Summary
The effects of human recombinant plasminogen activator inhibitor (rPAI-1) on thrombolysis
with recombinant tissue-type plasminogen activator (rt-PA) were studied in a rabbit
model of jugular vein thrombosis. Two functionally distinct rPAI-1 preparations were
used in these experiments, including latent rPAI-1 (~2 units of t-PA neutralizing
activity per µg protein) and reactivated rPAI-1 (~150 units/µg).
Simultaneous intravenous infusion over 4 h of 1.7 mg/kg of reactivated rPAI-1 (inhibitory
capacity ~0.5 mg/kg rt-PA) with 0.5 mg/kg of rt-PA completely prevented lysis of a
jugular venous thrombus, whereas an equivalent amount of latent PAI-1 did not significantly
influence clot lysis. These findings demonstrate that reactivated human rPAI-1 efficiently
neutralizes thrombolysis with rt-PA in vivo. Since previous studies have suggested
that elevated endogenous levels of PAI-1 do not attenuate the thrombolytic potency
of rt-PA in the endotoxin-treated model, we compared the stability of complexes formed
by 125I-rt-PA with reactivated human rPAI-1 and with rabbit PAI-1 in vitro. Our findings
indicate that both forms of PAI-1 form SDS-stable complexes following incubation with
125I-rt-PA. Thus, it seems likely that elevated levels of active PAI-1 can negate the
thrombolytic effects of rt-PA in vivo and argues against the possibility that t-PA
can dissociate from PAI-1 and have its activity restored in the presence of a thrombus.
We propose that the present model may be a valuable tool in monitoring and evaluating
the in vivo thrombolytic efficacy of various t-PA mutants designed to be less sensitive
to the inhibitory effects of PAI-1.
