Depletion of circulating alpha(2)-antiplasmin by intravenous plasmin or immunoneutralization reduces focal cerebral ischemic injury in the absence ofarterial recanalization

In the absence of arterial recanalization, thrombolytic agents induce a dos e-related extension of focal cerebral ischemic injury (FII) in experimental animals. However, Fil is smaller in mice lacking alpha (2)-antiplasmin (al pha (2)-AP), the physiologic inhibitor of plasmin, suggesting its depletion might reduce FII in the absence of reperfusion. Therefore, the effect of h uman plasmin (Pli), human miniplasmin (mPli), and an Fab fragment neutraliz ing murine alpha (2)-AP (Fab-4H9) on FII after middle cerebral artery (MCA) ligation was studied in mice and in hamsters. In BALB/c mice, the median F II after 24 hours was 28 muL (range, 20-34) (n = 10) with saline and 23 muL (range, 17-26) (n = 9) with a single bolus of 0.07 mg Pli, given after MCA ligation (P =.010), which reduced alpha (2)-AP to 44% and fibrinogen from 0.75 to 0.44 g/L. FII was 20 muL (range, 13-26) (n = 6, P =.025) with 0.2 m g mPli and was 24 rhoL (range, 20-27) (n = 6, P =.020) with 1.7 mg Fab-4H9. Neuronal atrophy and reduction of laminin immunoreactivity were comparably observed in the infarct area after saline and Pli. In hamsters, a single b olus injection of 1 mg Pli, after MCA ligation, depleted alpha (2)-AP and f ibrinogen and reduced Fil at 24 hours from 20 muL (range, 9.9-38) (n = 6) t o 7.0 muL (range, 0.44-31) (n = 7, P =.032). Thus, reduction of circulating alpha (2)-AP, with a single bolus of plasmin or of a neutralizing antibody fragment, significantly reduced FII after MCA ligation in mouse and hamste r models, suggesting that, provided these observations can be extrapolated to human beings, transient depletion of circulating alpha (2)-AP might redu ce ischemic stroke in the absence of reperfusion. (Blood. 2001;97:3086-3092 ) (C) 2001 by The American Society of Hematology.