A 28-year-old man with a family history of bleeding disorder presents with spontaneous hemarthrosis and easy bruising. Coagulation studies show normal PT, prolonged aPTT, and normal bleeding time. Mixing study corrects the prolonged aPTT. Regarding factor VIII deficiency (hemophilia A), all of the following statements are correct EXCEPT:

Explanation

## Hemophilia A — Genetics, Pathophysiology, and Clinical Management ### Correct Answer Analysis **The statement about inhibitor development (Option B) is INCORRECT.** Inhibitor development (alloantibodies against factor VIII) occurs in approximately **25–30% of patients with severe hemophilia A**, not 5–10% as stated. This is one of the most significant complications of hemophilia A treatment, particularly following intensive factor VIII replacement. The 5–10% figure substantially underestimates the true incidence in severe disease. ### Why the Other Options Are Correct | Statement | Evidence | |-----------|----------| | **Factor VIII synthesis (A)** | Factor VIII is produced by hepatocytes (~80%) and sinusoidal endothelial cells (~20%); this explains why liver disease worsens bleeding and why liver transplantation may correct hemophilia A | | **DDAVP efficacy (C)** | Desmopressin releases vWF from Weibel-Palade bodies of endothelial cells; vWF stabilizes and carries factor VIII, raising levels 2–4-fold; effective in mild-to-moderate hemophilia A (baseline factor VIII >5%) | | **X-linked recessive inheritance (D)** | Hemophilia A is X-linked recessive; carrier females (X^A^X^a^) carry one mutant allele and can transmit the disorder; rare carriers with skewed X-inactivation may have reduced factor VIII levels and mild bleeding symptoms | ### Inhibitor Incidence — The Key Fact **High-Yield:** According to Harrison's Principles of Internal Medicine (21e) and the World Federation of Hemophilia guidelines, inhibitors develop in **~25–30% of patients with severe hemophilia A** (factor VIII <1%). The risk is lower in moderate and mild disease (~5–10% overall across all severities). Option B incorrectly applies the overall/mild-moderate figure to severe hemophilia A specifically. **Clinical Pearl:** Inhibitor development is suspected when a patient with hemophilia A fails to respond adequately to factor VIII replacement. Bethesda assay quantifies inhibitor titer. Management includes immune tolerance induction (ITI) or bypassing agents (recombinant FVIIa, activated prothrombin complex concentrate). **Key Point:** The clinical vignette describes classic hemophilia A: normal PT, prolonged aPTT, normal bleeding time, and correction on mixing study (indicating factor deficiency rather than an inhibitor). Factor VIII assay confirms diagnosis and severity. [cite: Harrison 21e Ch 179; Williams Hematology 9e Ch 123]