Retinoic Acid Enhances Fibrinolytic Activity In-Vivo by Enhancing Tissue Type Plasminogen Activator (t-PA) Activity and Inhibits Venous Thrombosis

J J J van Giezen; G d I A Boon; J W C M Jansen; B N Bouma

doi:10.1055/s-0038-1651616

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1993; 69(04): 381-386
DOI: 10.1055/s-0038-1651616

Original Article

Fibrinolysis

Schattauer GmbH Stuttgart

Retinoic Acid Enhances Fibrinolytic Activity In-Vivo by Enhancing Tissue Type Plasminogen Activator (t-PA) Activity and Inhibits Venous Thrombosis

J J J van Giezen

¹Solvay Duphar B. V., Dept. of Vascular Pharmacology, Weesp, The Netherlands

,

G d I A Boon

¹Solvay Duphar B. V., Dept. of Vascular Pharmacology, Weesp, The Netherlands

,

J W C M Jansen

¹Solvay Duphar B. V., Dept. of Vascular Pharmacology, Weesp, The Netherlands

,

B N Bouma

²University Hospital Utrecht, Dept. of Haematology, Utrecht, The Netherlands

› Author Affiliations

Abstract

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Summary

We studied the profibrinolytic effect and the anti-thrombotic potential of retinoic acid in-vivo. Male Wistar rats were treated with retinoic acid either acutely or twice daily for a period of 5 consecutive days in a dose range of 0.01 to 3.0 mg/kg. Fibrinolytic activity was measured ex-vivo using the diluted blood clot lysis test and net t-PA activity in tissue extracts was measured in a spectrophotometric rate assay. Clot lysis was dose dependently increased by retinoic acid up to about 170% (relative to vehicle treated rats) at a dose of 3 mg/kg. No tachyphylaxis could be detected. Ex-vivo measured fibrinolytic activity after single administration of 1 mg/kg of retinoic acid peaked at 3 h after ingestion. Even after 18 h a significantly higher clot lysis rate was measured. Lysis of blood clots from vehicle and retinoic acid treated rats could be completely blocked by addition of tranexamic acid or antibodies against rat t-PA before clot formation. t-PA activity in plasma was slightly increased after retinoic acid treatment; no effects were measured on plasma PAI-1, u-PA, plasminogen, and α₂-antiplasmin levels. t-PA activity in lung and kidney was marginally enhanced by retinoic acid but in heart and aortic tissue extracts t-PA activity was increased by about 50%. We confirmed this potential anti-thrombotic property in an in-vivo venous thrombosis model. A reduced clot size was observed after retinoic acid administration (35% reduction at a dose of 1 mg/kg). We could not detect any effect on ex-vivo measured platelet aggregation, bleeding time, prothrombin time, thrombin time, partial thromboplastin time or plasma fibrinogen level, indicating that there were no effects on platelet aggregation or blood coagulation. We conclude that retinoic acid enhanced fibrinolytic activity in-vivo by selectively enhancing t-PA activity and that retinoic acid is a potential anti-thrombotic agent in-vivo.

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References

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