Coumadin
(warfarin) Metabolism Panel
**This panel available in all states except New York.. These tests not yet
approved by New York State Department of Health for clinical diagnostics**
Warfarin has been unequivocally demonstrated to prevent and to be useful
for treating thromboembolic disease. It is the most widely prescribed
anticoagulant for thromboembolic therapy in Europe and North America.
In the context of atrial fibrillation warfarin reduces the risk of ischemic
stroke by 65%. If left untreated, patients with atrial fibrillation have a
mortality risk 2.5 times greater than anticoagulated controls.
Nevertheless, warfarin has a narrow therapeutic range and a 20-fold
inter-individual variation in dose requirements. Incorrect dosage, especially
during the initial dosing phase is associated with either severe bleeding or
failure to prevent thromboembolism. Hemorrhage during warfarin therapy is
one of the leading causes of drug-related death in Western countries. It is
used in atrial fibrillation, recurrent stroke, pulmonary embolism, deep vein
thrombosis, and in patients with heart valve prosthesis and joint
replacement.
Warfarin acts in the vitamin K cycle by interfering with the regeneration of
reduced vitamin K from oxidized vitamin K in the VKOR (Vitamin K
OxidoReductase) complex. A recently identified gene for the major
subunit of VKOR called the VKORC1 has recently been identified. A
polymorphism in the E-element at base -1639 in the promotor region of
this complex explains 44% of the variance in warfarin dose. In vitro the
-1639G allele exhibited 44% less activity than the -1639A allele. It is well
known that the Chinese population requires a much lower warfarin
maintenance dose than Caucasians. It was found in one study that in
Caucasians the A/A genotype made up only 14% while the A/G and G/G
genotypes made up 47% and 39%, respectively. In the Chinese the A/A
genotype included 82% of the population (1).
A new combination of factors explains 60% of the variable response to
warfarin. Environmental and genetic factors influence the warfarin effective
dose necessary for therapeutic response. Factors such as weight, body
mass index, age, diet and concurrent medication are known to affect dose
requirement. Warfarin occurs in two enantiomeric, the R- and the
S-enantiomers. The S- form is 3-5 times more active than the
R-enantiomer and the S-form is metabolized by the cytochrome P450
enzyme CYP2C9. The CYP2C9*2 and CYP2C9*3 have been shown to
decrease the enzyme activity which has led to warfarin sensitivity and in
serious cases, bleeding complications. Using CYP2C9*1 as the normal, or
wild type allele, the genotype frequencies CYP2C9*1/*2 and
CYP2C9*1/*3 were 20% and 12%, respectively in the Caucasian
population, while in the Asian population the are either completely absent
or rare.
The genetic test panel will consist of 3 genetic tests:
VKORC1 -1639, CYP2C9*2, and CYP2C9*3
The algorithm (Sconce et al., 2005) to determine dose will be:
SqRdose = 0.628 - 0.0135 (Age) - 0.240 (CYP*2) - 0.370
(CYP)*3 -0.241 (VKOR) + 0.0162 (height)
Age in years; height in centimeters; CYP2C9 genotype: input 0, 1, 2 for the number
of *2 and *3 alleles with the patient's genotype; VKORC1: input 1 for GG, 2 for GA,
and 3 for AA.
For example, a 170 cm tall 90 year old patient with CYP2C9*1/*3 and VKORC1 A/A
genotype would require a more than 6 times lower daily maintenance dose than a
patient of the same height and with CYP2C9*1/*1 and VKORC1 G/G. (1.16 mg vs.
7.39 mg)
Research is underway to include the MDR1 (Multi Drug Resistance 1) gene and the
Apo E genotype in the algorithm. Diet or drugs known to interact with warfarin
action or metabolism will be included on this web site later.
References:
1. Yuan HY, Chen JJ, Lee MT, Wung JC, Chen YF, Charng MJ, Lu MJ, Hung CR,
Wei CY, Chen CH, Wu JY, Chen YT. A novel functional VKORC1 promoter
polymorphism is associated with inter-individual and inter-ethnic differences in
warfarin sensitivity. Hum Mol Genet. 2005 Jul 1;14(13):1745-51. Epub 2005 May 11
Sconce EA, Khan TI, Wynne HA, Avery P, Monkhouse L, King BP, Wood P, Kesteven
P, Daly AK, Kamali F The impact of CYP2C9 and VKORC1 genetic polymorphism
and patient characteristics upon warfarin dose requirements: proposal for a new
dosing regimen. Blood. 2005 Oct 1;106(7):2329-33. Epub 2005 Jun 9
For a free PDF file of this article please click on this link:
http://www.bloodjournal.org/cgi/reprint/106/7/2329
For more information go to National Center for Biotechnology Information
(NCBI). Most abstracts and many full length articles can be printed from this
web site.
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