An Unlikely Culprit of Hospital-Acquired Warfarin Resistance: A Case Report and Review of Literature

Abstract

Purpose

Warfarin is an anticoagulant medication used to prevent thromboembolic events in many conditions, but therapeutic monitoring requires close attention to prevent serious side effects. Resistance to warfarin can be acquired or hereditary, and many foods and medical conditions have been implicated in acquired warfarin resistance, such as supplemental nutrition shakes in this case presentation.

Case Summary

A 65-year-old woman with a prior mechanical aortic valve replacement presented for an elective non-cardiac surgery. She was chronically stable at an international normalized ratio (INR) goal of 2.5–3.5. Surgery was performed without complication, and postoperative INRs were persistently low at 1.5–1.8, despite escalating warfarin doses up to 15 mg warfarin daily at day 12. After a thorough medication and dietary review, the culprit was identified as Boost Plus Nutritional Drinks, a significant source of vitamin K, that she had consumed only while hospitalized postoperatively. Her INR normalized after stopping the shake consumption.

Discussion

This is the first known case of a hospitalized patient who developed acquired warfarin resistance from nutritional shakes. Hospitalized patients routinely require supplemental nutrition, and hospitals have a variety of nutritional shakes available, all of which have varying amounts of vitamin K. A review of available supplemental nutrition shakes revealed MightyShakes as the only brand without a significant amount of vitamin K, but other brands also have relatively small quantities of Vitamin K.

Conclusion

Supplement administration requires close attention in hospitalized patients on warfarin. Certain brands of nutritional shakes, like MightyShakes, can be safely utilized in such patients if caution is exercised.

Introduction

Warfarin is an anticoagulant medication that has been in clinical use in the United States since the 1950s. It works by inhibiting an important enzyme in the coagulation cascade, the vitamin K epoxide reductase.¹ This enzyme is necessary for the generation of coagulation cascade factors II, VII, IX, and X. By inhibiting these factors adequately, anticoagulation can be achieved. Many conditions require therapeutic anticoagulation, and in patients who have mechanical prosthetic heart valves and antiphospholipid syndrome, warfarin is the preferred anticoagulant.^2,3 Use of Warfarin requires constant monitoring to achieve and maintain a safe therapeutic range. Under and over anticoagulation both have profound consequences such as gastrointestinal or cerebral hemorrhages or embolic strokes, which can all be life-threatening.⁴

Monitoring warfarin therapy requires the use of the international normalized ratio (INR). The INR serves to measure the patient’s prothrombin time (PT) and compares it against the mean normal PT.⁵ Titrating the INR to the appropriate range is vital and challenging at times. Dietary intake of certain foods or supplements has been known to interfere with warfarin and its anticoagulant effects in the body, and thereby, the INR.¹

While there are no definitive warfarin resistance dosage criteria, it has been accepted as requiring over 105 mg per week (15 mg/day) to reach target INR levels.⁶ Warfarin resistance can be further classified into two categories: hereditary or acquired resistance. Hereditary resistance (HR) arises from polymorphisms in genes such as CYP2C9 and VKORC1 that affect warfarin metabolism or activity. Acquired resistance includes external factors that influence warfarin’s metabolism and pharmacodynamics, such as poor medication compliance as well as dietary and drug interactions.^6–8 Even after an exhaustive workup, an underlying etiology for warfarin resistance occasionally cannot be ascertained.⁹ The medical literature lacks specific data on the prevalence of acquired warfarin resistance, but partial, and less commonly complete, hereditary warfarin resistance is seen in up to 20% of Caucasian patients.¹⁰

Acquired warfarin resistance is more common and can result from a variety of factors. Drug interactions play a key role including medications that induce the cytochrome P450 enzyme, such as oxcarbazepine, which thereby accelerates warfarin’s metabolism and reduces its efficacy.¹¹ Additionally, significant intake of vitamin K-rich foods, such as green leafy vegetables, counteracts warfarin’s anticoagulant effects by promoting clotting factor synthesis, and Table 1 below demonstrates some foods that are rich sources of vitamin K.¹²

Table 1.

