Warfarin sensitivity is a condition in which individuals have a low tolerance for the drug warfarin. Warfarin is an anticoagulant, which means that it thins the blood, preventing blood clots from forming. Warfarin is often prescribed to prevent blood clots in people with heart valve disease who have replacement heart valves, people with an irregular heart beat (atrial fibrillation), or those with a history of heart attack, stroke, or a prior blood clot in the deep veins of the arms or legs (deep vein thrombosis).
Many people with warfarin sensitivity take longer than normal to break down (metabolize) warfarin. The medication remains active in their body longer than usual, so they require lower doses. These individuals are classified as "slow metabolizers" of warfarin. Other people with warfarin sensitivity do not need as much drug to prevent clots because their clot-forming process is naturally slower than average and can be stopped by low warfarin doses. If people with warfarin sensitivity take the average dose (or more) of warfarin, they are at risk of an overdose, which can cause abnormal bleeding in the brain, gastrointestinal tract, or other tissues, and may lead to serious health problems or death.
Warfarin sensitivity does not appear to cause any health problems other than those associated with warfarin drug treatment.
The prevalence of warfarin sensitivity is unknown. However, it appears to be more common in people who are older and those with lower body weights.
Of the approximately 2 million people in the U.S. who are prescribed warfarin annually, 35,000 to 45,000 individuals go to hospital emergency rooms with warfarin-related adverse drug events. While it is unclear how many of these events are due to warfarin sensitivity, the most common sign is excessive internal bleeding, which often occurs when individuals with warfarin sensitivity are given too much of the medication.
Many genes are involved in the metabolism of warfarin and in determining the drug's effects in the body. Certain common changes (polymorphisms) in the CYP2C9 and VKORC1 genes account for most of the variation in warfarin metabolism due to genetic factors. Polymorphisms in other genes, some of which have not been identified, have a smaller effect on warfarin metabolism. The polymorphisms associated with warfarin sensitivity often differ by population and ethnic background.
The CYP2C9 gene provides instructions for making an enzyme that breaks down various substances in the body. The CYP2C9 enzyme breaks down steroids, fatty acids, and certain drugs, including warfarin. Several CYP2C9 gene polymorphisms decrease the activity of the CYP2C9 enzyme and slow the body's metabolism of warfarin. As a result, the drug remains active in the body for a longer period of time, leading to warfarin sensitivity.
The VKORC1 gene provides instructions for making a vitamin K epoxide reductase enzyme. The VKORC1 enzyme helps turn on (activate) clotting proteins in the pathway that forms blood clots. Warfarin prevents (inhibits) the action of the VKORC1 enzyme and slows the activation of clotting proteins and clot formation. Certain VKORC1 gene polymorphisms decrease the amount of functional VKORC1 enzyme available to help activate clotting proteins. Individuals develop warfarin sensitivity because a lower warfarin dose is needed to inhibit the VKORC1 enzyme, as there is less functional enzyme that needs to be suppressed.
While changes in specific genes, particularly CYP2C9 and VKORC1, affect how the body reacts to warfarin, many other factors, including sex, age, weight, diet, and other medications, also play a role in the body's interaction with this drug.
The polymorphisms associated with this condition are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to result in warfarin sensitivity. However, different polymorphisms affect the activity of warfarin to varying degrees. Additionally, people who have more than one polymorphism in a gene or polymorphisms in multiple genes associated with warfarin sensitivity have a lower tolerance for the drug's effect or take even longer to clear the drug from their body.
