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Am Fam Physician. 2000;62(10):2318-2321

Many drugs and foods are known to interfere with the anticoagulation effect of warfarin. Interactions occur through a variety of mechanisms, including interference with warfarin metabolism, displacement from protein binding sites and disturbances of vitamin K absorption or metabolism. Demirkan and colleagues reviewed the literature to study the effects of concurrent disease on response to warfarin.

A MEDLINE search was performed to identify prospective trials, case reports and retrospective studies of the effects of various disease states on response to warfarin. The authors found that the effects of liver disease, hyperthyroidism and hypothyroidism on the response to warfarin are well documented in the literature.

The liver is the principal site of synthesis of plasma proteins and clotting factors. A severe coagulation defect and an exaggerated response to warfarin has been documented in patients with liver failure. A retrospective study of predictors of major bleeding in hospitalized patients receiving warfarin revealed that bleeding episodes correlated with evidence of worsening liver function. Another study found that the presence of alcoholism and severe liver disease was a probable cause of a high International Normalized Ratio.

Hyperthyroid and hypothyroid states alter warfarin efficacy. Hyperthyroidism is associated with an increased sensitivity to oral anticoagulants. The mechanism may be that thyroxine increases the affinity of warfarin for receptor sites in the liver, leading to decreased production of clotting factors. Another mechanism may be increased catabolism of vitamin K–dependent clotting factors. In hypothyroid states, decreased catabolism of vitamin K–dependent clotting factors is believed to cause the decreased response to oral anticoagulants.

One study revealed that the mean half-life of warfarin is significantly reduced in patients with renal dysfunction, but the few studies of the effects of renal disease show no clinically relevant change in the response to warfarin. Small studies and case reports indicate that heart failure, cancer and febrile illness may alter warfarin metabolism, with potentially important clinical results.

The authors conclude that hepatic and thyroid diseases are well documented as disorders that can alter the response to warfarin. Other disease states may also influence coagulation control during warfarin therapy, but more research is needed. The authors urge physicians to consider the effect of concomitant disease as well as food or drug interactions when monitoring anticoagulation with warfarin.

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