title: Acenocoumarol Pharmacogenetic Dosing Algorithms and Their Application in Two Bulgarian Patients with Low Anticoagulant Requirements.
abstract: BACKGROUND
  The anticoagulant therapy with acenocoumarol is generally associated with a high risk of bleeding and thromboembolic events.
  
  
  OBJECTIVE
  We applied eight already existing acenocoumarol dosing algorithms to Bulgarian patients with low acenocoumarol dose requirements and investigated which of these algorithms would predict most precisely the dose anticoagulant.
  
  
  METHODS
  Two patients with Bulgarian origin were referred to the outpatient clinical laboratory of "St. Ekaterina" University Hospital for Cardiovascular Surgery and Cardiology, Sofia, Bulgaria. After obtaining written informed consent, both patients were genotyped for polymorphisms in genes for Cytochrome P450 2C9 (CYP2C9), Vitamin K epoxide reductase (VKORC1), Apolipoprotein E (APOE), and Cytochrome P450 4F2 (CYP4F2).
  
  
  RESULTS
  All applied acenocoumarol dosing algorithms predicted relatively similar doses of coumarin anticoagulant in both patients. However, van Schie et al.'s algorithm allowed more accurate calculation of the optimal dose in our patients with extremely low acenocoumarol requirements. Genotyping of selected polymorphic variants in CYP2C9 and VKORC1 showed that both patients were compound heterozygotes for CYP2C9 (CYP2C9*2/*3) and homozygotes for both variants in VKORC1 (VKORC1 1173 T/T, and VKORC1-1639 A/A). This combination of genotypes suggested high sensitivity to acenocoumarol leading to the low anticoagulant dose requirements (0.25 and 1 mg/day, respectively) needed to reach the target International Normalized Ratio of 2.5-3.5.
  
  
  CONCLUSIONS
  The genotyping of polymorphic variants in VKORC1 and CYP2C9, together with clinical and demographic parameters, can serve for more precise definition of the individual starting and maintenance doses of coumarin derivatives in each patient.
authors.affiliation: Department of Clinical Laboratory, University Hospital of Cardiovascular Surgery and Cardiology "St. Ekaterina"- Sofia, 52A Pencho Slaveykov bul., 1431, Sofia, Bulgaria.
authors.forename: Antoaneta
authors.initials: A
authors.lastname: Dimitrova-Karamfilova
authors.affiliation: Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical Faculty, Medical University - Sofia, 2 Zdrave str, 1431, Sofia, Bulgaria. renitzveova@abv.bg.
authors.forename: Reni
authors.initials: R
authors.lastname: Tzveova
authors.affiliation: Department of Clinical Laboratory, University Hospital of Cardiovascular Surgery and Cardiology "St. Ekaterina"- Sofia, 52A Pencho Slaveykov bul., 1431, Sofia, Bulgaria.
authors.forename: Nezabravka
authors.initials: N
authors.lastname: Chilingirova
authors.affiliation: Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical Faculty, Medical University - Sofia, 2 Zdrave str, 1431, Sofia, Bulgaria.
authors.forename: Teodora
authors.initials: T
authors.lastname: Goranova
authors.affiliation: Department of Cardiovascular Surgery, University Hospital of Cardiovascular Surgery and Cardiology "St. Ekaterina"- Sofia, 52A Pencho Slaveykov bul., 1431, Sofia, Bulgaria.
authors.forename: Gencho
authors.initials: G
authors.lastname: Nachev
authors.affiliation: Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical Faculty, Medical University - Sofia, 2 Zdrave str, 1431, Sofia, Bulgaria.
authors.forename: Vanio
authors.initials: V
authors.lastname: Mitev
authors.affiliation: Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical Faculty, Medical University - Sofia, 2 Zdrave str, 1431, Sofia, Bulgaria.
authors.forename: Radka
authors.initials: R
authors.lastname: Kaneva
mesh_terms: D000074:Acenocoumarol / Q000627:therapeutic use*; D000465:Algorithms; D000925:Anticoagulants / Q000627:therapeutic use*; D001021:Aortic Valve / Q000601:surgery*; D002031:Bulgaria; D003374:Coumarins / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D008943:Mitral Valve / Q000601:surgery*; D010597:Pharmacogenetics / Q000379:methods; D020641:Polymorphism, Single Nucleotide; D013923:Thromboembolism / Q000188:drug therapy*
chemical_list: D000925:Anticoagulants; D003374:Coumarins; C030123:coumarin; D000074:Acenocoumarol
keywords: Acenocoumarol; Bulgarian patients; CYP2C9; Extremely low dose; VKORC1