Terra Sigillata

Late last week saw two announcements from the US FDA on genetic issues in drug safety. The first of these addresses the prescribing guidelines for Coumadin, or warfarin. Coumadin is a “blood-thinner” (or anticoagulant) prescribed for conditions from heart valve and hip/knee joint replacements to pulmonary hypertension and following strokes due to inappropriate blood clotting.

The reasons for this warning relate to data that has accumulated whereby individual patients respond quite differently to the same dose of Coumadin. Two genetic markers have been identified to account for much of this variation and the FDA has suggested that they be used to determine the minimal starting dose of Coumadin; patients with variations in these genetic markers may require a smaller dose of Coumadin than those with the normal, or “reference,” gene marker.

Let’s step back a moment to appreciate the awesome complexity of the blood clotting process, or hemostasis. Our physiology must keep our blood flowing freely but, when faced with a breach in the system due to injury, we must quickly mobilize processes to cause blood to clot and prevent bleeding to death. This amazing balance is altered in some disease processes or following surgery (for joint replacements) such that we must intervene with Coumadin, a drug that reduces blood clotting. However, too much Coumadin can cause inappropriate bleeding. Using the word “balance” is a great metaphor for this process because clinicians are walking a tightrope between preventing blood clotting and preventing too much bleeding.

One genetic marker for Coumadin sensitivity is a drug metabolizing enzyme, called CYP2C9, which serves to metabolically inactivate Coumadin. Some people have a genetic change, called a polymorphism, in the DNA that codes for CYP2C9. As a result, they metabolize Coumadin more slowly and require a lower Coumadin dose. These differences occur in 10-20% of Caucasians and African-Americans.

The other genetic marker is called VKORC1 and is the target of Coumadin. VKORC1 encodes a vitamin K-dependent enzyme whose action is required normally for blood clotting. So, when Coumadin inhibits VKORC1 enzyme, you get the desired therapeutic effect of reduced blood clotting. However, some people have a polymorphism in the control region of the VKORC1 gene that causes the body to make less of the enzyme. With less VKORC1, you need less Coumadin for the same amount of blood thinning relative to patients without the polymorphism. These differences occur in 14-37% of Caucasians and African-American but can be as high as 89% in Asian patients.

If you are a very person with changes in both the CYP2C9 and VKORC1 genes, you require a very low dose of Coumadin.

There are tests for these polymorphisms or variations in each gene that can help clinicians estimate the proper starting dose of Coumadin together with other classical measures such as altered liver or kidney function. Currently, clinicians start with a low dose and monitor a measure called the INR (or international normalized ratio) that tells them how “thin” the blood is. This is still probably okay for most patients. But, the alterations in these genes are now part of the prescribing information for Coumadin.

For readers who are patients, you should not change you Coumadin dose without consulting your doctor.

To read more about the biology and clinical implications of this labeling information, the FDA has a great Q&A document.

For clinicians who direct anticoagulant therapy, the Barnes-Jewish Hospital at Washington University in St. Louis has an excellent dosing calculator based upon these genetic changes and other physiological factors at WarfarinDosing.org.


Note to sticklers: Yes, I know I use the CYP2C9 and VKORC1 nomenclature for the gene and protein without italicizing the gene name or the * notation for polymorphisms, but I just wanted to be simple for the average reader who might stumble upon this post.

Comments

  1. #1 d adams
    September 3, 2007

    I seem to metabolize Coumadin quickly, and as a result, they keep making my doses higher (12 mg’s a day). At 12 mg every day, I still haven’t been able to hit the 2.0 INR but the dose is causing me considerable problems with side effects (to the extent of becoming disabled – dizziness, headaches, body pain, tremendous gas, etc.) So if you have 2C9 or ORC1, will the INR (protime) read the same, ie, will the lower dose still show the same 2.0 to 3.0 or will it reflect differently?

  2. #2 Pam
    December 29, 2007

    I have been taking coumadin since September and I cant keep my levels right, they stay very low and I take 7.5, I have been taking 7.5 and 5 ,one my 7.5 for 4 days and my 5 for 3 days checked my levels in a month they were 1.2 doctor put me on 7.5 for a week and my level was 1.4, so now for a week she put me on 10mg daily so I need help I dont miss my medcine and I feel bad.