INTRODUCTION
Factor VIII (FVIII) is a glycoprotein essential for the intrinsic pathway of blood coagulation because of its ability to accelerate the proteolytic activation of Factor X (FX) by the serine protease Factor IXa (FIXa).1 Synthesized mainly in hepatocytes, the mature form of FVIII is a single-chain, 2332 amino acid polypeptide, with a molecular ratio of approximately 265,000 Daltons. The molecule is comprised of two homologous groups separated by a third segment and organized with the domain structure of A1-A2-B-A3-C1-C2.2 Cleaved intracellularly into a two-chain heterodimer, a heavy-chain of domains A1-A2-B and a light-chain of domains A3-C1-C2, FVIII is secreted into the blood stream and forms a stable, non-covalent complex with von Willebrand Factor (vWF)3,4. FVIII is activated by proteolytic cleavage and released from its vWF carrier protein by thrombin2.
The activated protein, FVIIIa, consists of the domains A1-A2 and the A3-C1-C2 light chain, both of which are necessary for sustained activity.5 The B domain does not contribute to the active molecule and is lost after activation.6,7 FVIIIa is a cofactor for fIXa along with calcium and phospholipids. Binding to phospholipids and to platelets occurs via the light chain and has been determined to be associated with sequences within the C domain.8 The light chain is also responsible for the binding to vWF9.