What causes a deranged prothrombin time (PT) or international normalized ratio (INR)?

Causes of Deranged PT/INR

A deranged PT/INR is primarily caused by vitamin K antagonist (warfarin) therapy, liver disease affecting synthesis of clotting factors (I, II, V, VII, X), consumption of coagulation factors (such as in DIC), vitamin K deficiency, or drug interactions—but critically, the INR was designed and validated only for monitoring warfarin therapy and should not be interpreted the same way in other clinical contexts. 1, 2, 3

Primary Causes in Warfarin-Treated Patients

For patients on vitamin K antagonists, the following factors increase PT/INR: 3

• Drug interactions (numerous medications through enzyme inhibition, reduced protein binding, or synergistic effects on hemostasis) 3
• Dietary changes (reduced vitamin K intake, changes in green leafy vegetables) 3
• Acute illness (fever, diarrhea, hyperthyroidism, congestive heart failure) 3
• Hepatic dysfunction (infectious hepatitis, steatorrhea) 3
• Poor nutritional state and vitamin K deficiency 3
• Genetic variations in CYP2C9 and VKORC1 enzymes affecting warfarin metabolism 1, 3

Factors that decrease PT/INR in warfarin patients include: 3

• Enzyme-inducing medications (rifampin, carbamazepine, phenobarbital, phenytoin) 3
• Vitamin K intake (dietary increases or supplementation) 3
• Hypothyroidism and hyperlipidemia 3
• Warfarin underdosing or non-adherence 3

Causes in Non-Warfarin Patients

In patients NOT on warfarin, an elevated PT/INR indicates: 1, 2

• Liver disease with impaired synthesis of procoagulant factors (I, II, V, VII, X), though this does NOT measure deficient anticoagulant factors like protein C 1
• Vitamin K deficiency from malabsorption, malnutrition, or prolonged antibiotic use 2, 3
• Consumptive coagulopathy (DIC) depleting clotting factors 2
• Lupus anticoagulant (though this typically causes only slight PT prolongation) 1, 2

Critical Caveat for Liver Disease

The INR in cirrhosis is fundamentally unreliable and should NOT be interpreted as indicating bleeding risk. 1 The test measures procoagulant factors but ignores the simultaneous reduction in anticoagulant factors (especially protein C), creating a misleading picture. 1 Additionally, INR values vary significantly between hospitals depending on which thromboplastin reagent is used, as the test is "normalized" against warfarin-treated patients, not liver disease patients. 1, 4

Technical and Laboratory Factors

PT/INR results can be artificially deranged by: 1, 5, 6

• Thromboplastin reagent variability (different ISI values between laboratories and instruments) 1, 5
• Incorrect citrate concentration in collection tubes (3.8% citrate yields higher INRs than 3.2%) 1
• Underfilled collection tubes (excess citrate spuriously prolongs PT) 1
• Automated clot detection methods affecting accuracy compared to manual methods 1
• Incorrect mean normal PT determination (should use geometric mean from 20 healthy individuals, not laboratory control PT) 1

Clinical Context Matters

The therapeutic INR range of 2.0-3.0 applies ONLY to patients on vitamin K antagonists for conditions like atrial fibrillation. 1 An INR below 2.0 in warfarin patients doubles stroke risk, while INRs above 3.0 increase bleeding risk. 1 However, there is no high-quality evidence supporting treatment of INRs below 2.0 in patients NOT receiving warfarin therapy. 1

Common Pitfall to Avoid

Never use PT/INR as a general screening test for coagulopathy or to predict procedural bleeding risk in non-warfarin patients. 1, 7 The test lacks validity for these purposes and leads to unnecessary plasma transfusions that provide no clinical benefit, increase costs, and cause harm (particularly worsening portal hypertension in cirrhosis). 1

Specific High-Risk Scenarios

In patients with INR >9 on warfarin: 8

• Outpatients have 11% bleeding risk with no mortality 8
• Hospitalized patients have 35% bleeding risk and 17% mortality 8
• Risk factors for bleeding include older age, renal failure, and alcohol use 8
• Withholding warfarin or vitamin K is often ineffective within 24 hours; plasma infusion immediately reduces INR to ~2.4 8

In patients NOT on anticoagulants with INR >9: 8

• This indicates severe underlying disease with 67% bleeding risk and 74% mortality 8
• Focus on treating the underlying condition rather than the INR itself 8