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 pro
cofactor. 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
