Structure

FVIII is synthesized as a single polypeptide chain, later cleaved to form a hetero dimer protein. This dimer has two polypeptide subunits, the factor VIII light chain and . The polypeptide has six evolutionarily conserved domains; three A (A1, A2, and A3), one B (B), and two C (C1 and C2). It is homologous to coagulation factor V.

Function

Normally, Factor VIII forms a non-covalent complex with another clotting glycoprotein, the von Willebrand factor, after being released from endothelium cells or sinusoidal cells in the liver. When it is not interacting with other proteins such as the von Willebrand factor, it is proteolytically inactivated. After inactivation, it is taken out of the blood stream. Factor VIII mainly acts during the Tissue Factor Pathway of the coagulation cascade. In the presence of Thrombin, Factor VIII cleaves into a heterotrimeric protein with an exposed C2 part of the domain that includes the highly selective membrane binding motif. This area interacts on its phosphatidyl-l-serine containing phospholipid membranes with its cofactor Factor IXa to form a tenase complex in the presence of Ca2+. The tenase complex speeds up the activation pathway for Factor X and blocks inhibitors, continuing the coagulation cascade. Factor X with its cofactor Factor Va activates more thrombin, which in turn cleaves fibrinogen into fibrin. Fibrin will polymerize and cross links to clot blood.

Genetics

Coagulation Factor VIII, otherwise known as Anti-Hemophilic Factor (AHF) is a glycoprotein procofactor. It is a single polypeptide chain coded by the F8 gene located on the X chromosome (Xq28). It is released by the vascular, glomerular, and tubular endothelium, and by sinusoidal cells in the liver. There are 1,300 known mutations in this gene, which could result in Factor VIII deficiency. Since it is part of the coagulation cascade, mutations creating deficiencies in Factor VIII result in the X-linked genetic disease Hemophilia A. Because of its importance to the coagulation cascade, concentrated Factor VIII from blood plasma is a key ingredient treatment for Hemophiliacs.