A 32-year-old woman presents with a 6-month history of menorrhagia and spontaneous bruising on the legs. Platelet count is 180,000/µL, PT is normal, but aPTT is prolonged at 52 seconds. Mixing study corrects the aPTT to 38 seconds. What is the most appropriate next investigation to confirm the diagnosis?

Explanation

## Clinical Context The patient presents with: - Menorrhagia and spontaneous bruising (mucocutaneous bleeding) - Normal platelet count (rules out thrombocytopenia) - Normal PT (rules out extrinsic/common pathway defects) - **Prolonged aPTT that corrects on mixing study** — indicates a factor deficiency, not an inhibitor ## Interpretation of Mixing Study **Key Point:** A correcting mixing study (aPTT normalizes when patient plasma is mixed 1:1 with normal plasma) indicates a **factor deficiency**, not a circulating inhibitor. The normal plasma provides the missing factor. ## Differential Diagnosis of Prolonged aPTT with Correcting Mix | Factor | Clinical Clue | Next Test | |--------|---------------|----------| | **Factor VIII deficiency (Hemophilia A)** | Menorrhagia, spontaneous bruising, female carrier/mild hemophilia | **Factor VIII assay** | | Factor IX deficiency (Hemophilia B) | Same bleeding pattern as Factor VIII | Factor IX assay | | Factor XI deficiency | Milder bleeding, Jewish ancestry | Factor XI assay | | Factor XII deficiency | Asymptomatic prolonged aPTT | Factor XII assay | ## Why Factor VIII Assay is Correct **High-Yield:** In a woman with: 1. Mucocutaneous bleeding (menorrhagia, bruising) 2. Prolonged aPTT + correcting mix 3. Normal PT and platelets **Factor VIII deficiency is the most common intrinsic pathway defect.** This can occur in: - Hemophilia A carriers (heterozygous females with low Factor VIII levels) - Mild hemophilia A in females with skewed X-inactivation - Acquired Factor VIII deficiency (rare) **Factor VIII assay** directly measures the deficient factor and confirms the diagnosis. The result will be **low (typically <40% activity)** in hemophilia A. ## Clinical Pearl **Menorrhagia is often the presenting symptom of Factor VIII deficiency in women.** Many female carriers of hemophilia A go undiagnosed until they present with heavy menstrual bleeding or postpartum hemorrhage. ## Mnemonic: Prolonged aPTT Workup **CORRECT MIX** = **C**orrects → **Factor deficiency** → Measure **individual factors** (VIII, IX, XI, XII) **NO CORRECT MIX** = **I**nhibitor present → Perform **Bethesda assay** for inhibitor titer