Anti-factor IXa Aptamer reduces propagation of thrombin generation in plasma anticoagulated with warfarin.
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.
Szlam
Fania
F
Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Luan
Deyan
D
Bolliger
Daniel
D
Szlam
Arthur D
AD
Levy
Jerrold H
JH
Varner
Jeffrey D
JD
Tanaka
Kenichi A
KA
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*
D000925:Anticoagulants; D052157:Aptamers, Nucleotide; D004338:Drug Combinations; C515724:RB 006; D014859:Warfarin; D015949:Factor IXa; D013917:Thrombin