Coagulation factor VIII (Factor VIII, FVIII) is an essential
blood-clottingprotein, also known as anti-hemophilic factor (AHF). In humans, factor VIII is encoded by the F8gene.[5][6] Defects in this gene result in
hemophilia A, an X-linked
bleeding disorder.[7] 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 another molecule called
von Willebrand factor, until an injury that damages blood vessels occurs.[8] 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.[8]
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.[9]
People with high levels of factor VIII are at increased risk for
deep vein thrombosis and
pulmonary embolism.[10] Copper is a required cofactor for factor VIII and copper deficiency is known to increase the activity of factor VIII.[11]
Factor VIII was first characterized in 1984 by scientists at Genentech.[13] 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 (F8A1) is embedded in one of its
introns.[14]
Structure
Factor VIII protein consists of six domains: A1-A2-B-A3-C1-C2, and is
homologous to
factor V.
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.[17]
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.[21][22]
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.[23]
Immunostain target
Factor VIII related antigen is used as a target for
immunohistochemistry, where endothelial cells, megakaryocytes, platelets and mast cells normally stain positive.[24]
In the 1980s, some pharmaceutical companies such as
Baxter International and
Bayer sparked controversy by continuing to sell
contaminated factor VIII after new heat-treated versions were available.[25] 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.
Food and Drug Administration (FDA).[25]
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.
History
Factor VIII was first discovered in 1937, but it was not until 1979 that its purification by
Edward Tuddenham,
Frances Rotblat and coworkers led to the molecular identification of the protein.[26][27]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Toole JJ, Knopf JL, Wozney JM, Sultzman LA, Buecker JL, Pittman DD, Kaufman RJ, Brown E, Shoemaker C, Orr EC (1984). "Molecular cloning of a cDNA encoding human antihaemophilic factor". Nature. 312 (5992): 342–47.
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^Truett MA, Blacher R, Burke RL, Caput D, Chu C, Dina D, Hartog K, Kuo CH, Masiarz FR, Merryweather JP (October 1985). "Characterization of the polypeptide composition of human factor VIII:C and the nucleotide sequence and expression of the human kidney cDNA". DNA. 4 (5): 333–49.
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10.1089/dna.1985.4.333.
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^Antonarakis SE (July 1995). "Molecular genetics of coagulation factor VIII gene and hemophilia A". Thrombosis and Haemostasis. 74 (1): 322–28.
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^Levinson B, Kenwrick S, Lakich D, Hammonds G, Gitschier J (May 1990). "A transcribed gene in an intron of the human factor VIII gene". Genomics. 7 (1): 1–11.
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10.1016/0888-7543(90)90512-S.
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^Hollestelle MJ, Geertzen HG, Straatsburg IH, van Gulik TM, van Mourik JA (February 2004). "Factor VIII expression in liver disease". Thrombosis and Haemostasis. 91 (2): 267–75.
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^Rubin R, Leopold L (1998). Hematologic Pathophysiology. Madison, Conn: Fence Creek Publishing.
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Lenting PJ, van Mourik JA, Mertens K (December 1998). "The life cycle of coagulation factor VIII in view of its structure and function". Blood. 92 (11): 3983–96.
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