hemophilia B

**Genetics/Pathophysiology:** Mutation in the F9 gene on the X chromosome (Xq27) leads to deficient or dysfunctional factor IX. X-linked recessive inheritance, so it mostly affects males; carrier females are usually asymptomatic but may have mild bleeding if there is skewed lyonization. About 1/3 of cases arise from de novo mutations. Factor IX (activated by XIa or by VIIa/tissue factor) combines with VIIIa, Ca2+, and phospholipid (the "tenase" complex) to activate factor X in the intrinsic pathway. Factor IX is vitamin K-dependent (II, VII, IX, X, protein C, protein S). Hemophilia B is clinically indistinguishable from hemophilia A (factor VIII deficiency), which is more common (about 80-85% of hemophilia cases vs 15% for B).

**Clinical features:** Severity correlates with residual factor activity: severe <1%, moderate 1-5%, mild 5-40%. Findings include hemarthroses (knees, elbows, ankles) leading to hemophilic arthropathy, deep muscle hematomas (iliopsoas), easy bruising, prolonged bleeding after circumcision, dental extraction, or surgery, hematuria, GI bleeding, and intracranial hemorrhage (the most serious complication). Mucosal bleeding and petechiae are typically absent because primary hemostasis (platelet plug) is intact.

**Labs:** Prolonged aPTT (intrinsic pathway), normal PT (extrinsic pathway), normal bleeding time, normal platelet count, and normal vWF. The aPTT corrects with a mixing study (this distinguishes factor deficiency from an inhibitor). Diagnosis is confirmed with a specific factor IX activity assay.

**Treatment:** Recombinant factor IX replacement (on demand or prophylactic). Extended half-life products are available. Non-factor and gene therapies are also available. Etranacogene dezaparvovec (Hemgenix) and fidanacogene elaparvovec (Beqvez) are AAV-based factor IX gene therapies. Desmopressin does NOT work in hemophilia B (it helps mild hemophilia A and vWD by releasing stored factor VIII/vWF). Fresh frozen plasma or prothrombin complex concentrate can be used if recombinant factor is unavailable. Antifibrinolytics (tranexamic acid, aminocaproic acid) are adjuncts for mucosal bleeding. Avoid NSAIDs and aspirin. Complications of therapy include inhibitor (alloantibody) development, which is less frequent than in hemophilia A but is more likely to be associated with anaphylaxis. Historically, plasma-derived products caused HIV and hepatitis C transmission.

**High-yield associations:** Also called Christmas disease (named after the first patient described, Stephen Christmas). Hemophilia B Leyden is a rare variant in which factor IX levels rise after puberty. Do not confuse it with hemophilia C (factor XI deficiency, autosomal, seen in Ashkenazi Jews, mild bleeding), vWD (autosomal dominant, prolonged bleeding time and aPTT), or vitamin K deficiency/warfarin (prolonged PT and aPTT).