Warfarin (also known under the brand names of Coumadin, Jantoven, Marevan, and Waran) is the most commonly prescribed anticoagulant for the treatment and prevention of thromboembolic events. FDA estimates that 2 million persons start taking warfarin in the United States every year to prevent blood clots, heart attacks and stroke. Nevertheless, warfarin is the second most common drug – after insulin –implicated in emergency room visits for adverse drug events.
Correct warfarin dose varies widely from patient to patient, for this reason, its activity has to be monitored by frequent blood testing for the international normalized ratio (INR). This can be a lengthy trial and error process where the patient is at increased risk until the most appropriate dosage is determined. An incorrect dose may lead to serious side effects, increasing the risk for severe bleeding that can be life-threatening and even cause death.
Warfarin activity can be partially determined by genetic factors. Besides, based on an analysis of recent studies, the American Food and Drug Administration (FDA) has recently announced the approval of updated labeling for the widely used blood-thinning drug, Coumadin, to explain that people's genetic makeup may influence how they respond to the drug:
New labeling approved by the FDA on August 16th, 2007 (FDA press release)
… The labeling change highlights the opportunity for healthcare providers to use genetic tests to improve their initial estimate of what is a reasonable warfarin dose for individual patients. Testing may help optimize the use of warfarin and lower the risk of bleeding complications from the drug… |
http://www.fda.gov/bbs/topics/NEWS/2007/NEW01684.html
In this context, DNAVision has developed TherapID™-Warfarin test to help doctors quickly and accurately establish the correct warfarin dose for each patient by the mean of the their genetic variations by minimizing side effects. You can find the instructions for ordering in the appended document.
Source [fda.gov]
TherapID™-Warfarin test is a simple test that analyze the genetic variation in the two genes, VKORC1 and CYP2C9, recommended by the American authorities in the updated coumadin labeling to help establish a safe and effective warfarin dose for every patient.
One-third of patients receiving warfarin metabolize it quite differently than expected. Research has shown that some of the unexpected response to warfarin depends on a patient's variants of the genes CYP2C9 and VKORC1.
The active component of warfarin is primarily metabolized by CYP2C9. Up to 35% of the population inherits a form of the CYP2C9 gene which results in a CYP2C9 enzyme deficiency. A deficiency in CYP2C9 causes slow metabolism and higher than expected concentrations of the active drug to accumulate. This increased warfarin concentration in the body increases the risk of bleeding.
Two variants, CYP2C9*2 and CYP2C9*3, have been largely examined with respect to warfarin dosing. Patients with either the CYP2C9*2 and CYP2C9*3 variant required a lower warfarin maintenance dose, and this is specially pronounced for patients with CYP2C9*3.
Table 1. Relationship between S-Warfarin clearance and CYP2C9 genotype in Caucasian patients
CYP2C9 Genotype |
N |
S-Warfarin Clearance /Lean Body Weight (mL/min/kg) Mean (SD)a |
*1/*1 |
118 |
0.065 (0.025)b |
*1/*2 or *1/*3 |
59 |
0.041 (0.021)b |
*2/*2, *2/*3 or *3/*3 |
11 |
0.020 (0.011)b |
Total |
188 |
|
a SD=standard deviation.
b p<0.001. Pairwise comparisons indicated significant differences among all 3 genotypes.
Warfarin inhibits the formation of active clotting factors by inhibition of vitamin K epoxide reductase complex subunit 1 (VKORC1). Inherited differences in VKORC1 increase or decrease the amount of warfarin needed to inhibit the formation of the clotting factors. When the amount of warfarin exceeds what is needed, the risk of bleeding is increased.
Certain variations in VKORC1 gene have been associated with lower dose requirements for warfarin. Polymorphisms in the vitamin K epoxide reductase complex 1 (VKORC1) gene explain 30% of the dose variation between patients, about 40% of the variance in warfarin dose could be attributed to variations in VKORC1 and CYP2C9 genes combined
Warfarin is a synthetic derivative of coumarin, originally developed as a rat poison, which belongs to the class of vitamin K antagonists because it decreases blood coagulation by interfering with vitamin K metabolism.
Warfarin is prescribed to people with an increased tendency for thrombosis or as prophylaxis in those individuals who have already formed a blood clot (thrombus) which required treatment. This can help prevent formation of future blood clots and help reduce the risk of embolism (migration of a thrombus to a spot where it blocks blood supply to a vital organ). Common clinical indications for warfarin use are:
Dosing of warfarin is complicated by the fact that it is known to interact with many commonly used medications and other chemicals that may be present in appreciable quantities in food. These interactions may enhance or reduce warfarin's anticoagulation effect. The dose of warfarin required to maintain a safe degree of anticoagulation ranges from about 2 mg/day to 10 mg/day. Patients who are not taking the dose that is right for them are at an increased risk for severe toxicity or an inadequate response
In order to optimize the therapeutic effect without risking dangerous side effects, such as bleeding, close monitoring of the degree of anticoagulation is required by blood testing (INR). Initially, checking may be as often as twice a week; the intervals can be lengthened if the patient manages stable therapeutic INR levels on an unchanged warfarin dose.
Warfarin is primarily metabolized by the cytochrome CYP2C9 and acts by inhibiting vitamin K epoxide reductase complex subunit 1 VKORC1. Any genetic variation in the genes sequence coding to both of these enzymes can potentially vary the efficacy or the toxicity of warfarin treatment. TherapID™-Warfarin test developed by DNAVision s.a. is able to determine the main mutation in CYP2C9 and VKORC1 to help establish right doses in a quickly and accurate way.
Warfarine dose and pharmacogenomics of CYP2C9 and VKORC1- Rationale and perspectives.2006. Thromb Res. 2007;120(1):1-10. Epub 2006 Dec 11. Review.
Carlquist, J.F. et al. Genotypes of the cytochrome p450 isoform, CYP2C9, and the vitamin K epoxide reductase complex subunit 1 conjointly determine stable warfarin dose: a prospective study. J Thromb Thrombolysis. 2006 Dec;22(3):191-7