What does a raised International Normalized Ratio (INR) mean?

What Does a Raised INR Mean?

A raised INR indicates prolonged blood clotting time, but its clinical significance depends entirely on whether the patient is taking vitamin K antagonists (warfarin)—the INR was designed and validated exclusively for monitoring warfarin therapy, not as a general predictor of bleeding risk. 1

Clinical Interpretation Based on Context

In Patients Taking Warfarin

• Therapeutic range (INR 2.0-3.0): This represents appropriate anticoagulation for most indications including atrial fibrillation, venous thromboembolism, and mechanical heart valves 2
• INR 3.0-4.5: Represents supratherapeutic anticoagulation with increased bleeding risk; warfarin dose adjustment is typically needed 2
• INR >4.0: Provides no additional therapeutic benefit and significantly increases bleeding risk 2
• INR >9.0: Associated with high bleeding risk (11% in stable outpatients, 35% in hospitalized patients) and requires urgent intervention 3

In Patients NOT Taking Warfarin

The INR has no validated clinical utility in patients not on vitamin K antagonist therapy. 1 The test was standardized using plasma samples from patients on stable warfarin therapy, specifically excluding those with liver disease, acute illness, or other coagulopathies 1

• Elevated INR without warfarin indicates severe underlying pathology: In one study, 67% of these patients experienced bleeding and 74% died, reflecting the severity of their underlying conditions (liver failure, disseminated intravascular coagulation, vitamin K deficiency) 3
• Poor predictor of procedural bleeding: A systematic review found weak or no association between pre-procedural INR and bleeding in 78 of 79 studies, with sensitivity under 50% 4
• Should not guide plasma transfusion decisions: Randomized trials found no reduction in bleeding when prophylactic plasma was given to correct INR values in non-warfarin patients 4

What the INR Actually Measures

• Evaluates the extrinsic coagulation pathway: Specifically factors II, V, VII, X, and fibrinogen 5
• Calculated using: INR = [PT patient/PT normal]^ISI, where ISI is the international sensitivity index of the thromboplastin reagent 5, 2
• Standardized only for warfarin monitoring: The standardization process compared clotting times in patients on stable warfarin therapy across different laboratory thromboplastins 1

Common Causes of Elevated INR

In Warfarin Patients

• Warfarin overdose or accumulation 2
• Drug interactions: Antibiotics (especially fluoroquinolones, metronidazole), amiodarone, NSAIDs, acetaminophen (high dose), and numerous others 2
• Dietary changes: Decreased vitamin K intake 2, 6
• Acute illness: Diarrhea, decreased oral intake, fever 2, 6
• Liver dysfunction: Impaired synthesis of clotting factors 2
• Renal failure: Associated with increased bleeding risk 3

In Non-Warfarin Patients

• Severe liver disease: Reduced synthesis of vitamin K-dependent clotting factors 1
• Vitamin K deficiency: Malnutrition, malabsorption, prolonged antibiotic use 1
• Disseminated intravascular coagulation (DIC): Consumption of clotting factors 5
• Warfarin/rodenticide poisoning: Accidental or intentional ingestion 7

Critical Pitfall to Avoid

Do not use INR targets below 2.0 to guide clinical decisions in non-warfarin patients—there is no high-quality evidence supporting this practice. 1, 4 The American Society of Hematology specifically recommends against relying on INR for bleeding risk assessment outside of warfarin monitoring, as plasma transfusion to correct mildly elevated INR values lacks biological plausibility and evidence of benefit 7, 4

Temporal Relationship with Bleeding

• In warfarin patients who bleed: The INR elevation is often brief and subtle, occurring an average of only 11.6 days before the bleeding event 8
• Bleeding may cause INR elevation: Rather than elevated INR always causing bleeding, hemorrhagic events themselves can lead to INR increases in previously stable patients 9
• Serial INRs are poor predictors: There appears to be only a brief warning period during which a slightly elevated INR predicts imminent bleeding 8

Management Implications

For Warfarin Patients with Elevated INR

• INR >9 without bleeding: Withholding warfarin or vitamin K alone may be ineffective at reducing INR within 24 hours; plasma infusion immediately drops INR to approximately 2.4 3
• Active bleeding with elevated INR: Rapid reversal with prothrombin complex concentrate (preferred over fresh frozen plasma) plus vitamin K is recommended 1
• Duration of warfarin interruption: After intracranial hemorrhage, the risk of ischemic events during warfarin cessation is 2.1% within 30 days, with median interruption of 10 days 1

For Non-Warfarin Patients

• Focus on underlying cause: The elevated INR reflects severe underlying pathology requiring specific treatment 3
• Avoid unnecessary plasma transfusion: No evidence supports correcting INR <2.0 in asymptomatic patients not on warfarin 1, 4
• Consider alternative testing: Thromboelastography (TEG) or rotational thromboelastometry (ROTEM) may provide more clinically useful coagulation assessment 4