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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
1   Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
,
Andreas Greinacher
2   Department of Immunology and Transfusion Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany
,
Sharon Craven
3   Canadian Blood Services, Hamilton, Ontario, Canada
,
Lori Dewar
3   Canadian Blood Services, Hamilton, Ontario, Canada
,
Jo-Ann I. Sheppard
1   Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
,
Frederick A. Ofosu
1   Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
3   Canadian Blood Services, Hamilton, Ontario, Canada
› Author Affiliations Financial support: Heart and Stroke Foundation of Ontario (grants #T-5207 [TEW] and #T-5203 [FAO]) and the Bundesministerium für Bildung und Forschung (German Federal Ministry for Education and Research; CAN04/006; NBL3 program, reference 01-ZZ0103 [AG]).
Further Information

Publication History

Received: 04 March 2005

Accepted after resubmission: 31 August 2005

Publication Date:
14 December 2017 (online)

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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
 

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