Other Names for This Condition
- Coumadin sensitivity
- Warfarin response
Additional Information & Resources
Genetic Testing Information
Genetic and Rare Diseases Information Center
Research Studies from ClinicalTrials.gov
Catalog of Genes and Diseases from OMIM
Scientific Articles on PubMed
- Deng J, Vozmediano V, Rodriguez M, Cavallari LH, Schmidt S. Genotype-guided dosing of warfarin through modeling and simulation. Eur J Pharm Sci. 2017 Nov 15;109S:S9-S14. doi: 10.1016/j.ejps.2017.05.017. Epub 2017 May 11. Review. Citation on PubMed
- Ferder NS, Eby CS, Deych E, Harris JK, Ridker PM, Milligan PE, Goldhaber SZ, King CR, Giri T, McLeod HL, Glynn RJ, Gage BF. Ability of VKORC1 and CYP2C9 to predict therapeutic warfarin dose during the initial weeks of therapy. J Thromb Haemost. 2010 Jan;8(1):95-100. doi: 10.1111/j.1538-7836.2009.03677.x. Epub 2009 Oct 30. Citation on PubMed or Free article on PubMed Central
- 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 Feb;10(2):139-50. doi: 10.1097/GIM.0b013e318163c35f. Citation on PubMed
- Johnson JA, Caudle KE, Gong L, Whirl-Carrillo M, Stein CM, Scott SA, Lee MT, Gage BF, Kimmel SE, Perera MA, Anderson JL, Pirmohamed M, Klein TE, Limdi NA, Cavallari LH, Wadelius M. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update. Clin Pharmacol Ther. 2017 Sep;102(3):397-404. doi: 10.1002/cpt.668. Epub 2017 Apr 4. Citation on PubMed or Free article on PubMed Central
- Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM, Anderson JL, Kimmel SE, Lee MT, Pirmohamed M, Wadelius M, Klein TE, Altman RB; Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther. 2011 Oct;90(4):625-9. doi: 10.1038/clpt.2011.185. Epub 2011 Sep 7. Review. Citation on PubMed or Free article on PubMed Central
- Kaye JB, Schultz LE, Steiner HE, Kittles RA, Cavallari LH, Karnes JH. Warfarin Pharmacogenomics in Diverse Populations. Pharmacotherapy. 2017 Sep;37(9):1150-1163. doi: 10.1002/phar.1982. Epub 2017 Sep 6. Review. Citation on PubMed
- Krishna Kumar D, Shewade DG, Loriot MA, Beaune P, Balachander J, Sai Chandran BV, Adithan C. Effect of CYP2C9, VKORC1, CYP4F2 and GGCX genetic variants on warfarin maintenance dose and explicating a new pharmacogenetic algorithm in South Indian population. Eur J Clin Pharmacol. 2014 Jan;70(1):47-56. doi: 10.1007/s00228-013-1581-x. Epub 2013 Sep 10. Citation on 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 Dec;84(12):1079-94. doi: 10.4065/mcp.2009.0278. Review. Citation on PubMed or Free article on PubMed Central
- Perera MA, Cavallari LH, Limdi NA, Gamazon ER, Konkashbaev A, Daneshjou R, Pluzhnikov A, Crawford DC, Wang J, Liu N, Tatonetti N, Bourgeois S, Takahashi H, Bradford Y, Burkley BM, Desnick RJ, Halperin JL, Khalifa SI, Langaee TY, Lubitz SA, Nutescu EA, Oetjens M, Shahin MH, Patel SR, Sagreiya H, Tector M, Weck KE, Rieder MJ, Scott SA, Wu AH, Burmester JK, Wadelius M, Deloukas P, Wagner MJ, Mushiroda T, Kubo M, Roden DM, Cox NJ, Altman RB, Klein TE, Nakamura Y, Johnson JA. Genetic variants associated with warfarin dose in African-American individuals: a genome-wide association study. Lancet. 2013 Aug 31;382(9894):790-6. doi: 10.1016/S0140-6736(13)60681-9. Epub 2013 Jun 5. Citation on PubMed or Free article on PubMed Central
- Saleh MI. Clinical Predictors Associated With Warfarin Sensitivity. Am J Ther. 2016 Nov/Dec;23(6):e1690-e1694. Citation on PubMed
- Scott SA, Patel M, Martis S, Lubitz SA, van der Zee S, Yoo C, Edelmann L, Halperin JL, Desnick RJ. Copy number variation and warfarin dosing: evaluation of CYP2C9, VKORC1, CYP4F2, GGCX and CALU. Pharmacogenomics. 2012 Feb;13(3):297-307. doi: 10.2217/pgs.11.156. Epub 2011 Dec 21. Citation on PubMed or Free article on PubMed Central
- van der Zee SA, Halperin JL. Anticoagulant therapy: warfarin sensitivity genotyping closer to clinical practice. Nat Rev Cardiol. 2010 Oct;7(10):549-50. doi: 10.1038/nrcardio.2010.126. Citation on PubMed