What causes elevated International Normalized Ratio (INR)?

Causes of Elevated INR

Elevated INR results from medication interactions (especially antibiotics, NSAIDs, and acetaminophen), liver disease reducing clotting factor synthesis, vitamin K deficiency from dietary changes or malabsorption, and laboratory factors—with warfarin-related drug interactions being the most common reversible cause in clinical practice.

Medication-Related Causes

Antibiotics and Antimicrobials

• Antibiotics elevate INR through multiple mechanisms: altering gut microbiome (reducing vitamin K-producing bacteria), inhibiting CYP2C9, and inhibiting CYP1A2 and CYP3A4 enzymes 1
• Fluoroquinolones, trimethoprim/sulfamethoxazole, erythromycin, and metronidazole are particularly potent INR elevators through enzyme inhibition 2

NSAIDs and Analgesics

• NSAIDs potentiate bleeding risk with warfarin through both pharmacological interactions and displacement of warfarin from plasma proteins 1
• Acetaminophen is an underrecognized cause of overanticoagulation, with doses ≥9,100 mg/week increasing the odds of INR >6.0 by 10-fold 3
• The acetaminophen effect is dose-dependent, making it a critical factor to assess in patients with unexplained INR elevation 3

Other Medications

• Amiodarone, omeprazole, esomeprazole, and azole antifungals inhibit warfarin metabolism 2
• Herbal supplements like bromelains, danshen, dong quai, garlic, and Ginkgo biloba increase INR, while St. John's wort decreases it through enzyme induction 1, 2
• Excessive alcohol consumption inhibits hepatic enzymes and impairs warfarin clearance 1

Endogenous and Physiological Causes

Liver Disease

• Liver disease reduces production of clotting factors, particularly factors I, II, V, VII, and X 1
• In ICU patients, a pattern of low Factor V, low or normal fibrinogen, and high Factor VIII suggests liver disease as the cause 4
• Factor VII levels correlate inversely with INR (r = -0.81), as does Factor X (r = -0.67), but not Factor V or fibrinogen 4
• In cirrhosis, INR elevation from decreased procoagulant factors is often offset by decreased anticoagulant factors like protein C 1

Vitamin K Deficiency

• A pattern of low Factor VII, Factor X, protein C, and protein S indicates vitamin K deficiency 4
• Diarrhea causes malabsorption of vitamin K and can result in INR elevation, particularly when combined with decreased oral intake 2, 5
• Poor nutritional state, dietary deficiencies, and prolonged hot weather contribute to vitamin K depletion 2

Other Endogenous Factors

• Hyperthyroidism, elevated temperature, cancer, infectious hepatitis, and congestive heart failure all elevate INR 2
• Blood dyscrasias, collagen vascular disease, and steatorrhea impair hemostasis and clotting factor synthesis 2

Laboratory and Technical Factors

• Underfilling blood collection tubes, variations in thromboplastin reagents, and lupus anticoagulants can falsely elevate INR 1
• Direct oral anticoagulants (DOACs) like apixaban can cause extreme INR elevation, particularly in patients with renal impairment, though INR monitoring is not recommended for DOACs 6

Clinical Context and Risk Stratification

High-Risk Populations

• In ICU patients with INR ≥1.5, vitamin K deficiency pattern (40%) and liver disease pattern (35%) are the most common causes 4
• Older age, renal failure, and alcohol use are independently associated with bleeding in patients with INR >9 7
• Hospitalized patients with INR >9 have a 35% bleeding rate and 17% mortality, compared to 11% bleeding and 0% mortality in outpatients 7

Patients Without Warfarin

• Patients with INR >9 who are not on anticoagulants have a poor prognosis: 67% experience bleeding and 74% die, indicating severe underlying disease 7
• This population requires urgent investigation for liver failure, vitamin K deficiency, or consumptive coagulopathy 7

Important Clinical Pitfalls

• New medications known to potentiate warfarin increase the odds of INR >6.0 by 8.5-fold 3
• Advanced malignancy increases the odds of INR >6.0 by 16.4-fold 3
• Taking more warfarin than prescribed increases the odds of INR >6.0 by 8.1-fold 3
• Higher vitamin K intake and moderate alcohol consumption (1 drink every other day to 2 drinks daily) are protective against excessive anticoagulation 3
• Withholding warfarin or giving vitamin K is often ineffective at reducing INR within 24 hours in hospitalized patients; plasma infusion immediately drops INR to 2.4 ± 0.9 7