Anti-factor IXa Aptamer reduces propagation of thrombin generation in plasma anticoagulated with warfarin

• Published in: Thrombosis research Vol. 125; no. 5; pp. 432 - 437
• Main Authors: Szlam, Fania, Luan, Deyan, Bolliger, Daniel, Szlam, Arthur D, Levy, Jerrold H, Varner, Jeffrey D, Tanaka, Kenichi A
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.05.2010; Elsevier
• Subjects: Anti-Factor IXa Aptamer; Anticoagulants - administration & dosage; Aptamers, Nucleotide - administration & dosage; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Coronary heart disease; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Dose-Response Relationship, Drug; Drug Combinations; Factor IXa - antagonists & inhibitors; Heart; Hematology, Oncology and Palliative Medicine; Humans; Medical sciences; Plasma - drug effects; Plasma - metabolism; Thrombin - metabolism; Thrombin Generation; Warfarin; Warfarin - administration & dosage; Warfarin; Thrombin Generation; Anti-Factor IXa Aptamer; Antivitamin K; Peptidases; Serine endopeptidases; Enzyme; Coumarine derivatives; Hydrolases; Cardiovascular disease; Thrombin; Anticoagulant
• ISSN: 0049-3848; 1879-2472
• DOI: 10.1016/j.thromres.2009.11.018

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 µg/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. Conclusion 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.