title: Extremely low warfarin dose in patients with genotypes of CYP2C9*3/*3 and VKORC1-1639A/A.
abstract: BACKGROUND
  Patients with the genotypes of both CYP2C9*3/*3 and VKORC1-1639 A/A are expected to require the lowest dose of warfarin, and to have a greatly increased risk of bleeding. The experience for the dosing of warfarin in such extremely rare cases has been seldom reported.
  
  
  METHODS
  Demographic and clinical data from two cases with stable low dose of warfarin in China were studied by resequencing the corresponding gene segments in their whole blood DNA. The potential clinical value of the pharmacogenetic algorithm for them was evaluated by calculating the stable dose of warfarin in pharmacogenetic algorithm developed by International Warfarin Pharmacogenetics Consortium.
  
  
  RESULTS
  Both cases (68-year-old female and 50-year-old male) were diagnosed as chronic nonvalvular atrial fibrillation needing warfarin treatment, with target international normalized ratio (INR) 2 to 3. Case 1 had stable warfarin dose of 0.625 mg/d and case 2 1.25 mg/d. They needed more than 1 month to stabilize their anticoagulation. Exceeding INR values were recorded for them when the dose of warfarin was no more than 2 mg/d. Hemorrhagic complication appeared in case 1 when the dose was titrated from 2.5 to 1.25 mg/d. No concomitant medicine to increase or decrease the INR value was recorded for them. Genotyping CYP2C9 and VKORC1 showed both patients were the carriers of the homozygous alleles -CYP2C9*3/*3 and VKORC1-1639 A/A. Their stable doses of warfarin calculated by the pharmacogenetic dose algorithm (0.672 mg/d for case 1 and 1.16 mg/d for case 2) were comparable with their actual stable therapeutic doses.
  
  
  CONCLUSIONS
  Two Chinese with the rare genotypes of both CYP2C9*3/*3 and VKORC1-1639 A/A were found to require the extremely low dose of warfarin. The pharmacogenetic algorithm incorporating the variances of VKORC1 and CYP2C9 genotypes, as well as the non-genetic factors could predict their stable dose of warfarin with high accuracy.
authors: Institute of Geriatric Cardiology, General Hospital of People's Liberation Army, Beijing 100853, China.
authors: Lei
authors: L
authors: Gao
authors: Lei
authors: L
authors: He
authors: Jin
authors: J
authors: Luo
authors: Bin
authors: B
authors: Xu
authors: Jie
authors: J
authors: Yang
authors: Yu-xiao
authors: YX
authors: Zhang
authors: Ting
authors: T
authors: Yang
authors: Ke
authors: K
authors: Li
authors: Jin-wen
authors: JW
authors: Tian
authors: Hong-juan
authors: HJ
authors: Wang
authors: Yu-sheng
authors: YS
authors: Zhao
authors: Cai-yi
authors: CY
authors: Lu
authors: Wen-zi
authors: WZ
authors: Zhang
authors: Tong
authors: T
authors: Yin
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000009:adverse effects*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005838:Genotype; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010597:Pharmacogenetics; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000009:adverse effects*
chemical_list: D000925:Anticoagulants; D014859:Warfarin; 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