CYP2C9 and VKORC1: why warfarin doses differ between people

Warfarin lowers the blood's ability to clot by interfering with vitamin K, which the liver needs to activate several clotting proteins. It is used to prevent clots in conditions such as atrial fibrillation and after some clots in the legs or lungs. The problem is a narrow margin: too little leaves a clot risk, and too much risks bleeding.

The NHS says the main side effect of warfarin is an increased risk of bleeding, and that doses may change according to blood test results. Part of the variation behind those changes is genetic, part is diet, other medicines, illness and age.

MedlinePlus Genetics explains that CYP2C9 plays a major role in breaking down warfarin and also helps with ibuprofen and some other medicines. In people of European ancestry the variants CYP2C9*2 and *3 slow that clearance, and the page describes typical warfarin dose reductions of about one third and one fifth respectively. In people of African ancestry, variants such as *5, *6, *8 and *11 are described as needing reductions in the range of one third to one sixth.

Those figures illustrate scale only; they are not a dosing instruction. People with more than one variant have severely reduced enzyme activity and a higher chance of overdose complications, including bleeding in the brain or gut. Dosing is set by the anticoagulation clinic from INR results.

VKORC1 encodes the enzyme that recycles vitamin K for clotting proteins. MedlinePlus Genetics notes that the common -1639G>A variant, especially frequent in people of Asian and European descent, lowers enzyme production. With less target enzyme, less warfarin is needed to achieve the same effect.

The opposite also happens. The Asp36Tyr variant reduces the enzyme's ability to bind warfarin, which produces warfarin resistance, meaning higher doses are required. Neither pattern is a disease in itself; each is simply a reason that some people sit far from the average dose.

• Sensitive to warfarin: lower doses are usually enough.

• Typical response: standard dose-finding through INR.

• Resistant to warfarin: higher doses are sometimes needed, which a clinic will notice when the INR will not rise as expected.

The FDA table of pharmacogenetic associations advises taking clinical and genetic factors into account when choosing a starting dose. In UK practice the NHS patient information does not describe a genetic test, and instead describes INR monitoring: frequent tests at first, then about every 12 weeks when stable.

In effect the INR result tells the clinic how your body is actually responding, which includes the effect of genes, food, illness and other medicines at the same time. A genetic result might help predict that response, but it cannot replace the real-time measure.

The NHS notes that foods high in vitamin K, including broccoli, spinach and leafy greens, can affect warfarin, and that cranberry products, grapefruit juice and heavy alcohol use should be avoided. NSAIDs, antibiotics and antidepressants are among medicines that can interact.

One striking example is miconazole. The MHRA reported that it inhibits CYP2C9, reducing warfarin clearance, and that among 146 reports about half involved INR rises above 10, where the usual target range is 2 to 3. Three reports had fatal bleeding outcomes. Anyone on warfarin should check with a pharmacist before using miconazole products.

The NHS lists blood in urine or stools, unexplained bruising, coughing up blood and a sudden severe headache with neurological symptoms as warning signs of bleeding. Seek emergency help (999) for a head injury, heavy bleeding that will not stop or signs of a bleed in the brain.

Tell the anticoagulation clinic about any new medicine, illness with vomiting or diarrhoea, or major diet change, because they can all alter the INR.