Factor VIII

Factor VIII (FVIII) is an essential blood-clotting is_associated_with::protein, also known as anti-hemophilic factor (AHF). In humans, factor VIII is encoded by the F8 is_associated_with::gene. Defects in this gene results in is_associated_with::hemophilia A, a recessive X-linked coagulation disorder. Factor VIII is produced in liver sinusoidal cells and endothelial cells outside of the liver throughout the body. This protein circulates in the bloodstream in an inactive form, bound to another molecule called is_associated_with::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 (sometimes written as coagulation factor VIIIa) 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 is_associated_with::blood coagulation; it is a cofactor for is_associated_with::factor IXa which, in the presence of Ca2+ and is_associated_with::phospholipids forms a complex that converts is_associated_with::factor X to the activated form Xa. The factor VIII gene produces two alternatively spliced transcripts. Transcript variant 1 encodes a large is_associated_with::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 is_associated_with::deep vein thrombosis and is_associated_with::pulmonary embolism. Copper is a required cofactor for factor VIII and copper deficiency is known to increase levels of factor VIII.

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

Physiology
FVIII is a is_associated_with::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 is_associated_with::endothelium, and the sinusoidal cells of the is_associated_with::liver. is_associated_with::Hemophilia A has been corrected by liver transplantation. Transplanting is_associated_with::hepatocytes was ineffective, but liver endothelial cells were effective.

In the blood, it mainly circulates in a stable noncovalent complex with is_associated_with::von Willebrand factor. Upon activation by is_associated_with::thrombin, (factor IIa), it dissociates from the complex to interact with is_associated_with::factor IXa in the coagulation cascade. It is a cofactor to is_associated_with::factor IXa in the activation of is_associated_with::factor X, which, in turn, with its cofactor is_associated_with::factor Va, activates more thrombin. Thrombin cleaves is_associated_with::fibrinogen into is_associated_with::fibrin which is_associated_with::polymerizes and crosslinks (using is_associated_with::factor XIII) into a blood clot.

No longer protected by vWF, activated FVIII is proteolytically inactivated in the process (most prominently by activated is_associated_with::protein C and is_associated_with::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 (is_associated_with::Aafact or Alphanate, Monoclate-P®), or alternatively recombinant FVIII can be given to is_associated_with::hemophiliacs to restore is_associated_with::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 is_associated_with::hepatitis B and C and is_associated_with::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.

Contamination scandal
In the 1980s, some pharmaceutical companies such as is_associated_with::Bayer sparked controversy by continuing to sell contaminated factor VIII after new heat-treated versions were available. Under FDA pressure, unheated product was pulled from US markets, but was sold to Asian, Latin American, and some European countries. The product was tainted with HIV, a concern that had been discussed by Bayer and the U.S. is_associated_with::Food and Drug Administration (FDA).

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.