Introduction:
Kawasaki disease (KD) is a systemic vasculitis and the leading cause of acquired coronary artery disease in children. Children with giant coronary artery aneurysms are at high risk of thrombosis and require long-term anticoagulation, commonly with warfarin which is challenging because of its narrow therapeutic index and substantial inter-individual dose variability. The Clinical Pharmacogenetics Implementation Consortium 2017 guideline recommends incorporating CYP2C9 and VKORC1 genotypes with clinical variables to guide warfarin dosing, however pediatric evidence is limited, and the relative contribution of pharmacogenetic factors versus anthropometric determinants is unclear.
Methods:
This cross-sectional analytical study was conducted at a tertiary care center in North India. Children with KD on warfarin therapy with stable anticoagulation (two consecutive INR values obtained at least seven days apart within ±0.5 of the target therapeutic range [INR 2–3]) were enrolled. Clinical characteristics, echocardiographic findings, warfarin dose, INR values, and adverse events were recorded. Genotyping for CYP2C9 (*2 and *3) and VKORC1 (–1639G>A) polymorphisms was performed using polymerase chain reaction–restriction fragment length polymorphism. Univariate analyses assessed associations between polymorphisms and maintenance warfarin dose. Multivariable linear regression evaluated the influence of genetic variants and clinical covariates, including body surface area (BSA), age, and sex, on weight-normalised warfarin dose.
Results:
Twenty-five children with KD were included, with giant coronary artery aneurysms being the predominant indication for anticoagulation (72%). Mean maintenance warfarin dose was 0.114±0.044 mg/kg/day. Warfarin-related adverse events occurred in 36% of patients, predominantly minor bleeding episodes. Pharmacogenetic analysis demonstrated VKORC1, CYP2C9*2 and CYP2C9*3 polymorphisms in 32%, 44%, and 40% patients respectively. Univariate analyses did not show significant association between individual polymorphisms and warfarin dose. On multivariable linear regression, BSA emerged as the strongest predictor of warfarin dose, while CYP2C9 and VKORC1 polymorphisms did not independently predict dose requirements.
Discussion:
In children with KD on stable long-term warfarin therapy, BSA is the dominant determinant of maintenance dose, outweighing independent contributions of individual pharmacogenetic polymorphisms. Although actionable CYP2C9 and VKORC1 variants are common, their modest effect suggests that pharmacogenetic testing may serve as an adjunct rather than a primary driver of dose individualization in pediatric Kawasaki disease.