Warfarin resistance

Warfarin resistance is a condition in which individuals have a high 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).

There are two types of warfarin resistance: incomplete and complete. Those with incomplete warfarin resistance can achieve the benefits of warfarin treatment with a high dose of warfarin. Individuals with complete warfarin resistance do not respond to warfarin treatment, no matter how high the dose. If people with warfarin resistance require anticoagulant therapy and take the average warfarin dose, they will remain at risk of developing a potentially harmful blood clot.

Both types of warfarin resistance are related to how the body processes warfarin. In some people with warfarin resistance, their blood-clotting process does not react effectively to the drug. Others rapidly break down (metabolize) warfarin, so the medication is quickly processed by their bodies; these individuals are classified as "fast metabolizers" or "rapid metabolizers" of warfarin. The severity of these abnormal processes determines whether the warfarin resistance is complete or incomplete.

Warfarin resistance does not appear to cause any health problems other than those associated with warfarin drug treatment.

Warfarin resistance is thought to be a rare condition, although its prevalence is unknown.

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 VKORC1 gene account for 20 percent 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 resistance often differ by population and ethnic background.

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 by binding to the enzyme and preventing it from binding to and activating the clotting proteins, stopping clot formation. Certain VKORC1 gene polymorphisms lead to the formation of a VKORC1 enzyme with a decreased ability to bind to warfarin. This reduction in warfarin binding causes incomplete warfarin resistance and results in a higher dose of warfarin needed to inhibit the VKORC1 enzyme and stop the clotting process. If the VKORC1 enzyme cannot bind to any warfarin, the result is complete warfarin resistance.

While changes in specific genes 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.

Genetic Testing Information

• Genetic Testing Registry: Warfarin response

Genetic and Rare Diseases Information Center

• Warfarin resistance

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Catalog of Genes and Diseases from OMIM

• COUMARIN RESISTANCE

Scientific Articles on PubMed

• PubMed

• Azzam H, Elwakeel H, Awad I, El-Farahaty R, El-Gilany AH, El-Sharawy S. VKORC1 and CYP2C9 genotypes in Egyptian patients with warfarin resistance. Blood Coagul Fibrinolysis. 2016 Mar;27(2):121-6. doi: 10.1097/MBC.0000000000000168. Citation on PubMed
• de Oliveira Almeida VC, Ribeiro DD, Gomes KB, Godard AL. Polymorphisms of CYP2C9, VKORC1, MDR1, APOE and UGT1A1 genes and the therapeutic warfarin dose in Brazilian patients with thrombosis: a prospective cohort study. Mol Diagn Ther. 2014 Dec;18(6):675-83. doi: 10.1007/s40291-014-0121-4. Citation on PubMed
• Issac MS, El-Nahid MS, Wissa MY. Is there a role for MDR1, EPHX1 and protein Z gene variants in modulation of warfarin dosage? a study on a cohort of the Egyptian population. Mol Diagn Ther. 2014 Feb;18(1):73-83. doi: 10.1007/s40291-013-0055-2. Citation on PubMed
• Kurnik D, Qasim H, Sominsky S, Lubetsky A, Markovits N, Li C, Stein CM, Halkin H, Gak E, Loebstein R. Effect of the VKORC1 D36Y variant on warfarin dose requirement and pharmacogenetic dose prediction. Thromb Haemost. 2012 Oct;108(4):781-8. doi: 10.1160/TH12-03-0151. Epub 2012 Aug 7. Citation on PubMed or Free article on PubMed Central
• Oldenburg J, Muller CR, Rost S, Watzka M, Bevans CG. Comparative genetics of warfarin resistance. Hamostaseologie. 2014;34(2):143-59. doi: 10.5482/HAMO-13-09-0047. Epub 2013 Nov 29. Citation on PubMed
• Rost S, Fregin A, Ivaskevicius V, Conzelmann E, Hortnagel K, Pelz HJ, Lappegard K, Seifried E, Scharrer I, Tuddenham EG, Muller CR, Strom TM, Oldenburg J. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature. 2004 Feb 5;427(6974):537-41. doi: 10.1038/nature02214. Citation on PubMed
• Sinxadi P, Blockman M. Warfarin resistance. Cardiovasc J Afr. 2008 Jul-Aug;19(4):215-7. Citation on PubMed
• Watzka M, Geisen C, Bevans CG, Sittinger K, Spohn G, Rost S, Seifried E, Muller CR, Oldenburg J. Thirteen novel VKORC1 mutations associated with oral anticoagulant resistance: insights into improved patient diagnosis and treatment. J Thromb Haemost. 2011 Jan;9(1):109-18. doi: 10.1111/j.1538-7836.2010.04095.x. Citation on PubMed