Warfarin sensitivity testing

WARF

Test Synonym:

CYP2C9 and VKORC1 allele testing

Test Synonym:

83891

83896 x 11

83908 x 3

83912

Turnaround Time:

2-3days

Methodology:

Verigene® Warfarin Metabolism Nucleic Acid Test (IVD)

Specimen Requirements:

5ml (min. 3ml) EDTA blood

Causes for Rejection:

<3ml blood, Improper specimen labeling

Specimen Stability:

18-25°C for 24 hours; 4° C for up to 4 days

Storage and Handling:

Ship at ambient temperature; If shipment is delayed, store at 2-8°C and ship with ice pack (do not allow ice pack to directly contact sample)

Reference Range:

CYP2C9*2 allele detected/not detected

CYP2C9*3 allele detected/not detected

VKORC1 1173C>T allele detected/not detected

Indication:

Identification of patients at risk for increased warfarin sensitivity.

The molecular target of warfarin is the Vitamin K Epoxide Reductase Complex, subunit 1 (VKORC1). In the body, the VKORC1 enzyme uses Vitamin K and other cofactors to activate clotting factors in the blood.Warfarin is metabolized in the liver by an enzyme called cytochrome P4502C9 (CYP2C9 or 2C9).

Inhibition of CYP2C9 enzyme function and thus metabolism of warfarin can be caused by underlying genetic variation. There are two common mutations in the CYP2C9 gene that give rise to less functional forms of the enzyme. These mutations are referred to as: CYP2C9*2 and CYP2C9*3. Having one or more of these mutations will impair an individual’s ability to metabolize warfarin and thus will require a lower dose to reach a stable PT-INR of 2.0-3.0.

Unlike CYP2C9, no VKORC1 mutations have been identified that produces a clearly dysfunctional protein. But rather, a series of mutations have been identified that alter the amount of VKORC1 protein that is produced. The presence of one or more of these VKORC1 mutations gives rise to two groups of patients. A high-dose group also referred to in the literature as haplotype B or haplotype BB and a low-dose group also referred to in the literature as haplotype A or haplotype AA.

Combined with other clinical data, knowledge of an individual’s CYP2C9 genotype (as it relates to CYP2C9*2 and CYP2C9*3) and their VKORC1 haplotype can explain a significant portion of the variability in Warfarin dose required to achieve a stable coagulation state (INR). Patient-specific dosing requirements can be obtained by combining this genetic information with additional relevant clinical information in a warfarin dosing algorithm such as:Warfarin dosing algorithm: www.warfarindosing.com.

It is important to note that not all patients who carry gene variations in their CYP2C9 and VKORC1 genes will have a bleeding event, nor will all patients without these genetic variants avoid a bleeding episode. As such, the Warfarin Sensitivity Test does not replace the PT INR for monitoring patients receiving warfarin therapy.

Related Tests:

Prothrombin time with INR(PT)

ThomboFLEX™ profile: Factor II Prothrombin, Factor V Leiden, Plasminogen Activator Inhibitor

References:

Wadelius M et al (2005). Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenetics J. 5:262-270.
Sanderson S et al (2005). CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HUGEnet systematic review and meta-analysis. Genet Med 7:97-104, 2005
McClain MR et al (2007). A rapid ACCE review of CYP2C9 and VKORC1 allele testing to inform warfarin dosing in adults at elevated risk for thrombotic events to avoid serious bleeding. www.acmg.net
McWilliams A et al (2006). Health care savings from personalizing medicine using genetic testing: The case of warfarin. http://www.aei.brookings.org/publications/abstract.php?pid=1127
www.fda.gov/medwatch/safety/2006/coumadin_PI_april2006.pdf