Hemophilia A is an X-linked recessive bleeding disorder caused by mutations in the F8 gene on Xq28 encoding coagulation factor VIII, an essential cofactor for factor IXa in the intrinsic tenase complex of the coagulation cascade. Incidence is approximately 1 in 5000 male births, with carrier mothers (usually asymptomatic) transmitting to 50% of sons. Spontaneous mutations account for ~30% of cases. Severity classification: severe (<1% factor VIII activity, spontaneous bleeding into joints and muscles), moderate (1-5% activity, bleeding with minor trauma), mild (5-40% activity, bleeding only with surgery or major trauma).
Clinical presentation in severe hemophilia includes recurrent hemarthroses (knees, ankles, elbows), muscle hematomas, prolonged bleeding after circumcision or trauma, intracranial hemorrhage in neonates, and progressive hemophilic arthropathy from repeated joint bleeds. Diagnosis requires factor VIII activity assay (one-stage clotting or chromogenic substrate), with prolonged aPTT correctable by mixing with normal plasma. Genetic testing identifies F8 mutations (intron 22 inversion in 45% of severe cases, intron 1 inversion 5%, point mutations, deletions, insertions) for carrier detection and prenatal diagnosis.
Treatment has evolved dramatically: standard recombinant factor VIII concentrates require intravenous infusion every 2-3 days for prophylaxis (target trough >=1% to convert severe to moderate phenotype). Extended half-life products (efmoroctocog alfa with Fc fusion, rurioctocog alfa pegol with PEGylation, damoctocog alfa pegol, lonoctocog alfa) extend half-life to 14-19 hours allowing dosing every 3-5 days with higher trough levels (>=3-5%). Emicizumab is a humanized bispecific antibody bridging factor IXa and factor X to mimic factor VIIIa function, given subcutaneously weekly to monthly, dramatically reducing bleeds in patients with and without inhibitors. Gene therapy with adeno-associated virus serotype 5 vector encoding B-domain deleted factor VIII (valoctocogene roxaparvovec, approved 2022 for adults with severe hemophilia A) provides durable factor VIII expression after single infusion. Inhibitor management uses bypassing agents (recombinant factor VIIa, activated prothrombin complex concentrate) and immune tolerance induction protocols.