What causes elevated International Normalized Ratio (INR)?

Causes of Elevated International Normalized Ratio (INR)

Elevated INR can be caused by numerous factors including medications, liver disease, and physiological conditions, with medication interactions being the most common cause in clinical practice. 1, 2

Medication-Related Causes

• Antibiotics can elevate INR through multiple mechanisms, including altering gut microbiome and inhibiting various CYP enzymes (CYP2C9, CYP1A2, and CYP3A4) 1
• NSAIDs potentiate bleeding risk with warfarin through both pharmacological interactions and displacement of warfarin from plasma proteins 1
• Herbal supplements can affect INR in different ways:
  • Some decrease INR (e.g., St. John's wort through enzyme induction)
  • Others increase INR (e.g., bromelains, danshen, Ginkgo biloba) 1
• Excessive alcohol consumption inhibits hepatic enzymes and impairs warfarin clearance 1
• Acetaminophen has a dose-dependent relationship with elevated INR, with doses ≥9100 mg/week increasing the odds of INR >6.0 by 10-fold 3
• Other medications that can increase INR include:
  • Antifungals (fluconazole, miconazole)
  • Amiodarone
  • Statins
  • Certain antibiotics (fluoroquinolones, macrolides)
  • Direct oral anticoagulants (can artificially elevate INR measurements) 2, 4

Endogenous and Physiological Causes

• Liver disease affects INR by reducing production of clotting factors, particularly factors I, II, V, VII, and X 1
• Cirrhosis may elevate INR due to decreased synthesis of procoagulant factors, though this is often partially offset by decreased anticoagulant factors like protein C 1
• Advanced malignancy is strongly associated with elevated INR (odds ratio 16.4) 3
• Hyperthyroidism can increase metabolism of clotting factors 2
• Poor nutritional state and vitamin K deficiency impair synthesis of clotting factors 2
• Diarrheal illness (odds ratio 3.5) and decreased oral intake (odds ratio 3.6) are independent risk factors for elevated INR 3

Laboratory and Technical Factors

• Underfilling blood collection tubes can falsely elevate INR 1
• Variations in thromboplastin reagents between laboratories can affect INR results 1
• Lupus anticoagulants can cause falsely elevated INR readings 1
• End-stage renal disease can affect drug clearance, potentially leading to drug accumulation and elevated INR 4

Warfarin-Specific Factors

• Taking more warfarin than prescribed (odds ratio 8.1) significantly increases risk of elevated INR 3
• Genetic variations in CYP2C9 and VKORC1 enzymes can affect warfarin metabolism and sensitivity 2
• New medications known to potentiate warfarin (odds ratio 8.5) 3
• Prolonged hot weather can affect warfarin metabolism 2

Protective Factors

• Higher vitamin K intake (odds ratio 0.7) is associated with decreased risk of elevated INR 3
• Moderate alcohol consumption (1 drink every other day to 2 drinks daily) appears protective (odds ratio 0.2) 3

Clinical Implications

• The risk of hemorrhage approximately doubles for each one-point increase in INR above 3.0 5
• Patients with INR >9 without anticoagulant treatment have poor prognosis (67% experience bleeding, 74% mortality) 6
• Outpatients on warfarin with INR >9 have lower bleeding risk (11%) and better survival 6
• Hospitalized patients with INR >9 may not respond quickly to withholding warfarin or vitamin K treatment, and may require plasma infusion to reduce INR within 24 hours 6

Common Pitfalls in Managing Elevated INR

• Failure to recognize acetaminophen as a significant cause of elevated INR 3
• Not accounting for dietary changes, especially fluctuations in vitamin K intake 2
• Overlooking herbal supplements and over-the-counter medications when assessing causes 1, 2
• Assuming direct oral anticoagulants don't affect INR (they can cause artificial elevations) 4
• Inadequate monitoring frequency after medication changes that might affect warfarin metabolism 2, 7