international normalized ratio

**Definition/formula:** INR = (PT_patient / PT_normal mean)^ISI, where ISI (International Sensitivity Index) is assigned to each thromboplastin reagent relative to a WHO reference. It was created to make PT comparable between labs.

**Pathway tested:** PT/INR evaluates the extrinsic pathway (factor VII) and common pathway (factors X, V, II [prothrombin], and fibrinogen). The intrinsic pathway is assessed by aPTT. Factor VII has the shortest half-life (~6 h), so PT/INR rises first with warfarin or early liver failure.

**Warfarin monitoring:** - Warfarin inhibits vitamin K epoxide reductase (VKORC1), reducing the gamma-carboxylation of factors II, VII, IX, X and of proteins C and S. - Target INR is 2–3 for most indications (DVT/PE, AF, bioprosthetic valves). The target is 2.5–3.5 for mechanical mitral valves, and some mechanical aortic valves with risk factors. - Early warfarin therapy can cause a transient hypercoagulable state, because protein C (half-life ~8 h) falls before the other factors. This can cause warfarin-induced skin necrosis, especially in protein C deficiency. Heparin bridging prevents this. - Warfarin is teratogenic (fetal warfarin syndrome: nasal hypoplasia, stippled epiphyses), so use heparin in pregnancy. - CYP2C9 and VKORC1 polymorphisms alter dose requirements. - Drug interactions: INR rises with CYP inhibitors (amiodarone, fluconazole, metronidazole, TMP-SMX, cimetidine, macrolides) and with alcohol binge or acute illness. INR falls with CYP inducers (rifampin, phenytoin, carbamazepine, barbiturates, St. John's wort, chronic alcohol use) and with dietary vitamin K.

**Causes of elevated INR:** - Warfarin - Liver disease (decreased synthesis of clotting factors; INR is a marker of synthetic function and part of MELD and Child-Pugh scores) - Vitamin K deficiency (malabsorption, biliary obstruction, antibiotics, neonates) - DIC - Factor VII, X, V, or II deficiency - Direct oral anticoagulants (rivaroxaban, apixaban, and dabigatran can modestly prolong it, but INR is not used for monitoring)

**Management of supratherapeutic INR:** - Without bleeding and INR < 10: hold or reduce the dose. - INR > 10 without bleeding: oral vitamin K. - Major bleeding: 4-factor prothrombin complex concentrate (PCC) plus IV vitamin K. Fresh frozen plasma is an alternative if PCC is unavailable. - Vitamin K takes about 6–24 h to work, while PCC or FFP works immediately.

**Limitations:** INR was validated for stable warfarin patients. It is less reliable for liver disease, lupus anticoagulant, and DOAC monitoring. It does not reflect true bleeding risk in cirrhosis, which involves rebalanced hemostasis.

**Board pearls:** - Prolonged PT with normal aPTT suggests early warfarin effect, early liver disease, or factor VII deficiency. - Both PT and aPTT prolonged suggests common pathway defects, severe liver disease, DIC, or high-dose warfarin. - Heparin affects aPTT (intrinsic pathway), and warfarin affects PT/INR. - Platelet count and bleeding time are normal with factor deficiencies.