efficacy to plasmin, slightly less than with t-PA; bleeding with t-PA only [49] Cerebral ischemia (rabbit, mouse, rat): systemic (not local administration) shows less intracranial hemorrhage than caused by t-PA, decreased cerebral injury as good or better than with t-PA, but question of adverse outcomes with higher dosages [59][60][61][62][63][64] Vitreolysis (cat, rabbit, pig): vitreous detachment induced by local injection [65][66][67]…”

The evolution of recombinant thrombolytics: Current status and future directions

“…16 It appears to have a comparable potency to full-length plasmin in vivo. 150 Microplasmin has been shown to reduce cerebral ischemic damage in animal models with lesser hemorrhage than t-PA. 152,153 During clinical trials too, intravenous microplasmin was generally well tolerated in patients with acute ischemic stroke. 154 Catheter malfunction due to thrombotic occlusion was overcome safely and effectively using microplasmin without any bleeding complications.…”