A 45-year-old-woman comes to the office for follow-up 2 weeks after hospitalization for acute pyelonephritis. The patient was treated with morphine for pain and a course of broad-spectrum antibiotics, which she has completed. Her symptoms have now resolved. The patient also has a history of mechanical mitral valve replacement and takes warfarin. Physical examination shows no new findings. Her INR was 2.5 at the time of hospital discharge but is 6.2 today despite no change to warfarin dosage. Which of the following best explains the laboratory findings in this patient?

Question

A 45-year-old-woman comes to the office for follow-up 2 weeks after hospitalization for acute pyelonephritis.  The patient was treated with morphine for pain and a course of broad-spectrum antibiotics, which she has completed.  Her symptoms have now resolved.  The patient also has a history of mechanical mitral valve replacement and takes warfarin.  Physical examination shows no new findings.  Her INR was 2.5 at the time of hospital discharge but is 6.2 today despite no change to warfarin dosage.  Which of the following best explains the laboratory findings in this patient?

Quizplus · Accepted Answer

Warfarin is a vitamin K antagonist that inhibits epoxide reductase in the liver, thereby preventing gamma carboxylation of vitamin K-dependent clotting factors (II, VII, IX, X). This creates an anticoagulant state that is reflected on laboratory assessment as a prolonged INR. Because the effect of warfarin is significantly altered by certain foods and medications, patients on long-term warfarin are at risk for subtherapeutic or supratherapeutic INR due to any of the following: Change in dietary vitamin K intake: Increase in dietary vitamin K increases the availability of vitamin K in the liver, which counters the inhibitory effect of warfarin on epoxide reductase. Therefore, patients on warfarin are advised to eat a consistent amount of vitamin K-containing foods (eg, leafy greens, brussels sprouts). Disruption to intestinal flora: Intestinal flora produce vitamin K as a byproduct of metabolism. Therefore, antibiotics that target gram-negative bacteria such as metronidazole, macrolides, and fluroquinolones can cause supratherapeutic INR due to destruction of vitamin K-producing bacteria in the gut. In this patient, the administration of an antibiotic (eg, ciprofloxacin) for pyelonephritis likely destroyed gram-negative bacteria in her gut, thereby reducing vitamin K production and causing a supratherapeutic INR. Alteration to cytochrome P450 2C9 activity: Several medications induce or inhibit cytochrome P450 2C9, which alters the speed of warfarin metabolism. For instance, phenytoin, carbamazepine, and rifampin increased cytochrome P450 2C9 activity, which can result in a subtherapeutic INR (Choice D). In contrast, metronidazole, fluconazole, and amiodarone inhibit cytochrome P450 2C9 activity, which can result in a supratherapeutic INR. (Choice A) Aspirin exerts an anticoagulation effect by inhibiting the release of thromboxane A2 by platelets, which subsequently reduces platelet aggregation. This can lead to prolonged bleeding time but does not increase INR. (Choice C) Anticlotting factor antibodies can occasionally occur due to recent pregnancy, malignancy, or rheumatologic disease. Most cases involve inhibition of factor VIII, which leads to a bleeding diathesis and prolonged aPTT (not INR, which reflects PT). This patient with a recent infection treated with antibiotics is more likely to have supratherapeutic INR due to disruption of vitamin K production by intestinal flora. (Choice E) Increased dietary vitamin K leads to a subtherapeutic INR due to increased vitamin K availability in the liver. Educational objective: Patients on warfarin who take antibiotics that target gram-negative microorganisms (eg, metronidazole, macrolides, fluroquinolones) can develop supratherapeutic INR due to disruption of vitamin K-producing intestinal flora.

A 45-Year-Old-Woman Comes to the Office for Follow-Up 2 Weeks