What are the causes of a deranged international normalized ratio in an acutely ill patient?

Causes of Deranged INR in Acutely Ill Patients

In acutely ill patients not on warfarin, a deranged INR most commonly reflects vitamin K deficiency, liver disease, or disseminated intravascular coagulation (DIC), and should not be interpreted as a predictor of bleeding risk or trigger for plasma transfusion. 1

Critical Context: INR Validity

The INR was specifically designed and validated only for monitoring vitamin K antagonist (warfarin) therapy, not as a general coagulopathy screen. 1, 2 There is no high-quality evidence supporting the use of INR to predict bleeding risk or guide plasma transfusion in patients not receiving warfarin. 1, 3

Primary Causes in Acutely Ill Patients

Vitamin K Deficiency Pattern

• Most common cause in ICU patients, accounting for approximately 40% of elevated INRs 4
• Characterized by low Factor VII, Factor X, Protein C, and Protein S levels 4
• Factor VII correlates inversely with INR (r = -0.81), as does Factor X (r = -0.67) 4
• Specific triggers include:
  • Prolonged vomiting with decreased oral intake (abrupt discontinuation of vitamin K-containing foods) 5
  • Diarrhea lasting 1-4 days with reduced dietary intake to 25-50% of normal 6
  • Poor nutritional intake in critically ill patients with nil per os (NPO) status 4
  • Antibiotic use disrupting gut flora vitamin K production 4

Liver Disease Pattern

• Accounts for approximately 35% of elevated INRs in ICU patients 4
• Characterized by low Factor V, low or normal fibrinogen, and high Factor VIII 4
• INR is a poor predictor of bleeding risk in liver disease despite its use in MELD scoring 3
• Factor V does not correlate with INR (r = -0.04), nor does fibrinogen (r = -0.15) 4
• Look for cirrhosis, hepatitis, elevated transaminases, or low albumin 3

Disseminated Intravascular Coagulation (DIC)

• Presents with consumption of coagulation factors causing PT/INR prolongation 3
• 71.4% of COVID-19 non-survivors developed DIC by day 4 of illness 1
• Accompanied by thrombocytopenia, elevated D-dimer, and declining fibrinogen 1, 3
• Common in sepsis, malignancy, trauma, or obstetric complications 3
• Distinct coagulation profile: In DIC, both aPTT and fibrinogen correlate with INR, unlike warfarin patients where they do not 7

Direct Oral Anticoagulants (DOACs)

• Approximately 15% of elevated INRs in ICU patients show anti-Xa activity >0.01 IU/mL 4
• Confirm no recent DOAC use, as these agents prolong both PT and aPTT 3

Additional Causes in Acutely Ill Patients

Sepsis-Associated Coagulopathy

• Modest PT prolongation noted in critically ill COVID-19 patients (15.5 seconds in non-survivors vs 13.6 seconds in survivors) 1
• Subtle changes may not be detected when PT is reported as INR rather than seconds 1
• Elevated D-dimers are more predictive of mortality than INR in septic patients 1

Lupus Anticoagulant

• Can cause elevated PT/INR, though typically causes only slight prolongation 2
• Antiphospholipid antibodies can interfere with INR measurement, requiring direct factor II and X measurement for warfarin monitoring 8

Technical/Laboratory Factors

• Thromboplastin reagent variability 2
• Incorrect citrate concentration or underfilled collection tubes 2
• Automated clot detection method errors 2
• Incorrect mean normal PT determination 2

Clinical Approach Algorithm

Step 1: Determine Warfarin Status

• If on warfarin: INR is valid for monitoring; assess for overdose, drug interactions, or dietary changes 9
• If not on warfarin: INR lacks validity as bleeding predictor; investigate underlying pathology 9, 3

Step 2: Assess for Active Bleeding

• Check for overt bleeding (gastrointestinal, intracranial, genitourinary) 9
• Look for occult bleeding signs: unexplained anemia, hemodynamic instability, new neurological deficits 9

Step 3: Investigate Underlying Cause

• Obtain comprehensive liver function tests: albumin, bilirubin, transaminases 9
• Check for vitamin K deficiency triggers: NPO status, prolonged vomiting/diarrhea, antibiotic use 4, 5, 6
• Assess for DIC: platelet count, fibrinogen, D-dimer 1, 3
• Confirm no DOAC use: anti-Xa assay if available 3, 4

Step 4: Consider Advanced Testing

• Measure specific clotting factors (II, V, VII, X) to differentiate vitamin K deficiency from liver disease 4
• Viscoelastic testing (TEG/ROTEM) when available, particularly in liver disease where PT/INR is unreliable 3

Critical Management Pitfalls to Avoid

Do not transfuse plasma to "correct" mildly elevated INR in non-bleeding patients not on warfarin. 1, 9, 3 Plasma transfusion for INR <2.0 lacks biological plausibility, does not reduce bleeding, and exposes patients to transfusion risks. 1, 3

Do not use INR as a general bleeding predictor in non-warfarin patients. 1, 2, 9 It has poor sensitivity for bleeding disorders and provides false reassurance. 9

For vitamin K deficiency, administer vitamin K rather than plasma. 4 This is the appropriate, evidence-based intervention that avoids unnecessary transfusion risks.

Recognize that equivalent INR values represent different coagulation profiles in DIC versus warfarin patients. 7 An INR of 2.0 in a septic patient does not carry the same bleeding risk as an INR of 2.0 in a warfarin patient.