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Background and Purpose Plasmin is a direct-acting thrombolytic (DAT) agent with a striking hemostatic safety advantage over plasminogen activators (PA) in animal models of thrombolysis and bleeding. In contradistinction to PAs, which risk bleeding at any effective thrombolytic dose, plasmin is tolerated without bleeding at several-fold higher amounts than needed for thrombolysis. Plasmin has been safe in a current trial in patients with peripheral arterial or graft occlusion, and efforts are now directed towards therapy of stroke caused by cerebral artery occlusion. Methods A rabbit (4 kg body weight) model of 2-hour, thrombin-induced middle cerebral artery (MCA) occlusion using angiographic documentation of vascular patency and recanalization was utilized to perform a dose-ranging study of plasmin, delivered by catheter over a median duration of 10 minutes. Results Plasmin induced early recanalization in all animals (3 per group) within 10 minutes after discontinuation of 3, 2, or 1 mg of agent infusion. Control saline infusion failed to induce recanalization in 3 of 3 subjects. Conclusions Plasmin rapidly induces MCA recanalization, as determined in an angiogram-based animal model of arterial occlusion. Based on these data and other information, a phase 1/2a clinical trial of plasmin in human MCA ischemic stroke has been initiated.

Background and purpose Plasmin is a direct-acting thrombolytic with a better safety profile than recombinant tissue-type plasminogen activator (rt-PA) in animal models. With the application of retrieval devices for managing acute ischemic stroke, extracted thromboemboli are available for ex vivo examination. We ask whether such thrombi are amenable to plasmin thrombolysis and whether such activity is different with rt-PA. Methods Thromboembolic fragments (total 29) were retrieved from the intracranial carotid artery system of 15 patients with acute ischemic stroke and randomly assigned to ex vivo thrombolysis with plasmin or rt-PA. After an initial 2-hour exposure, residual material was exposed to the other agent for an additional 2 hours. Thrombolysis was quantified by change in thrombus area and released D-dimer. Results Plasmin induced significant ex vivo thrombolysis of cerebral arterial thromboemboli, decreasing area by 45.9 +/− 29.4% and 69.2 +/− 52.5% and inducing median D-dimer release of 108,180 μg/L (range 16,780 - 668,050 μg/L) and 16,905 μg/L (range 240 - 403,085 μg/L) during the first and second 2-hour incubation periods, respectively. These changes were not different from those obtained with rt-PA, which decreased area by 34.7 +/− 57.8% (P=0.63) and by 68.4 +/− 26.9% (P=0.97), and induced median D-dimer release of 151,990 μg/L (9,870 - 338,350 μg/L) (P=0.51) and 34,520 μg/L (range 3,794 - 325,400 μg/L) (P=0.19), during the first and second 2-hour incubations. Conclusions Retrieved human cerebral thromboemboli were amenable to ex vivo lysis by plasmin, the rate and degree of which was not different than that achieved with rt-PA.

Twenty-five cats at a private animal sanctuary received multiple nonimmunosuppressive doses of parenteral methylprednisolone acetate for at least 3 yr. Complete blood count, chemistry, and T4 results from these cats were examined to look for statistically significant changes. Results found significant changes in triglycerides, amylase, and monocytes. However, these changes remained within the reference interval. All other values showed no significant changes. These results suggest that after 3 yr of chronic parenteral administration of nonimmunosuppressive doses of methylprednisolone acetate, the complete blood count, chemistry, and T4 values in 25 cats were not significantly affected and did not result in abnormal laboratory values.