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Pediatric Cardiology

, Volume 34, Issue 4, pp 984–990 | Cite as

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
Original Article

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 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 ≥2 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 patients (21.6%), including Kawasaki disease with coronary aneurysms (3), acquired mitral valve disease (3), and Marfan syndrome (2). Stable warfarin dose (mg/kg/day) was strongly associated with VKORC1 polymorphism (p < 0.0001) and goal therapeutic INR (p = 0.009). Negative correlations were observed between stable warfarin dose and age, weight, height, and BSA (p = 0.04, 0.02, 0.02, and 0.02 respectively). Factors which did not influence warfarin dose included CYP2C9 polymorphism (p = 0.17), concurrent medications (p = 0.85), sex (p = 0.4), race (p = 0.14), congenital heart disease (p = 0.09), and Fontan physiology (p = 0.76). The gene-dose effect was observed in children with homozygous wild type VKORC1 CC, who required higher warfarin dose compared to those carrying heterozygous TC or homozygous TT (p = 0.028 and 0.0004 respectively). The full multiple linear regression model revealed that VKORC1 genotypes accounted for 47% of dosing variability; CYPC29 accounted for 5%. Overall, the combination of VKORC1, CYP2C9, age, and target INR accounted for 82% of dosing variability. In children with heart disease, VKORC1 genotypes, age, and target INR are important determinants influencing warfarin dosing in children with heart disease. Future warfarin dosing algorithm in children should factor both genetic and clinical factors.

Keywords

Warfarin/administration & dosage Cytochrome P450 enzyme system Congenital heart disease Genetic polymorphism 

Notes

Acknowledgments

Funding for this research was supported in part by the Weinberg Academic Year Research Grant.

