Abstract 6074: Vitamin K Epoxide Reductase Genotype Alters Warfarin Dose Requirements in Pediatric Patients
Warfarin is an oral anticoagulant used for prevention of thromboembolism in children. Its dosing is difficult due to the narrow therapeutic index & individual variability in effective dosage. Genetic polymorphism in 2 enzymes involved in warfarin metabolism, vitamin K epoxide reductase (VKORC) & cytochrome P450 isoenzyme 2C9 (CYP2C9), have been associated with lower dose requirements in adults. Testing for these polymorphisms is now recommended and being performed to guide dosing in adult patients(pts). Currently there is no information available on these polymorphisms & warfarin dosing in children. To examine the relationship between warfarin dosing & polymorphisms of CYP2C9 & VKORC1 in pediatric patients. Pts 0 –18 years old on warfarin for minimum 2 weeks were included. Data included ethnicity, age, weight, body surface area, gender, indication, dose, INR, target INR, medical illness or medications & adverse effects. Blood sample tested for CYP2C9 & VKORC1 genotypes & correlated with above variables. Dose at time of stable INR was compared to genetic alleles. Multivariate linear regression analysis was performed to identify factors associated with warfarin dosing. 29 pts were studied(62% males). There were 18 Hispanics, 7 Caucasian, 2 African Americans & 2 Mixed ethnicities. Indication for warfarin included Congenital heart disease(CHD) 45% & non CHD 55%. Mean age 5yrs 2mo(6mo-18yrs) & wt 22kg(6.9 – 84). For VKORC1, there were 13 AA(44%), 9 GA(31%), & 7 GG (24%) alleles. For CYP29, 4/23 were *2(17%) & 0 *3 alleles. There was no relationship between ethnicity & VKORC1 alleles. Pts with VKORC1 AA + AG allele required a significantly lower dose/kg(0.10mg/kg) compared to GG allele(0.19mg/kg)(p <0.001) even after adjusting for target INR. In this study, pts with VKORC1 AA + AG alleles require a 47% lower dose/kg compared to pts with GG alleles. This preliminary data suggest that VKORC1 status is an important factor in dosing requirements in pediatric pts. A study using a larger pediatric population is necessary to construct a dosing nomogram based on presence of genetic polymorphism.