Summary
The aim of this study was to investigate the anti-thrombotic effects of an inhibitor
of the plasminogen activator inhibitor-1 (PAI-1) in rats given endotoxin. In studies
in vitro, PRAP-1, a Fab-fragment of a polyclonal antibody against human PAI-1, was
shown to inhibit PAI-1 activity in rat plasma as well as to stimulate clot-lysis of
the euglobulin fraction derived from rat plasma. Endotoxin administered to anaesthetised
rats produced a marked increase in plasma PAI-1 activity. To study fibrin formation
and lysis in vivo after intravenous (i. v.) injection of the coagulant enzyme batroxobin,
125I-fibrinogen was administered to the animals. The thrombi formed by batroxobin were
rapidly lysed in control animals, while the rate of lysis was markedly attenuated
in rats given endotoxin. PRAP-1 was administered i.v. (bolus + infusion) to rats given
endotoxin and batroxobin and the PAI-1 inhibitor caused a dose-dependent decrease
in the 125I-fibrin deposition in the lungs. An immunohistochemical technique was used to confirm
this decrease in density of fibrin clots in the tissue. Furthermore, PRAP-1 decreased
plasma PAI-1 activity in the rats and this reduction was correlated to the decrease
in lung 125I-fibrin deposition at the corresponding time point. It is concluded that in this
experimental model the PAI-1 antibody PRAP-1 may indeed inhibit thrombosis in animals
exposed to endotoxin.
