The Ability of Thrombin Inhibitors to Reduce the Thrombin Activity Generated in Plasma on Extrinsic and Intrinsic Activation

D Prasa; L Svendsen; J Stürzebecher

doi:10.1055/s-0038-1655996

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1997; 77(03): 498-503
DOI: 10.1055/s-0038-1655996

Coagulation

Schattauer GmbH Stuttgart

The Ability of Thrombin Inhibitors to Reduce the Thrombin Activity Generated in Plasma on Extrinsic and Intrinsic Activation

D Prasa

¹The Zentrum für Vaskuläre Biologie und Medizin, Klinikum der Friedrich-Schiller-Universität Jena, Germany

,

L Svendsen

²The Pentapharm Ltd., Basel, Switzerland

,

J Stürzebecher

¹The Zentrum für Vaskuläre Biologie und Medizin, Klinikum der Friedrich-Schiller-Universität Jena, Germany

› Author Affiliations

Abstract

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Summary

In a thrombin generation test with continuous registration of thrombin activity in plasma we studied the ability of a variety of thrombin inhibitors of different type and mechanism of action to influence the activity of thrombin after activation of the coagulation system. Depending on the inhibitor, the peak of thrombin activity is delayed and/or reduced.

By blocking the active site of generated thrombin inhibitors cause a concentration dependent reduction of the thrombin peak and inhibit feed-back reactions of thrombin resulting in a delay of thrombin generation. Highly potent synthetic active-site directed inhibitors (K_i ≤ 20 nM) reduce the thrombin activity formed in plasma after extrinsic or intrinsic activation with the same efficiency (IC₅₀ 0.1 - 0.6 μM) as hirudin. The delay and reduction of thrombin generation by inhibitors of the anion-binding exosite 1 of thrombin is only attributed to an inhibition of feed-back reactions of thrombin. For a 50% reduction of thrombin activity in plasma by this type of inhibitors relatively high concentrations were determined.

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References

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