title: Effects of lepirudin, argatroban and melagatran and additional influence of phenprocoumon on ecarin clotting time.
abstract: BACKGROUND
  Direct thrombin inhibitors (DTI) prolong the ecarin clotting time (ECT). Oral anticoagulants (OA) decrease prothrombin levels and thus interact with actions of DTIs on the ECT method during concomitant therapy.
  
  
  METHODS
  Actions of lepirudin, argatroban and melagatran on ECT were investigated in normal plasma (NP) and in plasma of patients (n=23 each) on stable therapy with phenprocoumon (OACP). Individual line characteristics were tested statistically.
  
  
  RESULTS
  Control ECT in OACP was prolonged compared to NP (50.1+/-0.9 vs. 45.7+/-0.8 s; p<0.001). Lepirudin prolonged the ECT linearly. Argatroban and melagatran delivered biphasic dose-response curves. OA showed additive effects on the ECT of lepirudin but not of argatroban and melagatran. Both in NP and OACP, the first and second slopes of melagatran were steeper compared to argatroban (primary analysis; p<0.001). When using the same drug, slopes in OACP were steeper than in NP (secondary analysis; p<0.001). At similar molar concentrations, the crossing points of both slopes were significantly higher with melagatran (323.1+/-11.0 s in NP and 333.2+/-8.2 s in OACP) than with argatroban (219.6+/-14.7 and 248.4+/-15.2 s) corresponding to ratios of 7.1+/-0.2 and 6.7+/-0.2 (melagatran) vs. 4.8+/-0.3 and 4.9+/-03 with argatroban (p<0.0001).
  
  
  CONCLUSIONS
  The patterns of interactions between vitamin K antagonists and DTI effects are different for bivalent (increase of slope without affecting linearity) and monovalent inhibitors (slight increase or alteration of nonlinear slopes), but there are also differences between the two monovalent inhibitors on thrombin inhibition as determined by ECT.
authors.affiliation: Fourth Department of Medicine, University Hospital Mannheim, Theodor Kutzer Ufer 1-3, 68167 Mannheim, Germany. tivadar.fenyvesi@med.ma.uni-heidelberg.de
authors.forename: Tivadar
authors.initials: T
authors.lastname: Fenyvesi
authors.forename: Ingrid
authors.initials: I
authors.lastname: Jörg
authors.forename: Christel
authors.initials: C
authors.lastname: Weiss
authors.forename: Job
authors.initials: J
authors.lastname: Harenberg
mesh_terms: D000925:Anticoagulants / Q000494:pharmacology; D001384:Azetidines; D001596:Benzylamines; D001777:Blood Coagulation / Q000187:drug effects*; D001780:Blood Coagulation Tests; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006629:Hirudins / Q000031:analogs & derivatives / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D010045:Outpatients; D010644:Phenprocoumon / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology*; D012016:Reference Values
chemical_list: D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D005343:Fibrinolytic Agents; D006629:Hirudins; D011994:Recombinant Proteins; C109573:melagatran; D010644:Phenprocoumon; D005998:Glycine; C083544:lepirudin