A 58-year-old man with atrial fibrillation on warfarin (INR target 2–3) presents to the clinic. He was recently started on fluconazole for oral candidiasis. After 5 days, his INR is 8.2 (previously 2.5). Which investigation is most appropriate to assess the severity and guide immediate management?

## Clinical Context: Warfarin–Fluconazole Interaction **Key Point:** Fluconazole inhibits CYP2C9, the major enzyme responsible for warfarin metabolism. This causes warfarin accumulation, prolonged PT/INR, and bleeding risk. ## Why PT and aPTT? **High-Yield:** PT (or INR) directly measures the anticoagulant effect of warfarin and is the gold standard for monitoring warfarin therapy. aPTT is included to assess the intrinsic and common coagulation pathways and detect any additional coagulation defect. ### Investigation Rationale | Investigation | Utility in Warfarin Toxicity | |---|---| | **PT/INR** | Directly reflects warfarin effect; guides dose adjustment or reversal | | **aPTT** | Detects defects in intrinsic pathway; rules out other coagulation disorders | | **Fibrinogen** | Nonspecific; only abnormal in severe DIC or liver disease | | **CBC** | Detects bleeding (anaemia) but not the coagulation defect itself | | **LFTs** | Relevant only if liver disease is suspected as cause of INR elevation | **Clinical Pearl:** The combination of PT/INR and aPTT provides a complete picture of the extrinsic and intrinsic pathways. A markedly elevated PT/INR with normal aPTT confirms isolated warfarin effect (expected here). A prolonged aPTT would suggest additional pathology (e.g., lupus anticoagulant, factor deficiency). ## Management Implication Once PT/INR is confirmed elevated, the next step is: 1. **Stop fluconazole** (or switch to an alternative antifungal with less CYP2C9 inhibition, e.g., terbinafine). 2. **Reduce warfarin dose** or hold a dose. 3. **If INR > 10 and no bleeding:** vitamin K₁ 2.5–5 mg PO. 4. **If INR > 10 with bleeding or life-threatening:** fresh frozen plasma + vitamin K₁ IV. **Warning:** Do not order D-dimer or fibrinogen in isolation — these are neither sensitive nor specific for warfarin toxicity and may delay appropriate management.