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Next investigation if INR is raised

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Here is a structured approach to investigating a raised INR (prolonged PT/INR):

Raised INR — Next Investigations

Understanding What the PT/INR Measures

The PT (reported as INR) reflects the extrinsic and common pathways: Factor VII, Factor X, Factor V, prothrombin (Factor II), and fibrinogen.
Coagulation cascade showing PT (extrinsic) and aPTT (intrinsic) pathways
Classic coagulation cascade — Goldman-Cecil Medicine

Step 1: Check the aPTT

This is the critical first step. The pattern of PT vs aPTT narrows the differential:
PT (INR)aPTTLikely Cause
↑NormalFactor VII deficiency; early vitamin K deficiency; early liver disease
↑↑Common pathway defect (FV, FX, FII, fibrinogen); DIC; severe liver disease; vitamin K deficiency (advanced); warfarin; supratherapeutic heparin
Normal↑Intrinsic pathway defect (FVIII, FIX, FXI — haemophilia A/B; vWD); lupus anticoagulant

Step 2: Mixing Study (1:1 Mix)

Mix patient plasma 1:1 with normal pooled plasma, then re-run the PT:
  • Corrects → factor deficiency (the normal plasma supplies the missing factor to 50%, which is sufficient for clotting)
    • Proceed to individual factor assays (FVII, FX, FV, FII, fibrinogen depending on aPTT result)
  • Does NOT correct → inhibitor present (an antibody is interfering with coagulation in both the patient's and normal plasma)
    • Proceed to inhibitor identification (specific factor antibody, e.g. anti-FVIII; or lupus anticoagulant testing)

Step 3: Targeted Follow-Up Tests

If factor deficiency (mixing study corrects):

  • Individual factor assays: FVII (if aPTT normal), or FX, FV, FII (if both PT and aPTT raised)
  • Fibrinogen level (functional/clottable + antigenic) — if Thrombin Time (TT) also prolonged
  • Vitamin K levels / response to vitamin K administration
  • Liver function tests — liver produces all coagulation factors (except FVIII)
  • Consider DIC screen: fibrinogen, D-dimer, platelet count, peripheral blood film

If inhibitor suspected (mixing study does not correct):

  • Factor VIII inhibitor assay (Bethesda assay) — most common acquired inhibitor
  • Lupus anticoagulant screen: dilute Russell's viper venom time (dRVVT), Silica clotting time

Additional tests based on clinical context:

  • LFTs + synthetic function (albumin, bilirubin) — liver disease
  • Vitamin K status — nutritional, malabsorption (coeliac screen, faecal elastase), broad-spectrum antibiotics
  • Drug history — warfarin, broad-spectrum antibiotics disrupting gut flora
  • FBC + film — DIC (thrombocytopenia, schistocytes), haematological malignancy
  • TT (Thrombin Time) — prolonged in fibrinogen deficiency, dysfibrinogenaemia, heparin effect

Common Causes to Guide Investigation

CauseKey Distinguishing Tests
Warfarin / anticoagulant drugsDrug history; corrects with vitamin K
Liver diseaseLFTs, albumin; both PT and aPTT raised
Vitamin K deficiencyNutritional Hx; responds to IV vitamin K
DICD-dimer ↑↑, fibrinogen ↓, platelets ↓
Isolated FVII deficiencyaPTT normal; FVII assay
Acquired inhibitorMixing study does not correct
DysfibrinogenaemiaProlonged TT; discordant clottable vs antigenic fibrinogen
Sources: Goldman-Cecil Medicine; Harrison's Principles of Internal Medicine 22E (2025)
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