Factor VIII
Coagulation factor VIII[Noncovalent bonding|] is an essential blood clotting protein. In humans, it is encoded by F8 gene. Defects in this gene result in hemophilia A, an X-linked bleeding disorder.
Factor VIII is produced in the liver's sinusoidal cells and endothelial cells outside the liver throughout the body. This protein circulates in the bloodstream in an inactive form, bound to a plasma carrier called von Willebrand factor, until an injury that damages blood vessels occurs. In response to injury, coagulation factor VIII is activated and separates from von Willebrand factor. The active protein interacts with another coagulation factor called factor IX. This interaction sets off a chain of additional chemical reactions that form a blood clot.
Factor VIII participates in blood coagulation; it is a cofactor for factor IXa, which, in the presence of Ca2+ 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.
People with high levels of factor VIII are at increased risk for deep vein thrombosis and pulmonary embolism. Copper is a required cofactor for factor VIII and copper deficiency is known to increase the activity of factor VIII.
Factor VIII is on the WHO Model [List of Essential Medicines|World Health Organization's List of Essential Medicines].
Genetics
Factor VIII was first characterized in 1984 by scientists at Genentech. The gene for factor VIII is located on the X chromosome. The gene for factor VIII presents an interesting primary structure, as another gene is embedded in one of its introns.Structure
Factor VIII protein consists of six domains: A1-A2-B-A3-C1-C2, and is homologous to factor V.The A domains are homologous to the A domains of the copper-binding protein ceruloplasmin. The C domains belong to the phospholipid-binding discoidin domain family, and the C2 domain mediate membrane binding.
Activation of factor VIII to factor VIIIa is done by cleavage and release of the B domain. The protein is now divided to a heavy chain, consisting of the A1-A2 domains, and a light chain, consisting of the A3-C1-C2 domains. Both form non-covalently a complex in a calcium-dependent manner. This complex is the pro-coagulant factor VIIIa.
Physiology
FVIII is a glycoprotein procofactor. Although the primary site of release in humans is ambiguous, it is synthesized and released into the bloodstream by the vascular, glomerular, and tubular endothelium, and the sinusoidal cells of the liver. Hemophilia A has been corrected by liver transplantation. Transplanting hepatocytes was ineffective, but liver endothelial cells were effective.In the blood, it mainly circulates in a stable
noncovalent complex with von Willebrand factor. Upon activation by thrombin, 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 into a blood clot.
The factor VIII protein has a half-life of 12 hours in the blood stream when stabilized by the von Willebrand factor.
No longer protected by vWF, activated FVIII is proteolytically inactivated in the process and quickly cleared from the blood stream.
Factor VIII is not affected by liver disease. In fact, levels usually are elevated in such instances.
Medical use
FVIII concentrated from donated blood plasma, or recombinant FVIII can be given to hemophiliacs to restore hemostasis. Bypassing agents such as recombinant FVIIa can be used in acquired hemophilia.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.