Ten Significant Food Sources of Vitamin K

Food Name	Percent of Recommended Daily Vitamin K Intake (120 mcg) per Measure (One Cup)
Frozen Kale	955%
Frozen Collards	883%
Canned Spinach	743%
Frozen Turnip Greens	709%
Cooked Mustard Greens	691%
Cooked Beet Greens	581%
Cooked Dandelion Greens	483%
Cooked Swiss Chard	477%
Frozen or Cooked Brussel Sprouts	250%
Raw Garden Cress	226%
Frozen Broccoli	135%

We hereby report a case of acquired warfarin resistance that occurred in a hospitalized patient with chronically stable outpatient INRs and was attributed to the intake of supplemental nutrition shakes.

Case Report

The case presented is that of a 65-year-old woman with a history of aortic valve disorder status post mechanical aortic valve replacement 12 years prior to presentation. She also had a history of heart failure with preserved ejection fraction, atrial fibrillation, hyperlipidemia, and hypertension. Her home medications at presentation included lisinopril 10 milligrams (mg) daily, dapagliflozin 10 mg daily, and warfarin 5 mg daily of which she was chronically stable at an INR goal of 2.5–3.5. She was electively admitted to the hospital for non-cardiac surgery.

Upon presentation, her vital signs were stable, and she had no evidence of infection. Preoperative laboratory values showed an INR of 2.8. Due to the planned surgery, it was deemed necessary to temporarily discontinue her warfarin and transition to intravenous heparin.

The surgery proceeded without any complication noted. Heparin was discontinued prior to the procedure and restarted 24 hours after the operation. Mild ileus delayed oral feeding and medication administration for an additional 3 days. After her ileus resolved, she was placed on oral warfarin with heparin bridging. She was also started on a liquid diet.

Postoperative INR lab results revealed persistent daily low INRs of 1.5–1.8 despite escalating warfarin doses. On day ten after her operation, she continued to require high doses of warfarin with a continued heparin infusion. At this point, it was evident that the patient was not achieving adequate anticoagulation despite significantly increased warfarin dosing. By postoperative day twelve, her INR was 1.5 with 15 mg of warfarin daily. This suggested acquired warfarin resistance, but an exhaustive review of medication interactions failed to identify any contributing factors. A dietary review then identified the daily intake of two bottles of Boost Plus Nutritional Drinks that the patient had been consuming only postoperatively in the hospital. The nutritional drink labelling identified each bottle as having 30 mcg of vitamin K or 25% of the recommended daily intake. This nutritional supplement was discontinued, and on postoperative day fifteen, two days after discontinuing the Boost drinks, her INR reached 2.0. On postoperative day seventeen, her INR was therapeutic at 2.6. Heparin was discontinued, and the patient was discharged on 6 mg of oral warfarin daily.

Discussion

This case offers a unique presentation of a patient on warfarin with a chronically stable outpatient INR who presented to the hospital for a non-cardiac surgery. The patient had a prolonged postoperative stay due to a persistently subtherapeutic INR. The low INR, despite high doses of warfarin, was attributed to acquired warfarin resistance from the vitamin K in her nutritional drinks. Cessation of the drink led to a stable therapeutic INR on a lower warfarin dosage. While it has been previously demonstrated that certain nutritional supplements, such as certain multivitamins, can lead to alterations in INR due to their Vitamin K content, this is the first known case report of a hospitalized patient who developed acquired warfarin resistance that was directly attributable to the intake of supplemental nutrition shakes.¹³ Acquired warfarin resistance in the hospital setting has only previously been linked to the initiation of parenteral nutrition when elevated levels of vitamin K were found to be present in the nutritional formula that was used.¹⁴

The vitamin K in our patient’s supplemental shakes led to her acquired warfarin resistance. Vitamin K has been shown to have a plasma half-life of around 8.8 hours but a tissue half-life of up to 215 hours.¹⁵ These pharmacokinetics demonstrate why it took an additional five days after nutritional shake cessation for our patient to reach a therapeutic INR. Furthermore, dapagliflozin and lisinopril do not have any clinically significant interactions with warfarin, so no confounding medications could explain this patient’s persistent subtherapeutic INR.^16,17

