Differences in the clinically effective molar concentrations of four direct thrombin inhibitors explain their variable prothrombin time prolongation

Theodore E. Warkentin; Andreas Greinacher; Sharon Craven; Lori Dewar; Jo-Ann I. Sheppard; Frederick A. Ofosu

doi:10.1160/TH05-03-0154

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2005; 94(05): 958-964
DOI: 10.1160/TH05-03-0154

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Differences in the clinically effective molar concentrations of four direct thrombin inhibitors explain their variable prothrombin time prolongation

Theodore E. Warkentin

¹Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada

,

Andreas Greinacher

²Department of Immunology and Transfusion Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany

,

Sharon Craven

³Canadian Blood Services, Hamilton, Ontario, Canada

,

Lori Dewar

³Canadian Blood Services, Hamilton, Ontario, Canada

,

Jo-Ann I. Sheppard

¹Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada

,

Frederick A. Ofosu

¹Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada

³Canadian Blood Services, Hamilton, Ontario, Canada

› Author Affiliations

Abstract

Summary

Four direct thrombin inhibitors (DTIs), lepirudin, bivalirudin, argatroban, and melagatran, differ in their ability to prolong the prothrombin time (PT). Paradoxically, the DTI in clinical use with the lowest affinity for thrombin (argatroban) causes the greatest PT prolongation. We compared the effects of these DTIs on various clotting assays and on inhibition of human and bovine factor Xa (FXa). On a mole-for-mole basis, lepirudin was most able to prolong the PT, activated partial thromboplastin time (APTT), and thrombin clotting time (TCT), whereas argatroban had the least effect. At concentrations that doubled the APTT (argatroban, 1 μmol/l; melagatran, 0.5 μmol/l; bivalirudin, 0.25 μmol/l; lepirudin, 0.06 μmol/l), the rank order for PT prolongation was: argatroban > melagatran > bivalirudin > lepirudin. Although the Ki’s associated with inhibition of human FXa by melagatran (1.4 μmol/l) and argatroban (3.2 μmol/l) approach their therapeutic concentrations, inhibition of FXa did not appear to be a major contributor to PT prolongation, since argatroban also prolonged the PT of bovine plasma (despite a Ki for bovine FXa of 2,600 μmol/l). Only melagatran inhibited prothrombinase-bound FXa. We conclude that the differing effects of the DTIs on PT prolongation are primarily driven by their respective molar plasma concentrations required for clinical effect. DTIs with a relatively low affinity for thrombin require high plasma concentrations to double the APTT; these higher plasma concentrations, in turn, quench more of the thrombin generated in the PT, thereby more greatly prolonging the PT.

Keywords

Argatroban - melagatran - bivalirudin - lepirudin - factor Xa - INR

Full Text

References

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