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Thromb Haemost 1997; 77(05): 0964-0969
DOI: 10.1055/s-0038-1656086
Fibrinolysis
Schattauer GmbH Stuttgart

The Fab-fragment of a PAI-1 Inhibiting Antibody Reduces Thrombus Size and Restores Blood Flow in a Rat Model of Arterial Thrombosis

J J J van Giezen
The Department of Pharmacology CV, Astra Hässle AB, Mölndal, Sweden
,
G Wahlund
The Department of Pharmacology CV, Astra Hässle AB, Mölndal, Sweden
,
V Nerme
The Department of Pharmacology CV, Astra Hässle AB, Mölndal, Sweden
,
T Abrahamsson
The Department of Pharmacology CV, Astra Hässle AB, Mölndal, Sweden
› Author Affiliations
Further Information

Publication History

Received 19 June 1996

Accepted after resubmission 20 December 1996

Publication Date:
26 July 2018 (online)

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Summary

The effect of PRAP-1, a Fab-fragment of a PAI-1 -inhibiting polyclonal antibody, on thrombus size and arterial blood flow was studied in a rat model of arterial thrombosis. It was shown that exposure of the carotid artery to FeCl3 led to the rapid formation of an occlusive thrombus with a morphology similar to that of arterial thrombi found in humans. Tranexamic acid (50 mg/kg), an inhibitor of fibrinolysis, increased thrombus size (p = 0.014) when given intravenously (i.v.) prior to the FeCl3-exposure. Heparin (1000 U), when given i.v. after FeCl3, did not affect the thrombus size per se, but caused a reduction in the interindividual variation of the size of the thrombus (p <0.05). Thus, heparin was included in all the subsequent experiments. An i.v. infusion of t-PA (1 mg/kg/h), starting before thrombus formation, induced a 3.3 fold increase in the perfusion rate (p = 0.006) and a 67% reduction in the thrombus size (p <0.001). PRAP-1, an inhibitor of rat PAI-1 activity, was given i.v. as a bolus followed by an infusion. Two doses of PRAP-1 were studied (7.5 and 15 mg/kg/h), and the administration of the PAI-1 inhibitor was started 10 min before FeCl3. The lower PRAP-1 dose caused a 3.8 fold increase in perfusion rate (p = 0.036), a 1.44 fold increase in the time to occlusion (p = 0.034), and the thrombus size was decreased by 18% (p = 0.104). The corresponding effects of the high PRAP-1 dose were a 6.5 fold increase in perfusion rate (p <0.001), a 1.6 fold increase in time to occlusion (p = 0.038) and a 32% reduction in thrombus size (p = 0.016). It is concluded that an inhibitor of PAI-1 activity, PRAP-1, caused a moderate decrease in thrombus size and partly restores blood flow in a rat model of arterial thrombosis. This finding suggests a potential role for an inhibitor of PAI-1 in the treatment of arterial thrombosis.

 

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