Warfarin has a complicated pharmacology: the dose you take today isn’t likely to affect you blood thinning level for about three days; and it has a complicated, yet very specific effect, blocking the production of Vitamin K in one’s liver. It blocks Vitamin K by “competitive inhibition:”
Warfarin inhibits epoxide reductase (specifically the VKORC1 subunit), thereby diminishing available vitamin K and vitamin K hydroquinone in the tissues, which inhibits the carboxylation activity of the glutamyl carboxylase. When this occurs, the coagulation factors are no longer carboxylated at certain glutamic acid residues, and are incapable of binding to the endothelial surface of blood vessels, and are thus biologically inactive. As the body stores of previously-produced active factors degrade (over several days) and are replaced by inactive factors, the anticoagulation effect becomes apparent. The coagulation factors are produced, but have decreased functionality due to undercarboxylation; they are collectively referred to as PIVKAs (proteins induced [by] vitamin K absence/antagonism). Hence, the effect of warfarin is to diminish blood clotting in the patient.But Vitamin K is not just made in the liver. Vitamin K is also made by bacteria that reside in the gut.
This is why blood thinning levels sky-rocket when people take antibiotics – not because they necessarily affect the production of Vitamin K in the liver, but rather that the antibiotic kills the gut bacteria that provide an important amount of Vitamin K to the blood stream. Genetic testing tests humans, not the bacteria that reside in human’s gut. And the number of other confounding drug interactions reads like a Who’s Who of pharmacology.
So it is interesting that today’s Wall Street Journal discusses that the FDA is going to add a labeling change to warfarin that says that the initial lower warfarin dose “should be considered for patients with certain genetic variations.”
Never mind that the testing is not covered by all insurers.
Never mind that this testing adds significant costs.
Never mind that the testing takes about 10 days to return, is performed at only one lab in North Carolina, and returns only AFTER the initial dosing is performed in the first place.
Never mind that there have been no prospective, multi-center, randomized real-world clinical trials demonstrating that the application of these tests effects outcomes or reduces the incidence of bleeding in patients – especially patients carefully monitored in specialized “coumadin clinics.”
Never mind that it exposes doctors to significant claims of negligence if the tests are not used.
Never mind the conflict of interest that exists within the FDA’s fee-for-review structure that makes this labeling change sound like a boon for the genetic testing companies and a kick-back to the FDA.
And what if a patient refuses warfarin because they were found to be positive for a genetic defect, citing their risk of bleeding might be too high without really knowing the risks?
Will the FDA want to talk to my patient after their stroke?
18:24 - Addendum: Links fixed.
19:30 - The FDA's News Release and the Package Insert (pdf) - Genetic recommendations are on page 25.