Factor VIII (FVIII) is an essential blood clotting factor also known as anti-hemophilic factor (AHF). In humans, Factor VIII is encoded by the F8 gene. Defects in this gene results in hemophilia A, a well known recessive X-linked coagulation disorder.
Factor VIII participates in blood coagulation; it is a cofactor for factor IXa which, in the presence of Ca⁺² and phospholipids forms a complex that converts factor X to the activated form Xa. The Factor VIII gene produces two alternatively spliced transcripts. Transcript variant 1 encodes a large glycoprotein, isoform a, which circulates in plasma and associates with von Willebrand factor in a noncovalent complex. This protein undergoes multiple cleavage events. Transcript variant 2 encodes a putative small protein, isoform b, which consists primarily of the phospholipid binding domain of factor VIIIc. This binding domain is essential for coagulant activity.

Genetics

The gene for Factor VIII is located on the X chromosome (Xq28). The gene for factor VIII presents an interesting primary structure, as another gene is embedded in one of its introns.

Physiology

FVIII is a glycoprotein procofactor. It has been found to be synthesized and released into the bloodstream by the vascular, glomerular, and tubular endothelium, and the sinusoidal cells of the liver, though there is still considerable ambiguity as to what the primary site of release in humans is. In the circulating blood, it is mainly bound to von Willebrand factor to form a stable complex. Upon activation by thrombin, (Factor IIa), it dissociates from the complex to interact with Factor IXa in the coagulation cascade. It is a cofactor to Factor IXa in the activation of Factor X, which, in turn, with its cofactor Factor Va, activates more thrombin. Thrombin cleaves fibrinogen into fibrin which polymerizes and crosslinks (using Factor XIII) into a blood clot.

No longer protected by vWF, activated FVIII is proteolytically inactivated in the process (most prominently by activated Protein C and Factor IXa) and quickly cleared from the blood stream.

Factor VIII is not affected by liver disease. In fact, levels usually are elevated in such instances.

Therapeutic use

FVIII concentrated from donated blood plasma (Aafact), or alternatively recombinant FVIII can be given to hemophiliacs to restore hemostasis.

The transfer of a plasma byproduct into the blood stream of a patient with hemophilia often led to the transmission of diseases such as hepatitis B and C and HIV before purification methods were improved. Antibody formation to Factor VIII can also be a major concern for patients receiving therapy against bleeding; the incidence of these inhibitors is dependent of various factors, including the Factor VIII product itself.
In the 1980s, some pharmaceutical companies such as Bayer sparked controversy by continuing to sell contaminated factor VIII after new heat-treated versions were available.
In the early 1990s, pharmaceutical companies began to produce recombinant synthesized factor products, which now prevent nearly all forms of disease transmission during replacement therapy.

See also

• Ryan White

• Gian Carlos