Identification of the factors influencing anticoagulation response to warfarin in children

Abstract

The requirement for anticoagulant therapy in children is increasing and warfarin remains the long-term anticoagulant agent of choice. However, little is known about the factors that influence inter-individual variability in response to warfarin among children. The aim of this MD was to gain a greater understanding of the factors that affect warfarin anticoagulant control and response in children. A retrospective study of a cohort of anticoagulated children identified factors contributing to poor anticoagulant control. It also highlighted the importance of the way in which anticoagulant control is assessed in children, with the study results showing that the use of a linear interpolation method may be more appropriate than the proportion of INRs within target range during intermittent periods of instability when INR measurements are carried out more frequently. A multi-centre, cross-sectional study of 120 children with stable anticoagulation with warfarin showed that 72% of the inter-individual variability in warfarin maintenance dose is accounted for by height, VKORC1 and CYP2C9 genotype, and indication for warfarin. The study results were used to develop a pharmacogenetics-based warfarin-dosing algorithm. The latter was demonstrated to have the power to accurately predict maintenance warfarin dose in an unrelated cohort of 23 children. Analysis of data for a subgroup of 51 children showed that VKORC1 and CYP2C9 genotype influence outcome variables during initiation of warfarin therapy, including peak INR response during week 1 and the proportion of supratherapeutic INRs during month 1 of therapy. The above findings have provided us with an insight into the factors influencing anticoagulant control and variability in response to warfarin in children. Application of a pharmacogenetics-based approach to initiation and maintenance warfarin therapy in children has the potential to improve efficacy and safety of warfarin therapy in this challenging patient population.