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 ...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 VKORCl and CYP2C9 genotypes, as well as the non-genetic factors could predict their stable dose of warfarin with high accuracy.展开更多
基金This work was supported by Science Foundation of China grants from the National Natural （No. 30971259）, the 15th Military Project for Tackling Key Problems in Science and Technology of China （No. 07CX306）, and the Scientific and Technological Innovation Fund for Young Investigation, General Hospital of People＇s Liberation Army （No. 09KMM23）.
文摘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 VKORCl and CYP2C9 genotypes, as well as the non-genetic factors could predict their stable dose of warfarin with high accuracy.
