What causes an elevated International Normalized Ratio (INR) in patients not taking warfarin (Coumadin)?

Elevated INR in Patients Not on Warfarin

In patients not taking warfarin, an elevated INR most commonly indicates vitamin K deficiency, liver disease, or the presence of direct oral anticoagulants (DOACs), and determining the specific cause is essential because plasma transfusion is inappropriate for most of these conditions. 1

Primary Causes of Elevated INR Without Warfarin

Vitamin K Deficiency Pattern

• Vitamin K deficiency is characterized by low Factor VII, Factor X, Protein C, and Protein S levels and represents one of the most common causes of elevated INR in ICU patients not on warfarin 1
• This pattern occurs due to malnutrition, prolonged antibiotic use (which disrupts gut microbiome vitamin K production), or malabsorption 2
• Factor VII levels correlate inversely with INR (r = -0.81), making it a key diagnostic marker 1
• Vitamin K deficiency is reversible with vitamin K administration, making plasma transfusion unnecessary 1

Liver Disease Pattern

• Liver disease causes elevated INR through reduced synthesis of clotting factors, characterized by low Factor V, low or normal fibrinogen, and high Factor VIII 1
• Factor V is synthesized exclusively in the liver and is not vitamin K-dependent, distinguishing this from vitamin K deficiency 1
• The INR is not validated for assessing bleeding risk in liver disease patients, as it was designed and standardized only for warfarin monitoring 2
• Plasma transfusion is inappropriate for liver disease coagulopathy as it provides only transient correction without addressing the underlying synthetic defect 1

Direct Oral Anticoagulants (DOACs)

• DOACs, particularly apixaban and rivaroxaban, can elevate INR even though INR monitoring is not recommended for these agents 3, 1
• In one study of ICU patients with elevated INR, 7 out of 48 cases (15%) were due to unrecognized DOAC presence (anti-Xa >0.01 IU/ml) 1
• Apixaban typically causes median INR elevations of 1.4-1.7, though extreme elevations (INR >20) have been reported in patients with renal impairment 3
• Plasma transfusion is completely ineffective for reversing DOAC-related INR elevation 1

Secondary and Contributing Factors

Critical Illness and Inflammatory States

• Most ICU patients with elevated INR demonstrate high Factor VIII and D-dimers with reduced anticoagulant proteins (Protein C and Protein S), indicating a prothrombotic state despite the elevated INR 1
• This paradoxical finding suggests the INR does not accurately reflect bleeding risk in critically ill patients 1

Medication Interactions

• Antibiotics alter gut microbiome and reduce vitamin K production, with sulfonamides and metronidazole having additional CYP2C9 inhibitory effects that can elevate INR 2
• Acetaminophen increases INR in a dose-dependent manner, with risk of INR >6 increasing 10-fold when intake exceeds 9.1 grams per week 2
• NSAIDs can displace anticoagulants from protein binding sites and independently increase bleeding risk 2

Poor Prognosis Indicators

• Patients without anticoagulant treatment who present with INR >9 have extremely poor outcomes: 67% experience bleeding and 74% mortality 4
• This suggests the elevated INR reflects severe underlying disease (sepsis, liver failure, DIC) rather than a reversible coagulopathy 4

Diagnostic Approach

Laboratory Evaluation

• Measure Factor VII, Factor X, Factor V, Factor VIII, fibrinogen, Protein C, Protein S, and anti-Xa activity to distinguish between vitamin K deficiency, liver disease, and DOAC presence 1
• Factor VII and Factor X correlate inversely with INR (r = -0.81 and r = -0.67 respectively), while Factor V and fibrinogen do not 1
• Review baseline INR if available; normal baseline INR prior to acute illness suggests acquired rather than chronic coagulopathy 3

Clinical Context Assessment

• Evaluate for malnutrition, recent antibiotic use, liver disease, critical illness, and medication history including over-the-counter drugs and supplements 2, 1
• In 48 ICU patients with elevated INR studied, 40% had vitamin K deficiency pattern, 35% had liver disease pattern, 15% had DOACs, and 10% were equivocal 1

Management Implications

Avoid Inappropriate Plasma Transfusion

• Plasma transfusion for mildly elevated INR (1.5-2.0) in non-warfarin patients lacks biological plausibility and credible evidence 2
• Plasma is ineffective for DOAC reversal, provides only transient correction in liver disease, and is unnecessary when vitamin K deficiency is the cause 1
• The practice of prophylactic plasma transfusion based on INR targets accounts for the majority of plasma use at many institutions despite lack of evidence 2

Appropriate Interventions

• For vitamin K deficiency: administer vitamin K 1-2.5 mg orally, which corrects INR within 24-48 hours 5, 6
• For liver disease: address underlying hepatic dysfunction; plasma provides no sustained benefit 1
• For DOACs: discontinue if inappropriate; use specific reversal agents (andexanet alfa for apixaban/rivaroxaban) only for life-threatening bleeding 3

Critical Pitfalls to Avoid

• Never assume elevated INR indicates warfarin effect without confirming warfarin use 1
• Do not use INR to predict bleeding risk in non-warfarin patients, as it lacks validation for this purpose 2
• Avoid reflexive plasma transfusion for INR 1.5-2.0 range, which represents the majority of inappropriate plasma use 2, 1
• Recognize that hospitalized patients with INR >9 may not respond quickly to vitamin K alone and may require plasma infusion only if active bleeding is present 4