INTRODUCTION Warfarin, a vitamin K antagonist (VKA), is commonly used to prevent thromboembolic events in patients with atrial fibrillation (AF) venous thromboembolism (VTE) or mechanical heart valve (1-4). However, VKA therapy is challenging because of its narrow therapeutic index combined with the wide inter-individual dosing variation. The efficacy and safety of warfarin treatment are highly dependent on the time for which the international normalized ratio (INR) is in the therapeutic range (TTR) (5). Factors influencing the TTR quality have been identified mostly in AF patients (5, 6). The risk of death, bleeding, myocardial infarction or stroke has been related to the quality of the INR control and was higher in patients with TTR < 60% (6). In recently published study on patients with mechanical heart valves, the risk of complications including bleeding and death but not thromboembolism has been significantly higher at lower TTR levels (7). In turn, AF patients who had TTR>75% were more frequently male, treated with rate control alone, and were less likely to suffer from heart failure, diabetes, myocardial infarction, and hepatic or renal failure (8). A maintenance dose of VKA depends on several factors predominantly diet but also age, body weight, concomitant medications and genetic polymorphisms (9). It has been proven by several studies that polymorphisms in two genes: vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 (CYP) 2C9 explain up to 50% of warfarin dosing variations (10-12). VKORC1 recycles oxidized vitamin K to the reduced form (KH 2 ) which is an essential cofactor for activation of clotting factors through their post-translational modification by conversion of glutamic acid to γ-carboxyglutamic acid (13). VKAs exert their anticoagulant effect by inhibition of vitamin K regeneration by VKORC1, and thereby reduce the synthesis of γ-carboxylated blood coagulation factors (14). Single nucleotide polymorphism (SNP) in the promoter region c.-1639 G>A of VKORC1 was identified as a marker for low dose of warfarin requirement (15). In turn, CYP2C9 is the major enzyme involved in the metabolism of the VKAs. Allelic variants of CYP2C9, CYP2C9*2 (p.Arg144Cys, c.430C>T) and CYP2C9*3 (p.Ile359Leu, c.1075A>C), code for enzymes with reduced activity and result in decreases by 15 – 20% and 30 – 40%, respectively, in the stable warfarin dose requirement relative to the wild type genotype CYP2C9*1*1 (16). The carriers of CYP2C9*2 allele and/or CYP2C9*3, who represent 10% and 6% of the European population, respectively, have an increased risk of bleeding complications, especially at the beginning of anticoagulation therapy and need longer time to stabilize the VKAs dose (17). Other genes polymorphisms including cytochrome P450 4F2 isoform (CYP4F2*3), apolipoprotein E (APOE), γ-glutamyl carboxylase (GGCX) or human multidrug resistance gene (MDR1) JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 2016, 67, 3, 385-393 www.jpp.krakow.pl E. WYPASEK 1,2 , P. MAZUR 1,2 , M. BOCHENEK 2 , M. AWSIUK 2 , G. GRUDZIEN 1,2 , D. PLICNER 2 , A. UNDAS 1,2 FACTORS INFLUENCING QUALITY OF ANTICOAGULATION CONTROL AND WARFARIN DOSAGE IN PATIENTS AFTER AORTIC VALVE REPLACEMENT WITHIN THE 3 MONTHS OF FOLLOW UP 1 Institute of Cardiology, Jagiellonian University School of Medicine, Cracow, Poland; 2 John Paul II Hospital, Cracow, Poland Warfarin dosage estimation using the pharmacogenetic algorithms has been shown to improve the quality of anticoagulation control in patients with atrial fibrillation. We sought to assess the genetic, demographic and clinical factors that determine the quality of anticoagulation in patients following aortic valve replacement (AVR). We studied 200 consecutive patients (130 men) aged 63 ± 12.3 years, undergoing AVR, in whom warfarin dose was established using a pharmacogenetic algorithm. The quality of anticoagulation within the first 3 months since surgery was expressed as the time of international normalized ratio (INR) in the therapeutic range (TTR). The median TTR in the entire cohort was 59.6% (interquartile range, 38.7 – 82.7). Ninety-nine (49.5%) patients with TTR ≥ 60% did not differ from those with poor anticoagulation control (TTR < 60%) with regard to demographic and cardiovascular risk factors. Coronary artery disease (n = 84, 42%) and previous stroke (n = 5, 2.5%) predicted higher TTR, while possession of CYP2C9*2 variant allele (n = 49, 25%) was associated with lower TTR (P = 0.01). In turn, VKORC1 c.-1639A, CYP2C9*2 and *3 variants were independently associated with actual warfarin dose (P < 0.0001). In AVR patients better anticoagulation control is observed in patients with coronary artery disease and history of stroke, which might result in part from previous lifestyle modification and therapy. Possession of CYP2C9*2 and/or CYP2C9*3 allele variants is associated with lower TTR values and warfarin dose variations in AVR patients, the latter affected also by VKORC1 c.-1693G>A polymorphism. Key words: aortic valve replacement, coronary artery disease, warfarin, pharmacogenetic algorithm, cytochrome P450 (CYP) 2C9, therapeutic range, atrial fibrillation, clotting factors