Causes of Prolonged Prothrombin Time (PT)
Primary Causes
Prolonged PT results from deficiencies in the extrinsic and common coagulation pathways, specifically factors VII, X, V, II, and fibrinogen. 1
Medication-Related Causes
- Warfarin therapy is the most common cause of prolonged PT, as it inhibits vitamin K-dependent clotting factors (II, VII, IX, and X) by blocking vitamin K epoxide reductase 2, 3
- Drug interactions that inhibit S-warfarin metabolism significantly prolong PT, including phenylbutazone, sulfinpyrazone, metronidazole, trimethoprim-sulfamethoxazole, and amiodarone 2
- Antibiotics commonly cause PT prolongation through vitamin K deficiency, particularly in patients receiving intravenous fluids without vitamin K supplementation 2
Vitamin K Deficiency
- Vitamin K deficiency is the most common cause of isolated prolonged PT in patients not taking anticoagulants, accounting for 69% of cases with prolonged PT in one large study 4
- Reduced dietary vitamin K intake occurs in sick patients treated with antibiotics and IV fluids, states of fat malabsorption (obstructive jaundice, biliary fistula, sprue, ulcerative colitis, celiac disease, intestinal resection, cystic fibrosis), and during weight-reduction diets 2, 3
- Malabsorption syndromes prevent adequate vitamin K absorption even with normal dietary intake 3
Liver Disease
- Hepatic dysfunction prolongs PT through impaired synthesis of coagulation factors, typically requiring loss of >70% of synthetic function to manifest as coagulopathy 2
- Liver disease was the most common cause of combined PT and aPTT prolongation, accounting for 14% of cases in outpatient studies 5
- PT prolongation from liver disease does not respond well to large doses of vitamin K, and failure to respond may indicate the condition is unresponsive to vitamin K 3
Congenital Factor Deficiencies
- Isolated factor VII deficiency causes isolated PT prolongation without aPTT abnormality 1
- A mutation in the factor IX propeptide (present in 1.5% of the population) causes marked factor IX decrease during warfarin therapy with bleeding risk not reflected in PT 2
- Hereditary warfarin resistance occurs but is rare, requiring 5- to 20-fold higher doses than average 2
Acquired Conditions
- Hypermetabolic states (fever, hyperthyroidism) increase PT by accelerating catabolism of vitamin K-dependent coagulation factors 2
- Disseminated intravascular coagulation (DIC) causes consumption of multiple clotting factors 6
- Lupus anticoagulant and other factor inhibitors can prolong PT, though they more commonly affect aPTT 5, 6
Critical Diagnostic Considerations
Laboratory Artifacts
- Underfilling blood collection tubes causes excess citrate and spuriously prolonged PT results 7
- Using 3.2% citrate collection tubes rather than 3.8% reduces the problem of excess citrate 7
- Laboratory artifact accounted for 5% of prolonged PT cases in outpatient studies 5
Important Caveats
- INR should only be used for warfarin monitoring, not for evaluating other causes of PT prolongation, as it lacks validity for liver disease, DIC, or acute bleeding 1
- PT may be only modestly prolonged in severe illness; in COVID-19 non-survivors, median PT was 15.5 seconds versus 13.6 seconds in survivors 2
- Combined PT and aPTT prolongation suggests common pathway defects (factors X, V, II, fibrinogen) or multiple factor deficiencies 1, 6
Risk Stratification
- Patients with liver disease, upper gastrointestinal surgery, or cimetidine use are at higher risk for PT prolongation, particularly when receiving certain antibiotics like moxalactam 8
- Elderly patients show exaggerated warfarin response due to reduced drug clearance with age 2
- Poor nutritional state, cancer, congestive heart failure, and infectious hepatitis all increase PT prolongation risk 9