What causes an elevated International Normalized Ratio (INR)?

From the Guidelines

Elevated International Normalized Ratio (INR) is primarily caused by factors that enhance the anticoagulant effect of warfarin, such as medication interactions, dietary changes, liver disease, alcohol consumption, acute illness, and dosing errors. These factors can lead to an increased risk of bleeding due to the blood becoming too thin. Common causes include medication interactions with warfarin, particularly antibiotics (such as ciprofloxacin, metronidazole, and trimethoprim-sulfamethoxazole), antifungals (fluconazole), amiodarone, and NSAIDs like ibuprofen 1. Dietary changes can also affect INR, especially sudden increases in vitamin K-rich foods like leafy greens, which decrease INR, or decreased intake of these foods, which can increase INR. Liver disease impairs clotting factor production, potentially raising INR, while alcohol consumption, particularly binge drinking, can elevate INR by affecting liver function 1. Acute illness, especially those with fever, diarrhea, or poor oral intake, can disrupt warfarin metabolism. Dosing errors, such as taking double doses or misunderstanding instructions, are another common cause.

Management of Elevated INR

When managing an elevated INR, the primary goal is to reduce the risk of bleeding while minimizing the risk of thromboembolism. According to the 2014 AHA/ACC guideline for the management of patients with valvular heart disease, in most patients with an INR of 5 to 10, excessive anticoagulation can be managed by withholding VKA and monitoring the level of anticoagulation with serial INR determinations 1. In patients with an INR >10 who are not bleeding, it is prudent to administer 1 mg to 2.5 mg of oral vitamin K1 (phytonadione) in addition to holding VKA therapy. When the INR falls to a safe level, VKA therapy is restarted with the dose adjusted as needed to maintain therapeutic anticoagulation.

Key Considerations

• Medication interactions with warfarin can significantly impact INR levels
• Dietary changes, liver disease, alcohol consumption, and acute illness can also affect INR
• Dosing errors are a common cause of elevated INR
• Management of elevated INR depends on the INR level and presence of bleeding
• Vitamin K administration, fresh frozen plasma, or prothrombin complex concentrate may be required in severe cases
• The 2014 AHA/ACC guideline provides recommendations for managing patients with valvular heart disease and elevated INR 1

From the FDA Drug Label

The following factors, alone or in combination, may be responsible for INCREASED PT/INR response: ENDOGENOUS FACTORS: blood dyscrasias — diarrhea hyperthyroidism see CONTRAINDICATIONS elevated temperature poor nutritional state cancer hepatic disorders steatorrhea collagen vascular disease infectious hepatitis vitamin K deficiency congestive heart failure jaundice EXOGENOUS FACTORS: Potential drug interactions with warfarin sodium tablets are listed below by drug class and by specific drugs.

The causes of an elevated International Normalized Ratio (INR) include:

• Endogenous factors:
  • Blood dyscrasias
  • Diarrhea
  • Hyperthyroidism
  • Elevated temperature
  • Poor nutritional state
  • Cancer
  • Hepatic disorders
  • Steatorrhea
  • Collagen vascular disease
  • Infectious hepatitis
  • Vitamin K deficiency
  • Congestive heart failure
  • Jaundice
• Exogenous factors:
  • Potential drug interactions with warfarin sodium tablets, including:
    • Other medications affecting blood elements
    • Dietary deficiencies
    • Prolonged hot weather
    • Unreliable PT/INR determinations
    • Specific drugs such as 17-Alkyl Penicillins, fluoroquinolones, and others 2 2

From the Research

Causes of Elevated International Normalized Ratio (INR)

• Elevated INR values can be caused by various factors, including:
  • Warfarin therapy: High doses or interactions with other medications can lead to elevated INR values 3, 4, 5, 6, 7
  • Kidney function: Lower estimated glomerular filtration rate (eGFR) is associated with a higher risk of bleeding and slower anticoagulation reversal 4
  • Age: Older age is a factor associated with bleeding in patients with elevated INR 5
  • Renal failure: Patients with renal failure are at a higher risk of bleeding and may not respond quickly to warfarin withdrawal or vitamin K treatment 5
  • Alcohol use: Alcohol consumption can increase the risk of bleeding in patients with elevated INR 5, 6
  • Dietary factors: Changes in vitamin K intake, such as increased consumption of vitamin K-rich foods, can affect INR values 6
  • Herbal supplements: Certain herbs, such as Hawthorn, can interact with warfarin and increase the risk of bleeding 6
  • Concurrent medication use: Interactions with other medications, such as Salicylates and Amiodarone, can increase the risk of bleeding and affect INR values 6
  • Noncompliance: Non-adherence to warfarin therapy can lead to elevated INR values 6
  • Comorbid diseases: Certain medical conditions, such as malabsorption, can affect INR values 6
  • Genetic factors: Polymorphisms of vitamin K-epoxide reductase complex (VKORC1) and cytochrome P450 2C9 (CYP2C9) genes can affect warfarin dose and INR values 6

Management of Elevated INR

• Treatment options for elevated INR include:
  • Warfarin withdrawal: Stopping warfarin therapy can help reduce INR values 3
  • Vitamin K administration: Oral or parenteral vitamin K can help reduce INR values 3, 7
  • Fresh frozen plasma (FFP) or prothrombin complex concentrates (PCC): These can be used to rapidly correct INR values in patients with active bleeding 3, 5