Structure

The Factor VIII polypeptide chain consists of 3 A domains, a B domains, and 2 C domains (A1-A2-B-A3-C1-C2). The A domains are homologous to ceruloplasmin, a copper binding protein; the C domains are homologous to phospholipid binding lectin, which has an effect on binding to other proteins. The polypeptide is cleaved between the B-A3 domains to make the (A1-A2-B) and light (A3-C1-C2) chains as a heterodimeric protein before secretion. Thrombin then activates the heterodimer to cleave into the Factor VIIIa. The C2 domain contains the major binding motif that has high affinity and selectivity for membrane binding sites such as phosphatidylserine and is stereo selective to phosphatidyl-l-serine. This is where it interacts with the cofactor Factor IXa to form a tenase complex for the continuation of the coagulation cascade. Further research has shown that there is interaction between the first epidermal growth factor domain of factor IXa and the A3 domain of factor VIIIa as well as the serine protease domain of factor IXa and the A2 domain of factor VIIIa.

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.