What causes elevated APTT, INR, and PT in a patient not taking anticoagulants?

Elevated APTT, INR, and PT Without Anticoagulant Use

Primary Differential Diagnosis

In a patient not taking anticoagulants who presents with APTT 43.5 seconds, INR 1.4, and PT 15.3 seconds, the most common causes are vitamin K deficiency (20% of cases with PT ratio ≥1.5), liver disease, lupus anticoagulant, factor XII deficiency, or early disseminated intravascular coagulation. 1, 2

Systematic Diagnostic Approach

Initial Interpretation of Values

• Your APTT of 43.5 seconds is prolonged (normal ~25-35 seconds), while INR 1.4 and PT 15.3 seconds represent mild elevation (PT ratio approximately 1.2-1.3 assuming normal control ~12 seconds). 2, 3

• The pattern of isolated or predominantly elevated APTT with mildly elevated PT/INR narrows the differential significantly. 3, 4

Most Common Causes by Frequency

Vitamin K Deficiency:

• Accounts for 20% of cases with PT ratio ≥1.5 in intensive care populations, making it the single most common etiology. 1
• Affects factors II, VII, IX, and X (vitamin K-dependent factors), causing both PT and APTT prolongation, though PT is typically more sensitive. 4
• Look for: malnutrition, prolonged antibiotic use, malabsorption, biliary obstruction, or lack of oral intake. 2

Lupus Anticoagulant:

• Common cause of isolated prolonged APTT without bleeding history. 2, 3
• Critical distinguishing feature: patients typically have NO history of increased bleeding tendency despite abnormal labs. 2, 3
• The APTT mixing study will fail to correct (remains prolonged), distinguishing this from factor deficiencies. 2, 3
• May see concurrent positive anticardiolipin antibodies. 2

Liver Disease:

• Causes global coagulation factor deficiency affecting both PT and APTT. 2
• Important caveat: The American College of Cardiology emphasizes that INR is a poor predictor of bleeding risk in liver disease patients, despite its use in MELD scoring. 5
• Look for: known cirrhosis, hepatitis, elevated transaminases, low albumin, or other signs of hepatic dysfunction. 2

Factor XII Deficiency:

• Causes markedly prolonged APTT (can be extreme) with normal PT/INR. 2
• Hallmark feature: NO bleeding tendency whatsoever, as Factor XII is not essential for hemostasis. 2
• Mixing study will correct the APTT, distinguishing it from lupus anticoagulant. 2

Early Disseminated Intravascular Coagulation (DIC):

• Can present with consumption of coagulation factors causing PT and APTT prolongation. 2, 4
• Look for: sepsis, malignancy, trauma, or obstetric complications. 6
• Usually accompanied by thrombocytopenia and elevated D-dimer. 6

Diagnostic Algorithm

Step 1: Assess Clinical Context

• Bleeding history present? If yes, consider factor deficiencies, vitamin K deficiency, liver disease, or DIC. 2, 3
• No bleeding history? Strongly suggests lupus anticoagulant or Factor XII deficiency. 2, 3

Step 2: Order Mixing Study

• Mix patient plasma 1:1 with normal pooled plasma and repeat APTT immediately and after 1-2 hour incubation. 2, 3
• If APTT corrects: Factor deficiency (vitamin K deficiency, hemophilia, Factor XII deficiency). 2, 3
• If APTT fails to correct: Inhibitor present (lupus anticoagulant most common). 2, 3

Step 3: Additional Testing Based on Mixing Study

If mixing study corrects (factor deficiency):

• Check specific factor levels: II, V, VII, VIII, IX, X, XI, XII. 2
• Assess for vitamin K deficiency: trial of vitamin K 10 mg IV or check factors II, VII, IX, X levels. 1, 2
• Evaluate liver function: AST, ALT, albumin, bilirubin. 2

If mixing study does not correct (inhibitor):

• Confirm lupus anticoagulant with specific testing (dilute Russell viper venom time, hexagonal phase phospholipid neutralization). 2, 3
• Check anticardiolipin and anti-β2-glycoprotein antibodies. 2

Step 4: Rule Out Occult Anticoagulant Exposure

• Verify no heparin contamination (can cause isolated APTT prolongation with false positive). 3, 7
• Confirm no recent direct oral anticoagulant use, as these can prolong both PT and APTT. 6

Critical Clinical Pitfalls

Do Not Overinterpret INR:

• The American College of Cardiology and American Heart Association emphasize that INR was specifically designed and validated only for monitoring vitamin K antagonist therapy, not as a general bleeding predictor. 5
• INR 1.4 is only mildly elevated and has poor sensitivity (<50%) for predicting bleeding risk in patients not on warfarin. 5

Avoid Unnecessary Plasma Transfusion:

• The American Society of Hematology states that plasma transfusion to correct mildly elevated INR values lacks biological plausibility and exposes patients to unnecessary risk. 5
• Randomized trials found no reduction in bleeding when prophylactic plasma was given to correct INR values. 5

Consider Elevated Factor VIII:

• Acute phase reactions can elevate Factor VIII, which may mask APTT prolongation and create false negatives. 7
• This is particularly relevant in inflammatory states or acute illness. 7

PT/INR More Reliable Than APTT in Some Contexts:

• In trauma settings, PT/INR shows 84% sensitivity for low coagulation factors versus only 50% for APTT. 7
• APTT can show false positives with lupus anticoagulants and false negatives with elevated Factor VIII. 7

When to Consider Advanced Testing

• If standard coagulation tests are insufficient, thromboelastography (TEG) or rotational thromboelastometry (ROTEM) provide comprehensive coagulation assessment, particularly useful in liver disease where PT/INR is unreliable. 5
• The American College of Surgeons recommends viscoelastic testing when available for optimizing coagulation function assessment. 5