title: Anti-factor IXa Aptamer reduces propagation of thrombin generation in plasma anticoagulated with warfarin.
abstract: BACKGROUND
  Warfarin is routinely used in the prevention and treatment of prothrombotic events. During initiation of warfarin therapy levels of factor (F) VII and protein C decrease rapidly but prothrombin, FIX and FX decline much slower. Therefore, propagation of thrombin generation (TG) remains unaffected much longer, increasing the risk of inadequate anticoagulation. Recently, a novel agent, anti-IXa aptamer, RB006, has been developed. Therefore, we have evaluated the in vitro effects of this agent in warfarin plasma.
  
  
  METHODS
  The investigation consisted of two parts. First, a computer simulated time course of TG with warfarin alone and in combination with FIXa inhibition was evaluated and, second, normal volunteer, protein C deficient, FVII deficient and commercial warfarin plasmas (INR 2.1 and 3.1) were spiked with increasing concentrations of aptamer (0-24 microg/ml) and its anticoagulant effects were evaluated using prothrombin time (PT), activated partial thromboplastin time (aPTT) and TG with tissue factor and Actin as activators. Direct effects of aptamer on protein C were also evaluated.
  
  
  RESULTS
  Simulation of coagulation during warfarin induction showed that TG can be significantly delayed and decreased by inhibiting FIXa (i.e., with anti-FIXa aptamer). The anti-FIXa aptamer inhibited TG in all tested plasmas, but was most efficacious in warfarin and FVII deficient plasma. The aptamer itself did not inhibit protein C and had no effect on PT, but concentration-dependently increased aPTT.
  
  
  CONCLUSIONS
  The anti-FIXa aptamer potentiates the inhibitory effects of warfarin on TG, and may fill the need as an adjuvant agent during initiation of warfarin therapy.
authors.affiliation: Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Fania
authors.initials: F
authors.lastname: Szlam
authors.forename: Deyan
authors.initials: D
authors.lastname: Luan
authors.forename: Daniel
authors.initials: D
authors.lastname: Bolliger
authors.forename: Arthur D
authors.initials: AD
authors.lastname: Szlam
authors.forename: Jerrold H
authors.initials: JH
authors.lastname: Levy
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Varner
authors.forename: Kenichi A
authors.initials: KA
authors.lastname: Tanaka
mesh_terms: D000925:Anticoagulants / Q000008:administration & dosage*; D052157:Aptamers, Nucleotide / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D015949:Factor IXa / Q000037:antagonists & inhibitors*; D006801:Humans; D010949:Plasma / Q000187:drug effects* / Q000378:metabolism*; D013917:Thrombin / Q000378:metabolism*; D014859:Warfarin / Q000008:administration & dosage*
chemical_list: D000925:Anticoagulants; D052157:Aptamers, Nucleotide; D004338:Drug Combinations; C515724:RB 006; D014859:Warfarin; D015949:Factor IXa; D013917:Thrombin