How to investigate an elevated International Normalized Ratio (INR)?

Investigation of Elevated INR

When investigating an elevated INR, immediately assess for bleeding and determine whether the patient is on warfarin or vitamin K antagonist (VKA) therapy, as the INR is only validated for monitoring VKA therapy and should not be used as a general coagulopathy screen in non-VKA patients. 1, 2

Initial Assessment Framework

1. Determine Clinical Context

Establish if the patient is on VKA therapy:

• The INR was specifically designed and validated only for patients receiving warfarin or other vitamin K antagonists 1, 2
• In non-VKA patients, an elevated INR lacks biological plausibility as a bleeding predictor and should prompt investigation for underlying liver disease, vitamin K deficiency, or other coagulopathies 1

Assess for active bleeding:

• Check for overt bleeding (gastrointestinal, intracranial, genitourinary, or other sites) 1
• Look for occult bleeding signs: unexplained anemia, hemodynamic instability, or new neurological deficits 3

2. Investigate Causative Factors in VKA Patients

Medication-related causes:

• Review all recent medication changes, including antibiotics (especially fluoroquinolones, metronidazole), antifungals, amiodarone, and NSAIDs 4
• Assess for new botanicals or herbal supplements, which lack standardization and can unpredictably affect INR 4
• Evaluate for medication non-adherence or accidental overdosing 1

Dietary and nutritional factors:

• Investigate recent changes in vitamin K intake (green leafy vegetables, nutritional supplements) 1, 4
• Assess for poor nutritional state, malabsorption, or diarrhea causing vitamin K deficiency 4

Medical conditions:

• Evaluate for acute illness, particularly infections with elevated temperature 4
• Check liver function tests to assess for hepatic dysfunction or infectious hepatitis 4
• Assess thyroid function, as hyperthyroidism increases warfarin sensitivity 4
• Consider congestive heart failure, which can alter warfarin metabolism 4
• Evaluate renal function, as renal failure is associated with increased bleeding risk 5

Laboratory verification:

• Repeat INR to confirm the elevation and rule out laboratory error 1, 4
• Ensure the test was performed with appropriate thromboplastin (ISI <1.5, preferably <1.2) 1
• Consider point-of-care testing limitations: variations increase significantly with INR >3.5 6

3. Risk Stratification for Bleeding

Patient-specific bleeding risk factors:

• Advanced age (>65 years) 1, 5
• History of previous gastrointestinal bleeding or stroke 1
• Renal failure 5
• Alcohol use 5
• Recent myocardial infarction or severe anemia 1
• Fall risk from disequilibrium, Parkinson's disease, or arthritis 1

INR-specific bleeding risk:

• INR <5.0: Modest elevation with low bleeding risk if no other risk factors 1
• INR 5.0-9.0: Intermediate risk requiring intervention based on patient bleeding risk 1
• INR >9.0: High bleeding risk (11% in outpatients, 35% in hospitalized patients) 5
• INR >4.5: Bleeding risk begins to rise; INR >6.0 rises steeply and exponentially 1

4. Investigation in Non-VKA Patients

When INR is elevated without VKA therapy:

• Recognize this represents a different clinical scenario requiring investigation for underlying pathology 1, 2
• Check comprehensive liver function tests and synthetic function (albumin, bilirubin, transaminases) 4
• Assess for vitamin K deficiency: dietary history, malabsorption syndromes, prolonged antibiotic use 4
• Consider disseminated intravascular coagulation if acutely ill 4
• Evaluate for occult malignancy or collagen vascular disease 4
• Do not use plasma transfusion to "correct" mildly elevated INR in non-bleeding patients, as there is no evidence of benefit and it exposes patients to transfusion risks 1, 2

Common Pitfalls to Avoid

• Never assume INR predicts bleeding risk in non-VKA patients—it has poor sensitivity for bleeding disorders and provides false reassurance 1
• Avoid plasma transfusion for INR <2.0—it does not change INR values below 1.5 and only minimally impacts values below 2.0 1
• Do not use intravenous vitamin K in prosthetic valve patients with elevated INR but no bleeding, as rapid INR reduction increases valve thrombosis risk 1
• Recognize that hospitalized patients with INR >9 may not respond quickly to withholding warfarin or oral vitamin K within 24 hours 5
• Remember that initial INR rise with warfarin can mask transient procoagulant effects early in treatment 1