What conditions can prolong prothrombin time (PT) in a patient, particularly those with a history of cardiovascular disease or those at high risk of thromboembolic events and on anticoagulant medications like warfarin (coumarin)?

Conditions That Prolong Prothrombin Time

Warfarin therapy is the most common cause of prolonged PT, but multiple pathological and iatrogenic conditions can prolong PT through deficiencies in the extrinsic and common coagulation pathways (factors VII, X, V, II, and fibrinogen). 1

Medication-Related Causes

Warfarin and Anticoagulants

• Warfarin prolongs PT by inhibiting vitamin K-dependent clotting factors (II, VII, IX, and X) through blockade of vitamin K epoxide reductase. 1, 2
• Heparin produces slight PT prolongation even in therapeutic doses. 3

Drug Interactions That Potentiate Warfarin

• Drugs that inhibit S-warfarin metabolism significantly prolong PT, including phenylbutazone, sulfinpyrazone, metronidazole, and trimethoprim-sulfamethoxazole. 3, 1
• Amiodarone inhibits both S- and R-isomer metabolism and markedly potentiates warfarin anticoagulation. 3, 1
• Second- and third-generation cephalosporins augment warfarin effect by inhibiting vitamin K cyclic interconversion. 3
• Thyroxine increases PT by accelerating metabolism of coagulation factors. 3
• Doses of salicylates ≥1.5 g per day and acetaminophen augment warfarin effect, possibly through warfarin-like activity. 3

Antibiotics and Vitamin K Deficiency

• Antibiotics commonly prolong PT through vitamin K deficiency, particularly in patients receiving intravenous fluids without vitamin K supplementation. 3, 1

Hepatic Dysfunction

• Hepatic dysfunction prolongs PT through impaired synthesis of coagulation factors, typically requiring loss of >70% of synthetic function to manifest as coagulopathy. 3, 1
• Liver disease affects both warfarin metabolism and coagulation factor synthesis. 3

Nutritional and Dietary Factors

Vitamin K Deficiency

• Reduced dietary vitamin K intake potentiates warfarin effect in sick patients treated with antibiotics and intravenous fluids without vitamin K supplementation. 3
• States of fat malabsorption reduce vitamin K absorption and prolong PT. 3

Hypermetabolic States

• Fever and hyperthyroidism increase PT by accelerating catabolism of vitamin K-dependent coagulation factors. 3, 1

Congenital Factor Deficiencies

Isolated Factor VII Deficiency

• Isolated factor VII deficiency causes isolated PT prolongation without aPTT abnormality. 1

Factor IX Propeptide Mutation

• 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. 3, 1
• Patients with this mutation experience factor IX levels that drop markedly while other vitamin K-dependent factors decrease only to 30-40%. 3

Hereditary Warfarin Resistance

• Hereditary warfarin resistance is rare but requires 5- to 20-fold higher doses than average to achieve anticoagulation. 3, 1

Age-Related Factors

• Elderly patients show exaggerated warfarin response due to reduced drug clearance with age, resulting in prolonged PT at lower doses. 3, 1

Critical Laboratory Artifacts

Collection Tube Issues

• Underfilling blood collection tubes causes excess citrate and spuriously prolongs PT results. 1, 4
• Using 3.2% citrate collection tubes rather than 3.8% reduces the problem of excess citrate. 1, 4

Combined Pathway Defects

• Combined PT and aPTT prolongation suggests common pathway defects (factors X, V, II, fibrinogen) or multiple factor deficiencies. 1

Common Pitfalls to Avoid

Warfarin Dose Adjustments

• Warfarin dose increment is the most common definite cause of excessive PT prolongation, followed by adding new medications (especially amiodarone) and recently started warfarin. 5
• Patients with excessive PT prolongation (INR >6) had significantly shorter median duration of warfarin treatment (12 months vs. 36 months in controls). 5

Dietary Non-Adherence

• Patients with excessive PT prolongation were significantly less likely to adhere to balanced diet (19 patients vs. 34 in control group). 5

PT Ratio Thresholds

• A prothrombin time ratio >2.5 is associated with a fourteen-fold increase in risk of major hemorrhage, but major hemorrhages can occur at all measured PT values. 6

INR Validity Concerns

• 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
• The regular INR (INR-vka) is not valid for cirrhotic patients and cannot minimize variability across different thromboplastins in this population. 3