Genetic and Clinical Determinants Influencing Warfarin Dosing in Children With Heart Disease
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ORIGINAL ARTICLE
Genetic and Clinical Determinants Influencing Warfarin Dosing in Children With Heart Disease Nguyenvu Nguyen • Peter Anley • Margaret Y. Yu Gang Zhang • Alexis A. Thompson • Larry J. Jennings
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Received: 1 August 2012 / Accepted: 7 November 2012 / Published online: 25 November 2012 Ó Springer Science+Business Media New York 2012
Abstract Warfarin is a common anticoagulant with narrow therapeutic window and variable anticoagulation effects. Single gene polymorphisms in cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) have been shown to impact warfarin dosing in adults. Insufficient data exists on genetic and clinical factors which influence warfarin dosing in children. Pediatric patients with heart disease who received long-term warfarin therapy were N. Nguyen (&) Division of Cardiology, Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Feinberg School of Medicine, Northwestern University, 225 E. Chicago, IL Box 21, Chicago, IL 60611, USA e-mail: [email protected] P. Anley Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Feinberg School of Medicine , Northwestern University, 225 E. Chicago, IL Box 21, Chicago, IL 60611, USA M. Y. Yu Feinberg School of Medicine, Northwestern University, 420 East Superior Street, Chicago, IL 60611, USA G. Zhang Children’s Hospital of Chicago Research Center, 2430 North Halsted Street, Chicago, IL 60641, USA A. A. Thompson Division of Hematology, Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Feinberg School of Medicine, Northwestern University, 225 E. Chicago, IL Box 21, Chicago, IL 60611, USA L. J. Jennings Pathology and Laboratory Medicine, Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Feinberg School of Medicine, Northwestern University, 225 E. Chicago, IL Box 21, Chicago, IL 60611, USA
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tested for VKORC1 and CYP2C9 polymorphisms. Clinical and demographic data were reviewed in those children who achieved stable therapeutic international normalized ratio (INR). Multiple linear regression modeling was used to assess relationships between stable warfarin doses and genetic or clinical variables. Fifty children were tested for VKORC1 and CYP2C9 polymorphisms; 37 patients (M 26: F 11) had complete data, achieved stable therapeutic INR, and were included in dose variability analysis. There were predominance of white race 73% and male sex 70.3%. The mean age was 9.6 years (1.8–18.6 years). The mean weight was 37.8 kg (7.7–95 kg). Fontan physiology and mechanical cardiac valves were two most common indications for chronic warfarin therapy (25/37 or 67.6%). Twelve patients (32.4%) had C2 indications for warfarin therapy. Three patients had documented venous or arterial clots, and 5 patients had strokes. Congenital heart disease was present in 29 patients (78.4%), including Fontan physiology (20), complex biventricular physiology (4), and congenital mitral valve disease (5). Acquired heart disease was present in 8 pati
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