What causes elevated International Normalized Ratio (INR)?

Causes of Elevated INR

The most common causes of elevated International Normalized Ratio (INR) include medication interactions (particularly antibiotics, NSAIDs, and acetaminophen), vitamin K deficiency, liver disease, and acute illness such as diarrhea or fever. 1, 2

Medication-Related Causes

• Drug interactions with warfarin are numerous and occur through pharmacodynamic or pharmacokinetic mechanisms, including enzyme inhibition, enzyme induction, and reduced plasma protein binding 2

• Antibiotics can elevate INR through multiple mechanisms:

  • All antibiotics can alter gut microbiome, which is a source of vitamin K, thereby potentiating anticoagulant effects 1
  • Specific antibiotics that inhibit CYP2C9 (such as sulfamethoxazole and metronidazole) can significantly increase INR values 1
  • Fluoroquinolones and macrolides can elevate INR through inhibition of CYP1A2 and CYP3A4 enzymes respectively 1

• NSAIDs potentiate the risk of bleeding with warfarin through both pharmacological interactions and displacement of warfarin from plasma proteins 1

• Acetaminophen increases INR in a dose-dependent manner, with doses exceeding 9100 mg/week increasing the odds of having an INR >6.0 by 10-fold 3

• Herbal supplements can significantly affect INR:

  • St. John's wort decreases INR through enzyme induction 1
  • Bromelains, danshen, dong quai, garlic, Ginkgo biloba, ginseng, and cranberry products typically increase INR 2

Endogenous and Physiological Causes

• Liver disease affects INR by reducing production of clotting factors, particularly factors I, II, V, VII, and X 1

  • In cirrhosis, INR may be elevated due to decreased synthesis of procoagulant factors, though this is often offset by decreased anticoagulant factors like protein C 1

• Vitamin K deficiency can result from:

  • Poor nutritional state 2
  • Dietary deficiencies 2
  • Malabsorption states 4

• Acute illness factors that can elevate INR include:

  • Diarrhea (through decreased vitamin K absorption and decreased oral intake) 4, 2
  • Elevated body temperature/fever 2
  • Congestive heart failure 2
  • Cancer, particularly advanced malignancy 3

• Bleeding events themselves can paradoxically cause INR elevation, creating a potentially dangerous cycle 5

Other Important Causes

• Genetic variations in CYP2C9 and VKORC1 enzymes can affect warfarin metabolism and sensitivity 2

• Excessive alcohol consumption inhibits hepatic enzymes and impairs warfarin clearance 1

• Laboratory factors that can falsely elevate INR:

  • Underfilling blood collection tubes (excess citrate) 1
  • Variations in thromboplastin reagents used in testing 1
  • Lupus anticoagulants can sometimes affect PT/INR results 1

Clinical Implications

• INR elevation >4.0 is associated with significantly increased bleeding risk 2
• INR >9 carries particularly high bleeding risk, especially in hospitalized patients (35% bleeding rate) compared to outpatients (11% bleeding rate) 6
• In patients with elevated INR due to warfarin therapy, management depends on the degree of elevation and presence of bleeding 1
• In non-warfarin patients, elevated INR may indicate serious underlying conditions like liver disease, which carries a poor prognosis 6, 7

Common Pitfalls

• Assuming all elevated INRs in patients on warfarin are due to medication overdose, when bleeding itself can cause INR elevation 5
• Failing to recognize that multiple factors often contribute simultaneously to INR elevation 2
• Not considering the possibility of herbal supplements or over-the-counter medications like acetaminophen as causes of elevated INR 3, 2
• Overreliance on INR as a measure of bleeding risk in patients with liver disease, as it does not account for the concurrent reduction in anticoagulant proteins 1