Anti-thrombotic Effect of a PAI-1 Inhibitor in Rats Given Endotoxin

T Abrahamsson; V Nerme; M Strömqvist; B Åkerblom; A Legnehed; K Pettersson; A Westin Eriksson

doi:10.1055/s-0038-1650231

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1996; 75(01): 118-126
DOI: 10.1055/s-0038-1650231

Original Article

Schattauer GmbH Stuttgart

Anti-thrombotic Effect of a PAI-1 Inhibitor in Rats Given Endotoxin

T Abrahamsson

¹The Department of Pharmacology CV, Astra Hässle AB, Mölndal, Sweden

,

V Nerme

¹The Department of Pharmacology CV, Astra Hässle AB, Mölndal, Sweden

,

M Strömqvist

¹The Department of Pharmacology CV, Astra Hässle AB, Mölndal, Sweden

,

B Åkerblom

¹The Department of Pharmacology CV, Astra Hässle AB, Mölndal, Sweden

,

A Legnehed

¹The Department of Pharmacology CV, Astra Hässle AB, Mölndal, Sweden

,

K Pettersson

¹The Department of Pharmacology CV, Astra Hässle AB, Mölndal, Sweden

,

A Westin Eriksson

¹The Department of Pharmacology CV, Astra Hässle AB, Mölndal, Sweden

› Author Affiliations

Abstract

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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.

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References

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