What could be the reasons for a significant increase in International Normalized Ratio (INR) from 2.6 to 5.6 in one week in a patient with a history of atrial fibrillation, deep vein thrombosis, or pulmonary embolism, and currently on warfarin (anticoagulation therapy)?

Causes of INR Elevation from 2.6 to 5.6 in One Week

The most common causes of this significant INR increase are drug interactions (particularly antibiotics), dietary changes reducing vitamin K intake, acute illness with fever or hepatic dysfunction, and medication non-adherence or dosing errors. 1, 2

Drug Interactions

Antibiotics are among the most frequent culprits for sudden INR elevation in warfarin patients:

• Cephalosporins (especially cefazolin) can cause dramatic INR increases, with documented cases showing INR >22 when combined with poor nutritional status 3
• Acetaminophen at doses >2g/day can significantly elevate INR after only a few days of therapy 4
• Dronedarone increases INR approximately 10 days after initiation, requiring warfarin dose reduction of approximately 20% 5
• Chemotherapy agents (carboplatin, etoposide) can cause delayed INR elevation up to 16 days after administration through protein displacement mechanisms 6
• Any CYP2C9 inhibitors will increase warfarin sensitivity and prolong INR 4, 2

Dietary and Gastrointestinal Factors

Changes in vitamin K intake or absorption directly affect warfarin response:

• Reduced dietary intake of vitamin K-containing foods (green leafy vegetables) enhances warfarin's anticoagulant effect 4, 2
• Acute diarrhea lasting 1-4 days causes vitamin K malabsorption and can produce repeated INR elevations, with INR changes correlating with diarrhea duration 7
• Decreased oral intake during illness (eating only 25-50% of normal) reduces vitamin K ingestion 7
• Malnutrition potentiates warfarin effect and increases risk of excessive anticoagulation 3

Acute Medical Illness

Intercurrent illness affects warfarin metabolism and clotting factor synthesis:

• Fever temporarily increases warfarin sensitivity 1
• Hepatic dysfunction potentiates warfarin response through impaired synthesis of clotting factors and decreased warfarin metabolism 2
• COVID-19 or other acute infections combined with poor nutritional intake create a high-risk scenario for INR elevation 3

Age-Related Factors

Elderly patients exhibit greater anticoagulant response to warfarin:

• Patients >60 years show increased sensitivity to warfarin's anticoagulant effects through combined pharmacokinetic and pharmacodynamic mechanisms 2
• Patients >75 years require approximately 1mg/day less warfarin than younger individuals to maintain comparable INR levels 4
• R-warfarin clearance may decrease slightly with age (half-life 37-89 hours), contributing to accumulation 2

Medication Adherence Issues

Dosing errors or changes in warfarin administration:

• Accidental double-dosing or taking extra doses
• Recent warfarin dose increase without appropriate monitoring
• Pharmacy dispensing errors providing higher strength tablets
• Patient confusion about dosing instructions, particularly in elderly patients 1

Critical Pitfalls to Avoid

Do not overlook these common scenarios:

• Antibiotic prescriptions require INR monitoring within 3-7 days of initiation, as this is the most frequent cause of sudden INR elevation in stable patients 1, 3
• Over-the-counter medications including acetaminophen, herbal supplements, and dietary supplements must be specifically queried 1, 4
• Recent medication changes of any kind warrant increased INR monitoring frequency 1
• Gastrointestinal symptoms (diarrhea, decreased appetite) should trigger more frequent INR checks even if seemingly minor 7

Immediate Assessment Algorithm

Systematically evaluate in this order:

1. Review all medications started or changed in the past 2 weeks, including antibiotics, over-the-counter drugs, and supplements 1, 4
2. Assess dietary changes specifically asking about reduced food intake or changes in green vegetable consumption 7
3. Evaluate for acute illness including fever, infection (particularly COVID-19), or gastrointestinal symptoms 3, 7
4. Verify warfarin dosing by reviewing pill bottles and patient understanding of current regimen 1
5. Check for signs of bleeding including bruising, hematuria, melena, or other hemorrhagic manifestations 1

Management Considerations

For INR 5.0-5.6 without bleeding:

• Withhold 1-2 doses of warfarin and resume at lower dose when INR approaches therapeutic range 1
• Recheck INR within 24-48 hours to ensure downward trend 1
• Identify and address the underlying cause to prevent recurrence 1
• Vitamin K administration is generally not required for INR 5.0-5.6 without bleeding, but consider oral vitamin K 1-2mg if INR continues rising 1, 8