Frequently, as in the case of our patient, hospitalized patients require supplemental nutrition due to the inability to tolerate oral intake for a variety of reasons ranging from gastrointestinal intolerance to a lack of appetite. The use of supplemental nutrition as opposed to gastrointestinal rest is universally practiced, even in critically ill patients.¹⁸ Many hospitals, including our own hospital, have supplemental nutrition shakes available, and many patients ask for these shakes by their brand name. There are many assorted brands of supplemental nutrition shakes readily available in hospitals. These include the following brands: Boost, Carnation, Ensure, and Glucerna.¹⁹ While the ease of access and the need for nutrition supplementation are important considerations in the implementation of these shakes in hospitalized patients, this case report serves as a reminder that careful review of nutrition labels should be implemented as well as consideration of specific patient circumstances before use of these shakes can be advised. A thorough dietary review, including supplements, is indicated when evaluating for an underlying cause of persistent, newfound subtherapeutic INRs, like the case of our patient, as a previous systematic review of 149 articles showed a considerable number of various foods and nutritional supplements that potentiated or inhibited the effects of warfarin.²⁰ Notably, harmful interactions with prescription medications and dietary and herbal supplements may occur in up to 3.7% of hospitalized patients.²¹

While most patients in the hospital are safe to consume these shakes, patients who use vitamin K antagonists, like warfarin, should attempt to avoid consumption of these shakes if at all possible due to the potential loss of efficacy of warfarin. A review of known nutritional supplement shakes available on the market and those specifically available for patients in our hospital was performed. Table 2 below lists those that are available in our hospital.

Table 2.

Vitamin K Content per Each Nutritional Shake Available in Our Hospital

Nutritional Shake Brand Name	Percent of Recommended Daily Vitamin K Intake (120 mcg) per Shake
Boost Very High Calorie	50%
Carnation Breakfast Essentials High Protein	33%
Carnation Breakfast Essentials Light Start	29%
Boost: Glucose, Plus, and High Protein	25%
Compleat Standard 1.4	25%
Novasource Renal	25%
Impact Advanced Recovery	18%
Boost Breeze	13%
Vivonex RTF	11%
MightyShake	0%

Other available supplements on the market include the following brands of nutritional shakes with associated percent of daily vitamin K: Osmolite 1 cal (21%), Ensure (21%), Advera (20%), Glucerna (17%), Slim Fast (17%), Nepro (16%), Jevity 1 cal (13%), and Isocal (11%).¹⁹ Ideally, when patients on warfarin therapy require supplemental nutrition in the hospital, a shake with as minimal an amount of vitamin K as possible should be implemented to not lead to profound deviations in INR from the baseline of patients. Based on its negligible vitamin K content and not based on any particular brand association, we would recommend implementation of MightyShakes for patients on chronic warfarin who require supplemental nutrition in the hospital. It is also reasonable to consider one Vivonex RTF or Isocal shake due to each shake only having 11% of the recommended daily vitamin K. Finally, in patients who request Boost products due to their popularity, such as our patient, we would recommend Boost Breeze shakes due to each shake having one half or one fourth of the amount of vitamin K per serving as compared to other Boost brand shakes. All suggested nutritional shakes are based solely on the quantity of vitamin K content and are not based on any particular brand associations.

Limitations to this case report include the fact that this case was based on temporal associations between the intake of a product rich in vitamin K and warfarin resistance. Plasma levels of vitamin K were never obtained. Furthermore, while it is likely that this patient’s case reflects acquired warfarin resistance, she was never tested for genetic variants that are known to be associated with hereditary warfarin resistance. Finally, this is a single-patient observation, and further examples are needed to demonstrate a stronger association between vitamin K-rich supplemental nutrition shakes and acquired warfarin resistance.

Conclusions

In hospitalized patients who require vitamin K-dependent anticoagulation, nutritional supplements require close attention, as these supplements can lead to acquired warfarin resistance. Nutritional shakes with the lowest vitamin K content can be safely utilized in such patients if caution is exercised.

Abbreviations

INR, international normalized ratio; PT, prothrombin time; HR, hereditary resistance.

Ethics Statement

Since this is a case report, an Ethics Committee/Institutional Review Board was not involved.

Patient Consent Statement

The patient provided written consent to allow their treatments to be studied to help improve care for themselves and others.

Disclosure

The authors report no conflicts of interest in this work.