What causes an elevated International Normalized Ratio (INR)?

Causes of Elevated INR

Elevated INR results from warfarin therapy, liver disease impairing clotting factor synthesis, vitamin K deficiency, drug interactions (especially antibiotics and NSAIDs), or laboratory/technical factors affecting measurement.

Warfarin-Related Causes

Drug Interactions

• Antibiotics are among the most common culprits, elevating INR through multiple mechanisms: altering gut microbiome (reducing vitamin K production), inhibiting CYP2C9, and inhibiting CYP1A2/CYP3A4 enzymes 1, 2
• NSAIDs potentiate bleeding risk through both pharmacological interactions and displacement of warfarin from plasma proteins, though the primary concern is bleeding rather than INR elevation per se 1
• Acetaminophen causes dose-dependent INR elevation: doses ≥9,100 mg/week increase the odds of INR >6.0 by 10-fold 3
• Fluoroquinolones, trimethoprim/sulfamethoxazole, erythromycin, and metronidazole are particularly problematic antibiotics 2

Herbal Supplements and Botanicals

• St. John's wort decreases INR through enzyme induction 1, 2
• Bromelains, danshen, dong quai, garlic, and Ginkgo biloba increase INR 1, 2
• Cranberry products are associated with increased warfarin effects 2
• Coenzyme Q10 decreases warfarin effects 2

Dietary and Lifestyle Factors

• Excessive alcohol consumption inhibits hepatic enzymes and impairs warfarin clearance 1
• Paradoxically, habitual moderate alcohol consumption (1 drink every other day to 2 drinks daily) is associated with decreased risk of excessive anticoagulation 3
• Dietary deficiencies and decreased oral intake increase INR 2, 3
• Higher vitamin K intake decreases INR 3

Endogenous and Disease-Related Causes

Liver Disease

• Liver disease reduces production of clotting factors (particularly factors I, II, V, VII, and X), directly elevating INR 1
• In cirrhosis, decreased synthesis of procoagulant factors elevates INR, though this may be partially offset by decreased anticoagulant factors like protein C 1
• Infectious hepatitis, hepatic disorders, and jaundice all elevate INR 2

Other Medical Conditions

• Hyperthyroidism increases warfarin sensitivity 2
• Congestive heart failure elevates INR 2
• Diarrheal illness increases risk of INR >6.0 by 3.5-fold 3
• Blood dyscrasias, cancer (especially advanced malignancy with 16-fold increased odds of INR >6.0), and collagen vascular disease 2, 3
• Poor nutritional state, steatorrhea, and vitamin K deficiency 2
• Elevated temperature/fever 2

Laboratory and Technical Factors

Pre-analytical Issues

• Underfilling blood collection tubes spuriously prolongs PT/INR due to excess citrate 4
• Higher citrate concentrations (3.8% vs 3.2%) lead to higher INR values; using 3.2% citrate collection tubes reduces this problem 4

Analytical Variability

• Variations in thromboplastin reagents affect INR reliability—reagents with higher ISI values result in higher coefficients of variation 4
• Automated clot detectors can influence INR accuracy since INR is based on manual clot detection methods 4
• ISI values provided by manufacturers are not invariably correct, adversely affecting measurement reliability 4

Special Populations

• Lupus anticoagulants usually cause only slight PT prolongation but can affect INR measurement depending on reagents used 4
• The INR is less reliable early in warfarin therapy (first 6 weeks) when results are obtained from different laboratories 4

Direct Oral Anticoagulants (DOACs)

Apixaban Effects

• Apixaban can significantly elevate INR despite not requiring monitoring—median INR of 1.4-1.7 has been reported, with 84.5% of hospitalized patients showing elevated INR on day 1 of therapy 5, 6
• Extreme elevations (INR >20) are rare but documented, particularly in patients with end-stage renal disease on hemodialysis 5
• INR monitoring is not recommended for DOACs as it does not accurately reflect anticoagulant activity 5, 6

Critical Clinical Pitfalls

Medication Changes

• Taking more warfarin than prescribed increases odds of INR >6.0 by 8-fold 3
• New medications known to potentiate warfarin increase odds of INR >6.0 by 8.5-fold 3
• More frequent INR monitoring is essential when medications (including botanicals) are initiated, discontinued, or taken irregularly 2

High-Risk Scenarios

• Patients without anticoagulant treatment who have INR >9 have extremely poor prognosis: 67% experience bleeding and 74% mortality 7
• Among hospitalized warfarin patients with INR >9,35% had bleeding and 17% died 7
• Risk factors for bleeding with elevated INR include older age, renal failure, and alcohol use 7

Management Considerations

• Withholding warfarin or vitamin K treatment may be ineffective at reducing INR within 24 hours in hospitalized patients 7
• Fresh frozen plasma immediately drops INR (to approximately 2.4) and may be needed for rapid reversal 7
• For non-bleeding patients with INR of 9, low-dose vitamin K1 (2.5 mg phytonadione orally) is appropriate 8