What are the causes of elevated activated partial thromboplastin time (aPTT) and international normalized ratio (INR) in a patient?

Causes of Elevated aPTT and INR

When both aPTT and INR are elevated simultaneously, this indicates either a deficiency or dysfunction affecting the common coagulation pathway (factors I, II, V, X), anticoagulant therapy, or consumption/inhibition of multiple coagulation factors. 1

Primary Diagnostic Categories

Anticoagulant Medications

• Warfarin therapy is the most common cause of elevated INR, and can also prolong aPTT, particularly when INR is in the therapeutic range or above 2
• Unfractionated heparin (UFH) prolongs both aPTT and PT/INR, with aPTT being the primary monitoring parameter 3
• Direct thrombin inhibitors (argatroban, bivalirudin, dabigatran) prolong both aPTT and PT/INR 3
• Supratherapeutic warfarin can cause severe elevation of both parameters, with aPTT >50 seconds combined with elevated INR indicating increased risk of postoperative hemorrhage 2

Disseminated Intravascular Coagulation (DIC)

• DIC causes consumption of coagulation factors leading to prolongation of both PT and aPTT, typically accompanied by thrombocytopenia, elevated D-dimer, and low fibrinogen 1, 4
• Fibrinogen <1 g/L was found in 29% of non-survivors with DIC 1
• Common triggers include: sepsis, malignancy, trauma, obstetric complications, and severe tissue injury 4
• In COVID-19,71% of non-survivors developed DIC versus 0.6% of survivors 1

Liver Disease

• Hepatic dysfunction impairs synthesis of multiple coagulation factors (factors II, V, VII, IX, X), prolonging both PT/INR and aPTT 3, 4
• INR is a poor predictor of bleeding risk in liver disease patients despite its use in MELD scoring 1, 4
• Look for: known cirrhosis, hepatitis, elevated transaminases, low albumin, or jaundice 3, 4

Vitamin K Deficiency

• Vitamin K deficiency affects factors II, VII, IX, and X, causing elevation of both PT/INR (more pronounced) and aPTT 3, 5
• Common causes include: malnutrition, malabsorption, prolonged antibiotic use, dietary deficiency 3
• Correction with vitamin K: 0.5 mg IV is optimal for most overanticoagulated patients; severely overanticoagulated patients (INR >9.5 with aPTT ratio >2) may require repeat dosing 6

Common Pathway Factor Deficiencies

• Factor II (prothrombin) deficiency - rare, congenital or acquired 5
• Factor V deficiency - rare, can be congenital or acquired 5
• Factor X deficiency - rare, congenital or acquired 5
• Fibrinogen deficiency (factor I) - can be congenital or acquired; fibrinogen <2 g/L has 100% positive predictive value for severe postpartum hemorrhage 1

Critical Clinical Context

High-Risk Bleeding Scenarios

Prognostic factors for major bleeding in ICU patients include: 3

• Prolonged aPTT (HR 1.2 per 10-second increase)
• Decreasing platelet count (HR 1.7 per 50×10⁹/L decrease)
• Elevated baseline INR
• Therapeutic heparin treatment
• Renal insufficiency requiring dialysis

Special Populations

In pregnancy: 1

• Use PT ratio and aPTT ratio ≥1.5 as the coagulopathy threshold rather than absolute values in seconds
• Coagulation factors increase toward term, making absolute values unreliable

In critically ill patients: 3

• Risk factors include: age, APACHE II score, surgical versus medical admission, pre-ICU renal status
• Most major bleeding events are gastrointestinal

Diagnostic Approach

Initial Laboratory Assessment

Standard coagulation panel should include: 1

• PT/INR and aPTT
• Fibrinogen level
• Platelet count
• D-dimer (if DIC suspected)

Advanced Testing When Available

Viscoelastic testing (TEG/ROTEM) should be utilized when available to characterize coagulopathy and guide therapy, particularly in trauma, massive bleeding, or emergency neurosurgery 1, 4

These tests provide advantages over standard tests: 1

• Predict need for massive transfusion
• Assess thrombotic/thromboembolic risk
• Predict mortality in surgical and trauma patients
• Provide results in 30-60 minutes faster than conventional testing

Common Pitfalls to Avoid

Do not rely solely on PT/INR and aPTT to guide hemostatic therapy, as they monitor only the initiation phase of blood coagulation (first 4% of thrombin production) and can appear normal while overall coagulation remains abnormal 1

Do not assume INR predicts bleeding risk in patients not on vitamin K antagonist therapy - INR was specifically designed and validated only for monitoring warfarin therapy 3, 1, 4

Do not transfuse plasma to correct mildly elevated INR values - randomized trials found no reduction in bleeding, and this practice lacks biological plausibility while exposing patients to unnecessary risk 1, 4

When heparin and warfarin are used together, blood for PT/INR should be drawn at least 5 hours after the last IV bolus of heparin, 4 hours after cessation of continuous IV infusion, or 24 hours after subcutaneous heparin injection 2

In patients with baseline prolonged aPTT or INR, there is increased risk of anticoagulant failure due to PTT/INR confounding when these tests are used to monitor anticoagulant therapy 7