Inadvertent Exaggerated Anticoagulation Following Use of Bismuth Subsalicylate in an Enterally Fed Patient Receiving Warfarin Therapy

Abstract

We report a case of an inadvertent increase in the international normalized ratio (INR) after the addition of bismuth subsalicylate for the treatment of diarrhea in an enterally fed patient receiving warfarin therapy. A 56-year-old Caucasian female presented to the trauma intensive care unit (ICU) with multiple lower extremity fractures. Warfarin was initiated for deep vein thrombosis prophylaxis due to the patient's inability to ambulate. The target INR was 2-3. Continuous intragastric enteral feeding was withheld 1 hour before and 1 hour after intragastric administration of warfarin. Bismuth subsalicylate 30 mL every 4 hours was prescribed for diarrhea. Within 3 days after starting bismuth subsalicylate therapy, the patient's INR increased from 2.56 to 3.54 and minor bleeding was noted from the patient's tracheostomy site. No significant change in warfarin dosage, variability in vitamin K intake, or medications that potentially alter warfarin metabolism were present during the unexpected rise in INR. When the bismuth subsalicylate was discontinued, the patient's INR stabilized into the target range on the same warfarin dose given at the time of the supratherapeutic INR. Salicylate displaces warfarin from plasma protein binding sites and may result in a significant increase in INR secondary to redistribution of warfarin to the free active form. Evaluation of this case report using the Drug Interaction Probability Scale and Naranjo Adverse Drug Reaction Probability Scale yielded scores consistent with a probable adverse drug interaction. Bismuth subsalicylate exaggerates warfarin's anticoagulant response and its concurrent use during warfarin therapy should be avoided.

Bismuth Subsalicylate Coagulopathy in a Patient with Chronic Liver Disease

“…The other bismuth subsalicylate case published by Bingham in 2013 resulted in a peak INR of 3.54 in a patient who was on warfarin already for DVT prophylaxis [12]. In contrast, this present case resulted in a peak INR of 7.7 in a patient who was not taking any other anticoagulants but had underlying liver disease.…”

“…Coagulopathy has been reported in patients using salicylate and relevant publications are summarized in the supplemental table, which provides a summary of eight case reports and two case series [10][11][12][13][14][15][16][17][18]. All cases had eventual resolution of coagulopathy before either being discharged from the hospital or expiring.…”

“…Note that several of the reported cases involved salicylate-related coagulopathy in patients with normal hepatic function. One other published case involved bismuth subsalicylate [12], six publications involved acetylsalicylic acid [ 10,11,14,[16][17][18], and two publications involved methyl salicylate [13,15].…”

“…This mechanism is similar to that of coumarin on clotting factor synthesis. It is important to note that case studies describing dangerous bleeding complications from the augmentation of coagulation factor inhibition due to drug interactions between warfarin and salicylate have been reported in literature, including two cases and the case series (see Supplemental Table) [12,13,15].…”

Effects of Enteral Formulas and Their Food Protein and Dietary Fiber Components on Postprandial Plasma Warfarin Concentration in Rats

“…In addition, many interactions with warfarin related to vitamin K and the drug-metabolizing enzyme CYP2C9 have been reported [3][4][5]. Warfarin is often used in combination with enteral formulas in critically ill patients, who are reported to be at risk of a plethora of potential drug-nutrient and drug-drug interactions [6]. In the clinical setting, the simultaneous administration of warfarin with an enteral formula may reduce its bioavailability [7], reduce the maximum serum warfarin concentration [8], or change the PT-INR [9].…”