What is PT/INR?
Prothrombin Time (PT) measures how long it takes blood plasma to clot after adding tissue factor (thromboplastin). The International Normalized Ratio (INR) is a standardized calculation derived from the PT that accounts for variations in laboratory reagents and methods.
How Does the Test Work?
The PT test specifically evaluates the extrinsic and common pathways of the coagulation cascade:
- Extrinsic pathway: Tissue factor + Factor VII → activated Factor VII (VIIa)
- Common pathway: Factors X, V, II (prothrombin), and I (fibrinogen) → fibrin clot formation
- PT measurement: Time from adding tissue factor until visible clot forms (normally 11-13.5 seconds)
- INR calculation: (Patient PT / Mean Normal PT)^ISI, where ISI is the International Sensitivity Index for the specific reagent
Understanding the Coagulation Cascade
The PT/INR tests the extrinsic pathway (initiated by tissue damage) and common pathway:
- Vitamin K-dependent factors: II (prothrombin), VII, IX, X - these are inhibited by warfarin
- Factor VII has the shortest half-life (~6 hours), so PT/INR rises first when starting warfarin
- Extrinsic pathway: Tissue factor (from damaged tissue) + Factor VII → clotting cascade activation
- Common pathway: Final conversion of prothrombin → thrombin → fibrinogen → fibrin clot
Why INR Instead of PT Alone?
Before INR standardization, PT results varied significantly between laboratories due to different reagents. This made warfarin dosing dangerous.
INR Standardization: The INR was introduced in the 1980s to standardize PT results worldwide. A patient's INR should be the same regardless of which laboratory performs the test, making warfarin management safer and more consistent. Always use INR (not raw PT seconds) for warfarin dosing decisions.
Prolonged PT/INR (Elevated INR)
An elevated INR indicates slower clotting and increased bleeding risk. Determine if this is therapeutic (on warfarin) or pathologic.
Medications - Intentional Anticoagulation
- Warfarin (Coumadin): Vitamin K antagonist; blocks synthesis of factors II, VII, IX, X and proteins C/S
- Goal: Therapeutic INR 2-3 for most indications, 2.5-3.5 for mechanical heart valves
- Monitoring: Check INR every 1-4 weeks once stable; more frequently after dose changes
Vitamin K Deficiency
- Dietary deficiency: Rare in adults; gut bacteria produce vitamin K
- Malabsorption: Celiac disease, Crohn's disease, chronic pancreatitis, biliary obstruction (fat-soluble vitamin)
- Prolonged antibiotic use: Kills gut flora that synthesize vitamin K
- Newborns: Physiologic deficiency (sterile gut, low breast milk content) → vitamin K prophylaxis at birth
Liver Disease
- Mechanism: Liver synthesizes all clotting factors except Factor VIII
- PT/INR rises in liver failure: Decreased production of factors II, V, VII, X, fibrinogen
- Factor VII has shortest half-life: PT/INR rises early in acute liver injury
- Does NOT correct with vitamin K: This distinguishes liver disease from vitamin K deficiency
Disseminated Intravascular Coagulation (DIC)
- Consumption coagulopathy: Widespread clotting consumes factors faster than liver can produce
- PT/INR prolonged: Along with prolonged aPTT, low fibrinogen, low platelets, elevated D-dimer
- Causes: Sepsis, trauma, malignancy, obstetric complications (abruption, amniotic embolism)
Congenital Factor Deficiencies
- Factor VII deficiency: Isolated prolonged PT/INR (aPTT normal) - rare autosomal recessive
- Factor X, V, II deficiency: Both PT and aPTT prolonged (common pathway factors)
Shortened PT/INR (Low INR)
A shortened PT (INR <0.8) suggests hypercoagulability, though this is less clinically significant than prolonged PT.
- High vitamin K intake: Excessive dietary vitamin K or supplements
- Sample collection issues: Overfilled tube, clotted sample (pre-analytical error)
- Elevated Factor VIII: Acute phase reactant (doesn't affect PT, but mentioned for completeness)
Approach to Elevated INR
Step 1: Determine if patient is on warfarin
- If YES → Assess if INR is therapeutic, subtherapeutic, or supratherapeutic
- If NO → Investigate pathologic causes (liver disease, vitamin K deficiency, DIC)
Step 2: Assess bleeding risk and active bleeding
- Is patient actively bleeding?
- Is bleeding life-threatening (intracranial, GI, retroperitoneal)?
