title: Differences in the clinically effective molar concentrations of four direct thrombin inhibitors explain their variable prothrombin time prolongation.
abstract: 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 micromol/l; melagatran, 0.5 micromol/l; bivalirudin, 0.25 micromol/l; lepirudin, 0.06 micromol/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 micromol/l) and argatroban (3.2 micromol/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 micromol/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.
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada. twarken@mcmaster.ca
authors.forename: Theodore E
authors.initials: TE
authors.lastname: Warkentin
authors.forename: Andreas
authors.initials: A
authors.lastname: Greinacher
authors.forename: Sharon
authors.initials: S
authors.lastname: Craven
authors.forename: Lori
authors.initials: L
authors.lastname: Dewar
authors.forename: Jo-Ann I
authors.initials: JA
authors.lastname: Sheppard
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Ofosu
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D001120:Arginine / Q000031:analogs & derivatives; D001384:Azetidines; D001596:Benzylamines; D001777:Blood Coagulation / Q000187:drug effects*; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006629:Hirudins / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D010314:Partial Thromboplastin Time; D010446:Peptide Fragments / Q000494:pharmacology; D010875:Pipecolic Acids / Q000494:pharmacology; D011517:Prothrombin Time; D011994:Recombinant Proteins / Q000494:pharmacology; D013045:Species Specificity; D013449:Sulfonamides; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013918:Thrombin Time; D013925:Thromboplastin / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D065427:Factor Xa Inhibitors; D006629:Hirudins; D010446:Peptide Fragments; D010875:Pipecolic Acids; D011994:Recombinant Proteins; D013449:Sulfonamides; C109573:melagatran; D013925:Thromboplastin; D001120:Arginine; D013917:Thrombin; D015951:Factor Xa; C031942:argatroban; D005998:Glycine; C074619:bivalirudin; C083544:lepirudin