Practice question

Hemophilia A 1 in 5000 males and B 1 in 30000 males result null mutations coagulation cofactors FVIII 280 kDa glycoprotein encoded F8 Xq28 domains A1 A2 B A3 C1 C2 and FIX vitamin K dependent serine protease encoded F9 Xq27 gamma carboxyglutamic acid residues binding calcium phospholipid. Both assemble intrinsic tenase complex FVIIIa cofactor enhancing FIXa protease activity 200000-fold toward FX activation on phosphatidylserine-rich platelet surface accelerating thrombin burst fibrin clot formation. Deficiency prolongs aPTT causing hemarthrosis, muscle hematoma. Replacement requires frequent IV infusions half-life FVIII 12h FIX 18h. Gene therapy delivers codon-optimized B-domain-deleted F8 central 908 aa dispensable removed reducing size 4.4 kb fitting AAV, or FIX Padua variant R338L leucine substitution arginine 338 increasing specific activity 8-fold improving secretion. Hepatotropic AAV5 AAV6 liver-specific promoter HLP transcribe hepatocytes synthesize factor secreting into sinusoids restoring plasma levels 5-150 percent converting severe to mild reducing annualized bleeding rate 90 percent in trials Hemgenix Roctavian leading to regulatory approvals.