- What is the INR level? (<5, 5-9, >9)
Step 3: Check aPTT to localize defect
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| PT/INR | aPTT | Interpretation |
|---|---|---|
| Prolonged | Normal | Extrinsic pathway defect (Factor VII) or early warfarin effect |
| Normal | Prolonged | Intrinsic pathway defect (Factors VIII, IX, XI, XII) |
| Prolonged | Prolonged | Common pathway defect (Factors X, V, II, fibrinogen) OR combined deficiency (warfarin, liver disease, DIC) |
Warfarin Management Based on INR
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| INR | Bleeding | Management |
|---|---|---|
| <2 (subtherapeutic) | No | Increase warfarin dose; check medication compliance, drug interactions |
| 2-3 (therapeutic) | No | Continue current dose; routine monitoring |
| 3-5 (mildly elevated) | No | Reduce dose or hold 1 dose; recheck INR in 3-7 days |
| 5-9 (moderately elevated) | No | Hold warfarin; consider oral vitamin K 2.5-5 mg; recheck daily |
| >9 (severely elevated) | No | Hold warfarin; oral vitamin K 5-10 mg; recheck next day |
| Any elevation | Minor bleeding | Hold warfarin; oral vitamin K 2.5-5 mg; monitor closely |
| Any elevation | Major bleeding | HOLD warfarin; 4-factor PCC (preferred) OR FFP + IV vitamin K 10 mg slow infusion |
Emergency Warfarin Reversal for Life-Threatening Bleeding:
- STOP warfarin immediately
- 4-factor Prothrombin Complex Concentrate (PCC): Preferred; dose 25-50 units/kg IV (max 5000 units). Reverses INR within 15 minutes
- Alternative: Fresh Frozen Plasma (FFP): 10-15 mL/kg IV (4-6 units for average adult). Slower reversal, volume overload risk
- PLUS Vitamin K 10 mg IV slow infusion: Takes 6-24 hours but provides sustained reversal
- Recheck INR after reversal: Ensure adequate correction; may need additional PCC/FFP
Indications for emergent reversal: Intracranial hemorrhage, GI bleeding with hemodynamic instability, retroperitoneal bleed, need for urgent surgery
Distinguishing Liver Disease from Vitamin K Deficiency
Vitamin K Trial: If PT/INR elevated and etiology unclear, give vitamin K 10 mg IV or PO and recheck INR in 24 hours:
- INR normalizes: Vitamin K deficiency (malnutrition, malabsorption, antibiotics)
- INR remains elevated: Liver disease (inability to synthesize factors despite vitamin K)
- Partial correction: Mixed picture (liver disease + vitamin K deficiency)
Medications That Increase PT/INR (Enhance Warfarin Effect)
- Antibiotics: Metronidazole, trimethoprim-sulfamethoxazole, fluoroquinolones, macrolides (kill vitamin K-producing gut bacteria)
- Antifungals: Fluconazole, ketoconazole (inhibit warfarin metabolism via CYP2C9)
- NSAIDs/Aspirin: Increase bleeding risk without directly affecting INR; antiplatelet effect
- Amiodarone: Strong CYP2C9 inhibitor; increases warfarin levels
- SSRIs: May enhance anticoagulation and increase bleeding risk
- Acetaminophen: High doses (>2g/day) can increase INR
Medications That Decrease PT/INR (Reduce Warfarin Effect)
- Vitamin K: Direct antagonist; found in green leafy vegetables, supplements
- Rifampin: Strong CYP inducer; increases warfarin metabolism
- Carbamazepine, phenytoin, phenobarbital: CYP inducers
- Azathioprine: May decrease warfarin effect
Dietary Factors
- High vitamin K foods: Kale, spinach, broccoli, Brussels sprouts, collard greens - decrease INR
- Cranberry juice: May increase INR (controversial; mechanism unclear)
- Alcohol: Acute binge increases INR; chronic use decreases INR
- Consistency is key: Advise patients to maintain consistent vitamin K intake, not avoid it entirely
Pre-analytical Errors
- Underfilled tube: Excess citrate causes falsely prolonged PT
- Overfilled tube: Insufficient citrate may shorten PT
- Clotted sample: Falsely normal or short PT; reject and redraw
- Delayed processing: Should be tested within 4 hours of collection
- Hematocrit >55%: May require special collection tube or correction factor
Clinical Pearl
"INR for dosing, PT for diagnosis": Always use INR (not raw PT seconds) when managing warfarin therapy, as INR standardizes results across laboratories. Use PT to diagnose coagulopathies when combined with aPTT to localize the defect.
Clinical Pearl
Factor VII drops first: Factor VII has the shortest half-life (~6 hours) of all vitamin K-dependent factors. Therefore, PT/INR rises before aPTT when starting warfarin. Conversely, Factor VII returns first after giving vitamin K, but sustained reversal requires 12-24 hours for other factors.
Clinical Pearl
PCC preferred over FFP for emergency reversal: 4-factor Prothrombin Complex Concentrate (PCC) reverses warfarin in 15 minutes with small volume (50-100 mL). FFP requires 4-6 units (1000+ mL), takes hours to infuse, and risks volume overload. Always use PCC for intracranial hemorrhage or life-threatening bleeds.
Supratherapeutic INR alone is NOT an indication for reversal: If INR is elevated but patient is NOT bleeding and does NOT need urgent surgery, simply hold warfarin and give oral vitamin K. Reserve PCC/FFP for active bleeding or emergent procedures. Unnecessary reversal wastes expensive blood products and exposes patients to thrombotic risk.
Warfarin "bridging" with heparin: When starting warfarin, overlap with heparin or LMWH for 5+ days AND until INR therapeutic for 24 hours. Warfarin initially creates a paradoxical hypercoagulable state by depleting Protein C (short half-life) before depleting clotting factors. This can cause warfarin-induced skin necrosis without heparin bridge.
Clinical Pearl
INR unreliable with DOACs: Direct oral anticoagulants (apixaban, rivaroxaban, dabigatran, edoxaban) can falsely elevate PT/INR, but this does NOT reflect bleeding risk or guide dosing. Do not use INR to monitor DOACs. Anti-Xa levels or drug-specific assays should be used if monitoring needed.
Clinical Pearl
"Green leafy vegetables won't kill you": Patients on warfarin fear eating vitamin K-rich foods. The key is CONSISTENCY, not avoidance. Eating the same amount of greens weekly keeps INR stable. Sudden large changes (starting/stopping green smoothies) cause INR swings.
INR >10 without bleeding still needs reversal: Even without active bleeding, INR >10 requires oral vitamin K 5-10 mg because bleeding risk is extremely high. Don't wait for bleeding to start. Recheck INR daily until <4.
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