Warfarin Sensitivity

  • Diagnosis
  • Background
  • Lab Tests
  • References
  • Related Topics
  • Videos

Indications for Testing

  • Insufficient evidence to recommend universal adoption of genotyping
  • May be indicated in individuals
    • With personal or family history of difficulty with anticoagulation
    • Who are therapy adherent but difficult to treat (eg, those requiring <21 mg per week or >49 mg per week to maintain therapeutic international normalized ratio [INR])
    • Who might be placed on warfarin prophylactically after surgery

Laboratory Testing

  • CYP2C9 and VKORC1 genotyping – for clinical dosing
    • Many algorithms and models for dosing are available
      • Algorithms predict maintenance dose but do not necessarily consider pharmacokinetic differences that may influence the time required to achieve a steady state
      • Algorithms typically do not offer guidance regarding dosing intervals or indicate when interpretation of an INR result is appropriate
      • Dose revision algorithms after INR response are also available (Lenzini, 2010)
    • See warfarin dosing calculator for therapeutic dose estimates – other models are available
    • 2010 revision of the Coumadin label includes expected maintenance dosing based on genotype
    • Consider warfarin/drug interactions
    • Pharmacogenetic testing does not replace the need for monitoring warfarin therapy using INR testing

Warfarin (Coumadin) is one of the most widely used anticoagulants worldwide, with potentially severe hemorrhagic or thrombotic consequences if dosed incorrectly. The labeling for warfarin was revised in August 2007 and February 2010 to include information about how the three most widely studied pharmacogenetic mutations (CYP2C9*2, CYP2C9*3, and VKORC1 -1639G>A) affect dose requirements (NDA 9-218/S-105).  These mutations account for as much as 45% of variation in warfarin response in Caucasians and 30% in African Americans.

Epidemiology

  • Incidence – allele frequencies differ among ethnic groups

    Mutation

    Caucasian

    Asian

    African American

    CYP2C9*2 (c.430C>T)

    13%

    <1%

    3%

    CYP2C9*3 (c.1075A>C)

    7%

    4%

    2%

    VKORC1 (c.-1639G>A

    39%

    91%

    11%

    • The VKORC1 (c.-1639G>A) mutation is in very strong linkage disequilibrium with the VKORC1 variant c.173+1000C>T

Risk Factors

  • CYP2C9 mutations reduce warfarin clearance
    • *2 allele (430C>T)
      • Reduces metabolism by ~30%
      • Extends half-life – requires a longer time to achieve steady state
      • Average daily warfarin requirement reduced (see table in Diagnosis tab)
    • *3 allele (1075A>C)
      • Reduces metabolism by ~80%
      • Extends half-life – requires a longer time to achieve steady state
      • Average daily warfarin requirement reduced more than with the CYP2C9*2 allele (see table in Diagnosis tab)
  • VKORC1 mutations reduce warfarin clearance
    • Many mutations are known and exist in linkage disequilibrium
    • Common promoter mutation (-1639G>A) predicts warfarin sensitivity haplotypes
    • Average daily warfarin requirement reduced (see table in Diagnosis tab)
  • Presence of one or more VKORC1and CYP2C9 mutations in concert further reduces warfarin requirement

Pathophysiology

  • Warfarin is prescribed for numerous conditions, including the following
    • Atrial fibrillation
      • Patients in therapeutic range ~55% of the time
    • Venous thromboembolism
    • Mechanical heart valves
    • Postoperative prophylaxis
  • Warfarin inhibits production of vitamin K epoxide reductase (VKOR) complex conversion of oxidized vitamin K to functional reduced vitamin K
    • Response to warfarin therapy  assessed through international normalized ratio (INR) testing
    • Warfarin has a narrow therapeutic index that is influenced by a variety of drugs and illnesses
      • Concentrations outside of narrow range may be associated with significant clinical issues
  • Warfarin is a racemic mixture of R and S enantiomers
    • S-warfarin – 3-5 times more potent than R; primarily metabolized by CYP2C9
  • Pharmacogenetics affect dosing
    • CYP2C9 genotype accounts for as much as 18% of the variability in warfarin dosing
    • VKORC1 genotype accounts for as much as 29% of the variability in warfarin dosing
    • Combining genotypes with clinical factors may account for 50-70% of variability in warfarin dosing
Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Warfarin Sensitivity, CYP2C9 and VKORC1, 3 Variants 2012772
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Limitations 

Only the targeted CYP2C9 and VKORC1 variants will be detected by this panel

Diagnostic errors can occur due to rare sequence variations

Risk of therapeutic failure or adverse reactions with warfarin may be affected by genetic and non-genetic factors that are not detected by this test

This result does not replace the need for therapeutic drug or clinical monitoring

This test does not identify patients at risk for warfarin resistance 

Cytochrome P450 2C9, CYP2C9 - 2 Variants 2012766
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Limitations 

Only the targeted CYP2C9 variants will be detected

Diagnostic errors can occur due to rare sequence variations

Risk of therapeutic failure or adverse reactions with CYP2C9 substrates may be affected by genetic and nongenetic factors that are not detected by this test

This result does not replace the need for therapeutic drug or clinical monitoring

 

Prothrombin Time/International Normalized Ratio 0030224
Method: Electromagnetic Mechanical Clot Detection

Guidelines

Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G, American College of Chest Physicians. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008; 133(6 Suppl): 160S-198S. PubMed

