title: Dabigatran attenuates thrombin generation to a lesser extent than warfarin: could this explain their differential effects on intracranial hemorrhage and myocardial infarction?
abstract: Compared with warfarin, dabigatran is associated with less intracranial hemorrhage, but an increased risk of myocardial infarction. To explore these phenomena, we compared their effects on thrombin generation. Thrombin generation in plasma from 10 patients taking therapeutic doses of warfarin (mean INR 2.6) was compared with that in plasma containing 250 ng/mL dabigatran. Although lag times were similar when thrombin generation was induced by recalcification or with a range of tissue factor concentrations, there was a greater reduction in peak thrombin generation and endogenous thrombin potential in plasma from warfarin-treated patients than in dabigatran-containing plasma. Similar results were obtained when thrombin generation was determined in plasma samples from 18 warfarin or 36 dabigatran treated patients entered into the RE-LY trial. Warfarin suppresses thrombin generation more efficiently than dabigatran. Greater suppression of normal hemostatic mechanisms in the brain and pathological thrombosis at sites of atherosclerotic plaque disruption may explain the higher rate of intracranial bleeding and lower rate of myocardial infarction with warfarin compared with dabigatran.
authors.affiliation: School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia.
authors.forename: Brian
authors.initials: B
authors.lastname: Dale
authors.forename: John W
authors.initials: JW
authors.lastname: Eikelboom
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Weitz
authors.forename: Ed
authors.initials: E
authors.lastname: Young
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Paikin
authors.forename: Michiel
authors.initials: M
authors.lastname: Coppens
authors.forename: Richard P
authors.initials: RP
authors.lastname: Whitlock
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Connolly
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ginsberg
authors.forename: Jack
authors.initials: J
authors.lastname: Hirsh
mesh_terms: D000925:Anticoagulants / Q000494:pharmacology / Q000627:therapeutic use; D000991:Antithrombins / Q000494:pharmacology / Q000627:therapeutic use; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D000069604:Dabigatran; D005260:Female; D006801:Humans; D020300:Intracranial Hemorrhages / Q000097:blood / Q000188:drug therapy*; D008297:Male; D009203:Myocardial Infarction / Q000097:blood / Q000188:drug therapy*; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014859:Warfarin / Q000494:pharmacology / Q000627:therapeutic use*; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000925:Anticoagulants; D000991:Antithrombins; D001562:Benzimidazoles; D015091:beta-Alanine; D014859:Warfarin; D013917:Thrombin; D000069604:Dabigatran