Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2005-12-20
pubmed:abstractText
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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Anticoagulants, http://linkedlifedata.com/resource/pubmed/chemical/Azetidines, http://linkedlifedata.com/resource/pubmed/chemical/Benzylamines, http://linkedlifedata.com/resource/pubmed/chemical/Factor Xa, http://linkedlifedata.com/resource/pubmed/chemical/Glycine, http://linkedlifedata.com/resource/pubmed/chemical/Hirudins, http://linkedlifedata.com/resource/pubmed/chemical/Peptide Fragments, http://linkedlifedata.com/resource/pubmed/chemical/Pipecolic Acids, http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Thrombin, http://linkedlifedata.com/resource/pubmed/chemical/Thromboplastin, http://linkedlifedata.com/resource/pubmed/chemical/argatroban, http://linkedlifedata.com/resource/pubmed/chemical/bivalirudin, http://linkedlifedata.com/resource/pubmed/chemical/lepirudin, http://linkedlifedata.com/resource/pubmed/chemical/melagatran
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0340-6245
pubmed:author
pubmed:issnType
Print
pubmed:volume
94
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
958-64
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:16363236-Animals, pubmed-meshheading:16363236-Anticoagulants, pubmed-meshheading:16363236-Azetidines, pubmed-meshheading:16363236-Benzylamines, pubmed-meshheading:16363236-Blood Coagulation, pubmed-meshheading:16363236-Cattle, pubmed-meshheading:16363236-Dose-Response Relationship, Drug, pubmed-meshheading:16363236-Factor Xa, pubmed-meshheading:16363236-Glycine, pubmed-meshheading:16363236-Hirudins, pubmed-meshheading:16363236-Humans, pubmed-meshheading:16363236-Partial Thromboplastin Time, pubmed-meshheading:16363236-Peptide Fragments, pubmed-meshheading:16363236-Pipecolic Acids, pubmed-meshheading:16363236-Prothrombin Time, pubmed-meshheading:16363236-Recombinant Proteins, pubmed-meshheading:16363236-Species Specificity, pubmed-meshheading:16363236-Thrombin, pubmed-meshheading:16363236-Thrombin Time, pubmed-meshheading:16363236-Thromboplastin
pubmed:year
2005
pubmed:articleTitle
Differences in the clinically effective molar concentrations of four direct thrombin inhibitors explain their variable prothrombin time prolongation.
pubmed:affiliation
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada. twarken@mcmaster.ca
pubmed:publicationType
Journal Article, Comparative Study, In Vitro, Research Support, Non-U.S. Gov't