Flockhart DA, O'Kane D, Williams MS, Watson MS, Flockhart DA, Gage B, Gandolfi R, King R, Lyon E, Nussbaum R, O'Kane D, Schulman K, Veenstra D, Williams MS, Watson MS, ACMG Working Group on Pharmacogenetic Testing of CYP2C9, VKORC1 Alleles for Warfarin Use. Pharmacogenetic testing of CYP2C9 and VKORC1 alleles for warfarin. Genet Med. 2008; 10(2): 139-50. PubMed

General References

Clinical Pharmacology Research Institute. P450 Drug Interaction Table: Abbreviated "Clinically Relevant" Table. Indiana University School of Medicine. Indianapolis, IN [Accessed: Nov 2015]

Coumadin [package insert]. Revised October 2015. Bristol-Myers Squibb Company. Princeton, NJ [Accessed: Nov 2015]

Dunn A. In AF or VTE, acenocoumarol or phenprocoumon dosing by genotype did not affect time in therapeutic range. Ann Intern Med. 2014; 160(6): JC10. PubMed

Dunn A. In AF or VTE, warfarin dosing by genotype improved time in therapeutic range but not clinical outcomes. Ann Intern Med. 2014; 160(6): JC9. PubMed

Dunn A. Warfarin dosing by genotype did not improve time in therapeutic range. Ann Intern Med. 2014; 160(6): JC8. PubMed

International Warfarin Pharmacogenetics Consortium, Klein TE, Altman RB, Eriksson N, Gage BF, Kimmel SE, Lee MM, Limdi NA, Page D, Roden DM, Wagner MJ, Caldwell MD, Johnson JA. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med. 2009; 360(8): 753-64. PubMed

King CR, Porche-Sorbet RM, Gage BF, Ridker PM, Renaud Y, Phillips MS, Eby C. Performance of commercial platforms for rapid genotyping of polymorphisms affecting warfarin dose. Am J Clin Pathol. 2008; 129(6): 876-83. PubMed

McMillin GA, Vazquez SR, Pendleton RC. Current challenges in personalizing warfarin therapy. Expert Rev Clin Pharmacol. 2011; 4(3): 349-62. PubMed

Moyer TP, O'Kane DJ, Baudhuin LM, Wiley CL, Fortini A, Fisher PK, Dupras DM, Chaudhry R, Thapa P, Zinsmeister AR, Heit JA. Warfarin sensitivity genotyping: a review of the literature and summary of patient experience. Mayo Clin Proc. 2009; 84(12): 1079-94. PubMed

Seip RL, Duconge J, Ruaño G. Implementing genotype-guided antithrombotic therapy. Future Cardiol. 2010; 6(3): 409-24. PubMed

Shahin MH A, Johnson JA. Clopidogrel and warfarin pharmacogenetic tests: what is the evidence for use in clinical practice? Curr Opin Cardiol. 2013; 28(3): 305-14. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Borgman MP, Pendleton RC, McMillin GA, Reynolds KK, Vazquez S, Freeman A, Wilson A, Valdes R, Linder MW. Prospective pilot trial of PerMIT versus standard anticoagulation service management of patients initiating oral anticoagulation. Thromb Haemost. 2012; 108(3): 561-9. PubMed

Crews N, Wittwer CT, Montgomery J, Pryor R, Gale B. Spatial DNA melting analysis for genotyping and variant scanning. Anal Chem. 2009; 81(6): 2053-8. PubMed

Flockhart DA, O'Kane D, Williams MS, Watson MS, Flockhart DA, Gage B, Gandolfi R, King R, Lyon E, Nussbaum R, O'Kane D, Schulman K, Veenstra D, Williams MS, Watson MS, ACMG Working Group on Pharmacogenetic Testing of CYP2C9, VKORC1 Alleles for Warfarin Use. Pharmacogenetic testing of CYP2C9 and VKORC1 alleles for warfarin. Genet Med. 2008; 10(2): 139-50. PubMed

Horne BD, Lenzini PA, Wadelius M, Jorgensen AL, Kimmel SE, Ridker PM, Eriksson N, Anderson JL, Pirmohamed M, Limdi NA, Pendleton RC, McMillin GA, Burmester JK, Kurnik D, Stein M, Caldwell MD, Eby CS, Rane A, Lindh JD, Shin J, Kim H, Angchaisuksiri P, Glynn RJ, Kronquist KE, Carlquist JF, Grice GR, Barrack RL, Li J, Gage BF. Pharmacogenetic warfarin dose refinements remain significantly influenced by genetic factors after one week of therapy. Thromb Haemost. 2012; 107(2): 232-40. PubMed

Lenzini P, Wadelius M, Kimmel S, Anderson JL, Jorgensen AL, Pirmohamed M, Caldwell MD, Limdi N, Burmester JK, Dowd MB, Angchaisuksiri P, Bass AR, Chen J, Eriksson N, Rane A, Lindh JD, Carlquist JF, Horne BD, Grice G, Milligan PE, Eby C, Shin J, Kim H, Kurnik D, Stein CM, McMillin G, Pendleton RC, Berg RL, Deloukas P, Gage BF. Integration of genetic, clinical, and INR data to refine warfarin dosing. Clin Pharmacol Ther. 2010; 87(5): 572-8. PubMed

Lyon E, McMillin G, Melis R. Pharmacogenetic testing for warfarin sensitivity. Clin Lab Med. 2008; 28(4): 525-37. PubMed

McMillin GA, Melis R, Wilson A, Strong MB, Wanner NA, Vinik RG, Peters CL, Pendleton RC. Gene-based warfarin dosing compared with standard of care practices in an orthopedic surgery population: a prospective, parallel cohort study. Ther Drug Monit. 2010; 32(3): 338-45. PubMed

Medical Reviewers

Last Update: August 2016