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Recombinant human microplasmin: production and potential therapeutic properties

Summary.  The effect of recombinant human microplasmin was studied in ischemic stroke models in mice and in an extracorporeal loop thrombosis model in rabbits. Human microplasminogen (µPlg), which lacks the five ‘kringle’ domains of plasminogen was expressed with high yield in Pichia pastoris. It was purified, converted to microplasmin (µPli) and equilibrated with 5 mmol L−1 citrate, pH 3.1, yielding a stable preparation. In mice with middle cerebral artery (MCA) ligation, an intravenous (i.v.) bolus of 5.0 mg kg−1µPli reduced infarct size at 24 h from 27 (26–30) to 25 (21–28) mm3 (median and range, n= 16 each, P= 0.0001), whereas 4.0 mg kg−1 rt‐PA and 40 mg kg−1µPlg had no effect. Infarct reduction was observed with administration at 4 h after occlusion. In mice with MCA, infarct size at 24 h was reduced from 20 (14–30) to 9.1 (3.1–25) mm3 with 5.0 mg kg−1µPli (n = 15 each, P < 0.002) and to 11 (5.2–27) mm3 with 4.0 mg kg−1 rt‐PA (n = 6; P= 0.02). Infarct reduction was still observed at 10 h after occlusion with µPli but not with t‐PA. In rabbits with radiolabeled clots in an extracorporeal arteriovenous loop, local infusion of 2.5 mg kg−1µPli over 2 h, induced 51 ± 15% lysis (mean ± SD, n= 11) vs. a control value of 23 ± 5.5%. µPli did not prolong template bleeding times, whereas equipotent doses of rt‐PA were associated with extensive rebleeding. The potency of µPli in both models was similar to that of intact plasmin. These findings indicate that recombinant µPli may be useful for treatment of ischemic stroke and arterial thrombosis.