Novel therapies for hemophilia A – the role of the von Willebrand factor chaperone

FVIII is a plasma sialoglycoprotein that plays a critical role in maintaining normal hemostasis. Patients with severe hemophilia A have markedly reduced plasma FVIII levels, and thus typically show a significant bleeding phenotype. Accumulating data suggest that plasma FVIII is predominantly derived from biosynthesis within sinusoidal cells and endothelial cells (ECs), particularly in the liver and lung 1. FVIII is initially synthesized as an inactive 2332 amino acid polypeptide composed of three distinct domain types: A, B, and C (domain structure A1–a1–A2–a2–B–a3–A3–C1–C2). Prior to secretion, this single‐chain FVIII undergoes complex post‐translational modification that includes significant glycosylation, sulfation, and limited intracellular proteolytic processing. Consequently, plasma FVIII circulates as a heterodimeric protein consisting of a heavy chain (A1–a1–A2–a2–B) and a light chain (a3–A3–C1–C2), held together through a metal ion‐dependent interaction.