References

  1. 1.
    Anticoagulants in the secondary prevention of events in coronary thrombosis (ASPECT) research group (1994) effect of long-term oral anticoagulant treatment on mortality and cardiovascular morbidity after myocardial infarction, Vol 343. Lancet, London pp 499–503Google Scholar
  2. 2.
    Biss TT et al (2012) VKORC1 and CYP2C9 genotype and patient characteristics explain a large proportion of the variability in warfarin dose requirement among children. Blood 119:868–873PubMedCrossRefGoogle Scholar
  3. 3.
    Bodin L et al (2005) Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity. Blood 106:135–140PubMedCrossRefGoogle Scholar
  4. 4.
    Bonduel M et al (2003) Acenocoumarol therapy in pediatric patients. J Thromb Haemost 1:1740–1743PubMedCrossRefGoogle Scholar
  5. 5.
    Budnitz DS et al (2007) Medication use leading to emergency department visits for adverse drug events in older adults. Ann Intern Med 147:755–765PubMedCrossRefGoogle Scholar
  6. 6.
    Cannegieter SC et al (1995) Optimal oral anticoagulant therapy in patients with mechanical heart valves. N Engl J Med 333:11–17PubMedCrossRefGoogle Scholar
  7. 7.
    Caraco Y, Blotnick S, Muszkat M (2008) CYP2C9 genotype-guided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective randomized controlled study. Clin Pharmacol Ther 83:460–470PubMedCrossRefGoogle Scholar
  8. 8.
    Carlquist JF et al (2010) An evaluation of nine genetic variants related to metabolism and mechanism of action of warfarin as applied to stable dose prediction. J Thromb Thrombolysis 30:358–364PubMedCrossRefGoogle Scholar
  9. 9.
    D’Andrea G et al (2005) A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood 105:645–649PubMedCrossRefGoogle Scholar
  10. 10.
    Guyatt GH et al. (2012) Executive summary: antithrombotic therapy and prevention of thrombosis. American college of chest physicians evidence-based clinical practice guidelines, 9th edn. Chest 141(2 Suppl):7S–47SGoogle Scholar
  11. 11.
    Kamali F et al (2004) Contribution of age, body size, and CYP2C9 genotype to anticoagulant response to warfarin. Clin Pharmacol Ther 75:204–212PubMedCrossRefGoogle Scholar
  12. 12.
    Kato Y et al (2011) Effect of the VKORC1 genotype on warfarin dose requirements in Japanese pediatric patients. Drug Metab Pharmacokinet 26:295–299PubMedCrossRefGoogle Scholar
  13. 13.
    Klein TE et al (2009) Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med 360:753–764PubMedCrossRefGoogle Scholar
  14. 14.
    Li T et al (2006) Polymorphisms in the VKORC1 gene are strongly associated with warfarin dosage requirements in patients receiving anticoagulation. J Med Genet 43:740–744PubMedCrossRefGoogle Scholar
  15. 15.
    Limdi NA et al (2008) Influence of CYP2C9 and VKORC1 on warfarin dose, anticoagulation attainment, and maintenance among European-Americans and African-Americans. Pharmacogenomics 9:511–526PubMedCrossRefGoogle Scholar
  16. 16.
    Lindh JD et al (2009) Influence of CYP2C9 genotype on warfarin dose requirements–a systematic review and meta-analysis. Eur J Clin Pharmacol 65:365–375PubMedCrossRefGoogle Scholar
  17. 17.
    Monagle P et al (2008) Antithrombotic therapy in neonates and children: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133(6 Suppl):887S–968SPubMedCrossRefGoogle Scholar
  18. 18.
    Moreau C et al (2012) Vitamin K antagonists in children with heart disease: height and VKORC1 genotype are the main determinants of the warfarin dose requirement. Blood 119:861–867PubMedCrossRefGoogle Scholar
  19. 19.
    Nowak-Gottl U et al (2010) In pediatric patients, age has more impact on dosing of vitamin K antagonists than VKORC1 or CYP2C9 genotypes. Blood 116:6101–6105PubMedCrossRefGoogle Scholar
  20. 20.
    Rieder MJ et al (2005) Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 352:2285–2293PubMedCrossRefGoogle Scholar
  21. 21.
    Schelleman H, Limdi NA, Kimmel SE (2008) Ethnic differences in warfarin maintenance dose requirement and its relationship with genetics. Pharmacogenomics 9:1331–1346PubMedCrossRefGoogle Scholar
  22. 22.
    Sconce EA et al (2005) The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood 106:2329–2333PubMedCrossRefGoogle Scholar
  23. 23.
    Streif W et al (1999) Analysis of warfarin therapy in pediatric patients: a prospective cohort study of 319 patients. Blood 94:3007–3014PubMedGoogle Scholar
  24. 24.
    Stroke prevention in atrial fibrillation III randomised clinical trial (1996) Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation, Vol 348. Lancet, London pp 633–638Google Scholar
  25. 25.
    Takeuchi F et al (2009) A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose. PLoS Genet 5:e1000433PubMedCrossRefGoogle Scholar
  26. 26.
    The stroke prevention in atrial fibrillation investigators (1996) bleeding during antithrombotic therapy in patients with atrial fibrillation, Vol 156. Arch Intern Med, Chicago pp 409–416Google Scholar
  27. 27.
    Wadelius M et al (2007) Association of warfarin dose with genes involved in its action and metabolism. Hum Genet 121:23–34PubMedCrossRefGoogle Scholar
  28. 28.
    Wadelius M et al (2009) The largest prospective warfarin-treated cohort supports genetic forecasting. Blood 113:784–792PubMedCrossRefGoogle Scholar
  29. 29.
    Wells PS et al (2010) A regression model to predict warfarin dose from clinical variables and polymorphisms in CYP2C9, CYP4F2, and VKORC1: derivation in a sample with predominantly a history of venous thromboembolism. Thromb Res 125:e259–e264PubMedCrossRefGoogle Scholar
  30. 30.
    Zhu Y et al (2007) Estimation of warfarin maintenance dose based on VKORC1 (-1639 G > A) and CYP2C9 genotypes. Clin Chem 53:1199–1205PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Nguyenvu Nguyen
    • 1
  • Peter Anley
    • 2
  • Margaret Y. Yu
    • 3
  • Gang Zhang
    • 4
  • Alexis A. Thompson
    • 5
  • Larry J. Jennings
    • 6
  1. 1.Division of Cardiology, Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Feinberg School of MedicineNorthwestern UniversityChicagoUSA
  2. 2.Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Feinberg School of Medicine Northwestern UniversityChicagoUSA
  3. 3.Feinberg School of MedicineNorthwestern UniversityChicagoUSA
  4. 4.Children’s Hospital of Chicago Research CenterChicagoUSA
  5. 5.Division of Hematology, Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Feinberg School of MedicineNorthwestern UniversityChicagoUSA
  6. 6.Pathology and Laboratory Medicine, Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Feinberg School of MedicineNorthwestern UniversityChicagoUSA

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