Modifications of Extrinsic Pathway Inhibitor (EPI) and Factor Xa that Affect their Ability to Interact and to Inhibit Factor Vila/Tissue Factor: Evidence for a Two-Step Model of Inhibition

Bonnie J Warn-Cramer; L Vijaya Mohan Rao; Steven L Maki; Samuel I Rapaport

doi:10.1055/s-0038-1646989

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1988; 60(03): 453-456
DOI: 10.1055/s-0038-1646989

Original Article

Schattauer GmbH Stuttgart

Modifications of Extrinsic Pathway Inhibitor (EPI) and Factor Xa that Affect their Ability to Interact and to Inhibit Factor Vila/Tissue Factor: Evidence for a Two-Step Model of Inhibition

Authors

Bonnie J Warn-Cramer

The Departments of Medicine and Pathology, University of California at San Diego, La Jolla, CA, USA
L Vijaya Mohan Rao

The Departments of Medicine and Pathology, University of California at San Diego, La Jolla, CA, USA
Steven L Maki

The Departments of Medicine and Pathology, University of California at San Diego, La Jolla, CA, USA
Samuel I Rapaport

The Departments of Medicine and Pathology, University of California at San Diego, La Jolla, CA, USA

Abstract

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Summary

Inhibition of factor VIIa/tissue factor (TF) by extrinsic pathway inhibitor (EPI) requires the participation of factor Xa. Through this inhibition, factor Xa generated initially may feed back to suppress continuing generation of factor Xa via the extrinsic pathway during hemostasis. We have utilized chemical modifications of EPI and factor Xa to study the reactions responsible for inhibition. The data are consistent with a two-step model. First, EPI binds to factor Xa in a Ca²⁺ independent reaction in which the gla-domain of factor Xa does not participate. A functional active site on factor Xa and arginine residues on EPI are essential for this step. Then the factor Xa/EPI complex binds to factor VIIa/TF with resultant inhibition of its enzymatic activity. The gla-domain of factor Xa is essential for this step. Intact positively charged lysines on factor Xa may also be important

Keywords

Extrinsic pathway inhibitor - Tissue factor - Factor VIIa - Factor Xa - Γ-Carboxyglutamic acid

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References

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