What are the causes of prolonged International Normalized Ratio (INR) in an adult patient with a history of atrial fibrillation, deep vein thrombosis, or pulmonary embolism, on anticoagulation therapy with warfarin?

Causes of Prolonged INR in Warfarin-Treated Patients

A prolonged INR in patients on warfarin therapy results from factors that either enhance warfarin's anticoagulant effect or impair vitamin K-dependent clotting factor synthesis, with the most common causes being drug interactions (especially antibiotics and herbal medications), dietary changes, liver disease, and patient non-adherence. 1

Pharmacologic Causes

Drug Interactions - Most Common Culprit

Numerous medications potentiate warfarin's effect through enzyme inhibition, reduced protein binding, or synergistic anticoagulant effects:

• Antibiotics are among the most frequent offenders, particularly fluoroquinolones (ciprofloxacin, levofloxacin, ofloxacin), macrolides (erythromycin), metronidazole, trimethoprim/sulfamethoxazole, and penicillins 1
• NSAIDs and COX-2 inhibitors (celecoxib, valdecoxib, diclofenac, naproxen) increase bleeding risk through dual mechanisms: potentiating warfarin effect and inhibiting platelet function 1
• Antifungals including fluconazole and miconazole (even topical/intravaginal formulations) are potent CYP2C9 inhibitors 1
• Cardiovascular drugs such as amiodarone, propafenone, and simvastatin significantly elevate INR 1
• Gastrointestinal agents including cimetidine, omeprazole, esomeprazole, and pantoprazole interfere with warfarin metabolism 1

Herbal and Botanical Medications

Herbal supplements represent an underrecognized but critical cause of INR elevation:

• Anticoagulant botanicals include dong quai, garlic, ginkgo biloba, ginger, and ginseng, which have additive antiplatelet or fibrinolytic effects 1
• Coumarins-containing botanicals such as sweet clover, bogbean, licorice, and meadowsweet directly enhance warfarin effect 1
• St. John's wort paradoxically decreases warfarin effect through enzyme induction 1
• The American Geriatrics Society emphasizes that lack of manufacturing standardization makes botanical interactions particularly unpredictable 1

Endogenous/Physiologic Causes

Disease States That Prolong INR

Multiple medical conditions impair hemostasis or vitamin K metabolism:

• Hepatic disorders (hepatitis, cirrhosis, steatorrhea) reduce synthesis of vitamin K-dependent clotting factors and impair warfarin metabolism 1, 2
• Hyperthyroidism accelerates catabolism of clotting factors 1
• Congestive heart failure alters hepatic perfusion and drug metabolism 1
• Fever and infectious illnesses increase metabolic rate and warfarin sensitivity 1
• Malignancy affects multiple coagulation pathways 1
• Diarrhea and malabsorption syndromes (steatorrhea, nephrotic syndrome) reduce vitamin K absorption 1
• Renal insufficiency, while not requiring dose adjustment, increases bleeding risk at any given INR 1

Nutritional Factors

Dietary changes significantly impact INR stability:

• Vitamin K deficiency from poor nutritional state, dietary deficiencies, or prolonged antibiotic use eliminates competitive antagonism of warfarin 1
• Decreased vitamin K intake (avoiding green vegetables) removes the counterbalancing effect 1
• Alcohol consumption has bipolar effects: acute intoxication inhibits metabolism (raising INR), while chronic use induces enzymes (lowering INR) 1

Genetic Factors

Pharmacogenomic variations substantially affect warfarin sensitivity:

• CYP2C9 polymorphisms (*2 and *3 alleles) reduce warfarin metabolism, with *3 carriers requiring 37% lower doses and *2 carriers requiring 17% lower doses compared to *1/*1 homozygotes 1
• VKORC1 gene variants (especially -1639G>A allele) confer increased warfarin sensitivity, accounting for 30% of dose variability alone 1
• Combined CYP2C9 and VKORC1 genotyping explains approximately 40-55% of warfarin dose requirements 1
• The FDA label notes that patients with these variants have approximately doubled risk of INR >3 during initial therapy 1

Age-Related Factors

Elderly patients exhibit heightened warfarin sensitivity through multiple mechanisms:

• Patients ≥60 years demonstrate greater-than-expected PT/INR response to warfarin 1
• Reduced clearance of R-warfarin occurs with aging 1
• The American Geriatrics Society emphasizes that older adults require lower maintenance doses and experience more INR fluctuations, particularly during intercurrent illness 2
• Advanced age (>65-75 years) is an independent bleeding risk factor even at therapeutic INR 3

Laboratory and Technical Causes

Point-of-care testing limitations can falsely suggest prolonged INR:

• Certain POC devices (particularly Hemochron Jr.) produce spuriously elevated INR readings in patients taking direct oral anticoagulants like rivaroxaban, with reported POC-INRs of 6.3-9.2 when laboratory INR was 2.0-2.7 4
• Biological variation in stable patients averages 9% (range 0.4-14.5%), meaning some INR fluctuation is expected even without external factors 5
• Unreliable PT/INR determinations from improper sample handling or assay issues can produce spurious results 1

Critical Clinical Pitfalls

Common errors in managing prolonged INR:

• Reflexive vitamin K administration for every elevated INR creates warfarin resistance lasting up to one week, making re-anticoagulation difficult in high-risk patients 3
• Inadequate investigation of causative factors (new medications, herbals, dietary changes, illness) leads to recurrent episodes 3
• Failure to recognize drug interactions when patients start over-the-counter medications or supplements without informing providers 1
• Assuming all INR elevations require intervention when INR 3.0-5.0 without bleeding may only require warfarin dose adjustment 3

Risk Stratification for Bleeding

The FDA label identifies key bleeding risk factors beyond INR elevation:

• High-intensity anticoagulation (INR >4.0) exponentially increases bleeding risk 1, 6
• Additional risk factors include age ≥65, highly variable INRs, history of GI bleeding, hypertension, cerebrovascular disease, serious heart disease, anemia, malignancy, trauma, and concomitant antiplatelet drugs 1
• Bleeding risk becomes clinically unacceptable once INR exceeds 5.0 6

Monitoring Recommendations

Guidelines emphasize intensified monitoring during high-risk periods:

• The ACC/AHA recommends at least weekly INR monitoring during warfarin initiation and monthly monitoring when stable 2
• More frequent monitoring (every 24-48 hours) is required when medications are started/stopped, during illness, or after INR elevation 3, 1
• The American Geriatrics Society specifically notes that older adults require more frequent monitoring due to greater INR variability 2