Warfarin Sensitivity Testing

Also Known As:
Warfarin Sensitivity or Response Genotyping

Formal Name:
CYP2C9 Genotype
VKORC1 Genotype

This article was on. September 18, 2020

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At a Glance

Why Get Tested?

To determine whether you have CYP2C9 and/or VKORC1 genetic variations and are likely to need lower, or less commonly, higher than average doses of the “blood-thinning” drug (anticoagulant) warfarin; however, not everyone who is prescribed warfarin will have this test done. At present, there is no consensus on the usefulness of this test and it is not yet widely accepted.

When To Get Tested?

A healthcare practitioner might order this test prior to prescribing warfarin for you or may sometimes order it when you are being treated with warfarin and have had bleeding or clotting episodes or dosing difficulties

Sample Required?

A blood sample drawn from a vein, a swab rubbed on the inside of your check (buccal swab), or you spit saliva into a clean container

Test Preparation Needed?

None

What is being tested?

Warfarin (Coumadin®) is a “blood-thinner” (anticoagulant), a drug that is commonly prescribed to help prevent inappropriate blood clotting (thrombosis and thromboembolism) in individuals at risk. This includes people who have had a blood clot or who have an excessive clotting disorder, atrial fibrillation, an artificial heart valve, or have undergone orthopedic surgery.

Warfarin sensitivity testing helps determine if you may be more sensitive (i.e., require lower doses) to treatment with warfarin because of your genetic makeup. This test primarily detects common genetic variations in two genes, CYP2C9 and VKORC1. A healthcare practitioner may sometimes order this test to help select appropriate doses of warfarin and/or to achieve appropriate dose levels more quickly.

Warfarin can be a challenging drug to administer and monitor because its levels can be affected by many different factors and it has a narrow window in which it is effective. If you are given too little drug, you may be at risk of forming a blood clot; if given too much drug, you may be at risk of moderate to severe bleeding episodes. The range between too much drug and too little drug is small and it varies significantly from person to person.

Historically, healthcare practitioners have given warfarin doses based upon age, weight, and sex, and then have monitored and adjusted dosages using frequent PT/INR (prothrombin time/international normalized ratio) tests to determine the medication’s anticoagulant (“blood-thinning”) effect. Healthcare practitioners then use periodic PT/INR tests to ensure that a stable dose with sufficient anticoagulation has been achieved. Although this dosing strategy is still commonly used, it can take as long as several weeks.

Genetic testing for warfarin sensitivity may help to shorten the time it takes for you to reach a stable dose; that is, to achieve adequate “blood-thinning” without bleeding episodes. Most often, it is determined that people are more sensitive to warfarin and may need smaller doses; however, there are some people who are less sensitive and may need larger doses. The reason for the relative sensitivity can be, at least in part, due to the individual’s genetic makeup and may involve two genes:

The VKORC1 gene codes for the production of a protein (VKOR) that is involved in the production of functional forms of certain clotting factors (II, VII, IX, X) that allows them to participate in the clotting process. Warfarin prevents the action of VKOR. Therefore, a variation in VKORC1 may cause you to be more or less sensitive (or resistant) to warfarin.
The CYP2C9 gene codes for the production of a protein (CYP2C9) involved in the breakdown (metabolism) of warfarin. People with CYP2C9 variations may not be able to get the drug out of their system as efficiently as others. The people who clear the drug more slowly may require lower (sometimes significantly lower) doses of warfarin.

You inherit one copy of each of your genes from your mother and one copy of each of your genes from your father. Thus, each of the CYP2C9 and VKORC1 genes is present in your body as two inherited gene copies (alleles). You could have both copies of a gene without any variants (wild-type, normal); one copy without variants and one copy with a variant (heterozygous); both copies with the same variant (homozygous); and both copies with different variants (“compound heterozygous”). The combination of CYP2C9 and VKORC1 gene copies that you have can determine the overall effect of warfarin and how rapidly it is metabolized and cleared from your body.

