title: Extreme sensitivity to acenocoumarol therapy in patient with both VKORC.-1639 A/A and CYP2C9*1/*3 genotypes.
abstract: The initiation phase of vitamin K antagonist (VKA) is a challenging and demanding process that can result in adverse event such as bleeding. Dosing is influenced by a variety of acquired factors, while another factor that is associated with the optimal dose is the presence of certain genetic variants. We describe a 73 years old male who required extremely low dose of acenocoumarol (0.33 mg/day) to reach the target INR of 2-2.5. During initiation of VKA he started with usually recommended doses of acenocoumarol: 4 mg/day for the first 2 days and 3 mg/day during next 2 days. On fifth day of initiation, massive haematuria occurred and INR level of 10.5 was recorded. Patient was transfused with three doses of fresh frozen plasma in order to stop the bleeding. Acenocoumarol dose was gradually reduced after every INR laboratory monitoring and finally a dose of 0.33 mg/day was required for maintain stable anticoagulation. The genotyping results performed after introducing of VKA showed the patient was homozygous for vitamin K epoxide reductase (VKORC1) c.-1639 G>A, and heterozygous for cytochrome P450 2C9 (CYP2C9)*3 which pointed to extreme sensitivity to acenocoumarol. Our case supports the need for prospective genotyping of CYP2C9 and VKORC1 prior to initiation of VKA where pharmacogenetics, as a good predictor of extreme sensitivity to VKA, could help to tailor optimal VKA dose.
authors.affiliation: Blood Transfusion Institute of Serbia, Hemostasis Department, Sv. Sava 39, Belgrade, Serbia. mkovac008@gmail.com
authors.forename: Mirjana K
authors.initials: MK
authors.lastname: Kovac
authors.forename: Ljiljana B
authors.initials: LB
authors.lastname: Rakicevic
authors.forename: Dragica P
authors.initials: DP
authors.lastname: Radojkovic
mesh_terms: D000074:Acenocoumarol / Q000008:administration & dosage / Q000009:adverse effects*; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D016913:Blood Component Transfusion; D065729:Cytochrome P-450 CYP2C9; D006417:Hematuria / Q000139:chemically induced* / Q000235:genetics* / Q000628:therapy; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics*; D017354:Point Mutation; D064417:Vitamin K Epoxide Reductases
chemical_list: D000925:Anticoagulants; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D000074:Acenocoumarol