What is International Normalized Ratio (INR)?

What is INR (International Normalized Ratio)?

The INR is a standardized mathematical conversion of the prothrombin time (PT) test, specifically designed and validated for monitoring vitamin K antagonist (warfarin) therapy—not as a general predictor of bleeding risk or coagulopathy in other clinical contexts. 1

Mathematical Definition and Calculation

The INR is calculated using the following formula 1:

INR = (patient PT / mean normal PT)^ISI

Where:

• Patient PT = the prothrombin time measured in the patient's plasma 1
• Mean normal PT = the average PT from healthy control plasma 1
• ISI (International Sensitivity Index) = a measure of the thromboplastin reagent's responsiveness to reductions in vitamin K-dependent clotting factors (II, VII, X) 1

The more responsive the thromboplastin reagent, the lower the ISI value (modern recombinant preparations have ISI values of 0.9-1.0) 1

Historical Context and Purpose

The INR was developed in 1982 by the World Health Organization to solve a critical problem: different thromboplastin reagents produced wildly different PT results even when testing identical blood samples. 1

Key historical points:

• Before INR standardization, thromboplastin ISI values in the United States varied from 1.4 to 2.8, causing dangerous inconsistencies in warfarin dosing 1
• The PT ratio (simple patient PT/control PT) was too imprecise because thromboplastins varied markedly in their responsiveness to warfarin 1
• These differences contributed to excessive and erratic anticoagulation in North America 1
• INR adoption increased from 21% to 97% of U.S. laboratories between 1991 and 1997 1

Clinical Applications: Where INR is Valid

The INR is validated and appropriate ONLY for:

• Monitoring warfarin (vitamin K antagonist) therapy during both initiation and maintenance phases 1, 2
• Assessing therapeutic anticoagulation intensity in patients on VKA therapy 1
• Guiding warfarin dosing adjustments to maintain therapeutic range (typically INR 2.0-3.0 for most indications) 2

The FDA-approved warfarin label specifies that PT/INR should be determined daily after initial dosing until results stabilize in the therapeutic range, then at intervals of 1-4 weeks once stable 2

Critical Limitations: Where INR Should NOT Be Used

The American Society of Hematology and Journal of Thrombosis and Haemostasis explicitly recommend against using INR for bleeding risk assessment in patients not on vitamin K antagonists, as it lacks biological plausibility and validation in this context. 1, 3, 4

Specific limitations include:

• INR has poor sensitivity (<50%) for predicting bleeding in non-VKA patients 5
• 78 out of 79 studies found weak or no association between pre-procedural INR and bleeding risk 5
• INR is unreliable in liver disease despite its use in MELD scoring 5
• INR is less reliable during the first 6 weeks of warfarin therapy (though still more reliable than unconverted PT ratio) 1, 6
• INR can be affected by automated clot detection methods used in modern laboratories 1

Common Clinical Pitfalls

Never assume INR predicts bleeding risk in non-VKA patients—this represents a fundamental misapplication of the test that drives unnecessary plasma transfusions without evidence of benefit. 1, 4

Additional pitfalls to avoid:

• Do not transfuse plasma to "correct" INR <2.0 in non-bleeding patients, as this provides no clinical benefit and exposes patients to transfusion risks 1, 4, 5
• Do not use INR as a general coagulopathy screen—it was designed specifically for VKA monitoring 4
• Low-sensitivity thromboplastins may give erroneously high INRs in the upper therapeutic range 7
• INR targets appearing in clinical guidelines for non-VKA patients lack high-quality supporting evidence 1, 5

Technical Considerations

Laboratories should use high-sensitivity thromboplastins (low ISI values) to minimize variability, particularly for patients maintained at the upper therapeutic range. 1, 7

Important technical factors:

• ISI verification/validation by individual laboratories is crucial, as reported INR values can differ even when using identical reagents and instruments 8
• Point-of-care INR monitors (like Coumatrak) correlate best with high-sensitivity thromboplastins 7
• The INR therapeutic range of 2.0-3.0 corresponds to specific prothrombin activity of 43%-21% 7