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Blood, 15 May 2001, Vol. 97, No. 10, pp. 3086-3092
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Depletion of circulating  2-antiplasmin by
intravenous plasmin or immunoneutralization reduces focal cerebral
ischemic injury in the absence of arterial recanalization
Nobus Nagai,
Maria De Mol,
Berthe Van Hoef,
Maria Verstreken, and
Désiré Collen
From the Center for Molecular and Vascular Biology and
Center for Transgene Technology and Gene Therapy, Flanders
Interuniversity Institute for Biotechnology, KU Leuven,
Leuven, Belgium.
In the absence of arterial recanalization, thrombolytic agents
induce a dose-related extension of focal cerebral ischemic injury (FII)
in experimental animals. However, FII is smaller in mice lacking
 2-antiplasmin (2-AP), the physiologic
inhibitor of plasmin, suggesting its depletion might reduce FII in the
absence of reperfusion. Therefore, the effect of human plasmin (Pli), human miniplasmin (mPli), and an Fab fragment neutralizing murine 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 FII after 24 hours was 28 µL (range, 20-34) (n = 10) with
saline and 23 µL (range, 17-26) (n = 9) with a single bolus of 0.07 mg Pli, given after MCA ligation (P = .010), which
reduced 2-AP to 44% and fibrinogen from 0.75 to 0.44 g/L. FII was 20 µL (range, 13-26) (n = 6, P = .025)
with 0.2 mg mPli and was 24 µL (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 bolus
injection of 1 mg Pli, after MCA ligation, depleted 2-AP and fibrinogen and reduced FII at 24 hours from 20 µL (range, 9.9-38)
(n = 6) to 7.0 µL (range, 0.44-31) (n = 7,
P = .032). Thus, reduction of circulating
2-AP, with a single bolus of plasmin or of a
neutralizing antibody fragment, significantly reduced FII after MCA
ligation in mouse and hamster models, suggesting that, provided these
observations can be extrapolated to human beings, transient depletion
of circulating 2-AP might reduce ischemic stroke in the
absence of reperfusion.
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