Warfarin sensitivity (or warfarin genotype) testing determines whether CYP2C9 and VKORC1 gene variants are present. Careful interpretation of the results can help the healthcare practitioner decide the appropriate doses of warfarin for your treatment.

Common Questions

How is the test used?

Warfarin sensitivity testing (genotyping) may be used to help determine your likely sensitivity to warfarin and to help select appropriate doses. Warfarin genotyping primarily identifies variations in the VKORC1 gene and the CYP2C9 gene. (See “What is being tested?” for more details on these genes.)

CYP2C9 and VKORC1 genetic testing is not widely used at this time. Although studies have shown that these genes contribute to a person’s sensitivity to warfarin and can account for a significant percentage of the person-to-person variation in warfarin doses, there is not a consensus on the need for the testing yet.

When is it ordered?

Warfarin sensitivity testing may be ordered prior to you taking warfarin for the first time, but it may also be ordered when you have had difficulties with achieving a stable anticoagulant (“blood-thinning”) effect or have experienced either excessive blood clotting or bleeding while taking warfarin.

What does the test result mean?

Warfarin sensitivity testing will identify the CYP2C9 and VKORC1 genetic variants (i.e., genotype) present. Laboratories most commonly look for the CYP2C9 variant alleles *2 and *3.The results must be interpreted carefully to help determine if you are likely to need a relatively lower dose of warfarin. These results are often interpreted by a specialist. Some laboratories also test for other genes that may be involved in warfarin sensitivity and dose optimization (e.g., CYP4F2). The laboratory should provide information about any additional genes included in a test.

If you have one or more variant CYP2C9 or VKORC1 gene copies, you are more likely to need a lower dose of warfarin. The amount needed will depend on the number and type of genetic variants present but will also greatly depend upon other factors, including your health, age, sex, diet, and other medications.

This test detects only the most common genetic variants in CYP2C9 and VKORC1. You may have a rare variant, resulting in a negative test result, but may still be more sensitive or resistant to warfarin.

Is there anything else I should know?

Some major health organizations support warfarin sensitivity testing, while others would like to see more data showing that the use of the testing actually has an impact on the health of the patient, such as a decrease in the number of clotting or bleeding events experienced by those on warfarin. Currently, there are studies underway that may provide additional data on health outcomes in the next few years, and that is likely to help determine the clinical usefulness of testing.

The U.S. Food and Drug Administration (FDA) has created changes to the warfarin label to provide information about the usefulness of CYP2C9 and VKORC1 genetic testing and to provide guidance on warfarin doses based upon testing results.

Many drugs interact with warfarin and can slow the metabolism of warfarin. Make sure all of your healthcare providers are aware of all the medications you are taking.

If I have genetic testing done, will I still need to be monitored with PT/INR tests?

Yes. Regardless of your genetic makeup, your response to warfarin therapy will still need to be monitored with regular PT/INR tests. This is because your individual degree of anticoagulation (“blood-thinning”) can be affected by other factors such as diet, age, weight, other medications and state of health, which can change over time.

Can warfarin sensitivity testing be done in my doctor's office?

No, it requires specialized equipment to perform and expertise to interpret. It is not offered by every laboratory and may need to be sent to a laboratory outside of your hospital (i.e., reference laboratory).

Will I need to have this test done more than once?

No. This test determines information about the genes you have inherited. This information does not change so you will only need to be tested once.

Should I tell other doctors about my warfarin sensitivity?

Yes, and you should always tell them that you are taking warfarin. The use of warfarin and your sensitivity to warfarin is important information for the medical professionals (including dentists) that you see. It can have an effect on your treatment options. CYP2C9 is involved in metabolism of many other drugs.

Should my other family members be tested for warfarin sensitivity?

This is something to discuss with your healthcare provider and family. It is not generally indicated unless a family member is also going to be taking warfarin, but having a family member who has warfarin sensitivity is important information to keep in mind and to share with your healthcare practitioner.

View Sources

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