Factor VIII is produced in theliver'ssinusoidal cells andendothelial cells outside the liver throughout the body. This protein circulates in the bloodstream in an inactive form, bound to a plasma carrier (another protein) calledvon Willebrand factor, until aninjury that damagesblood vessels occurs.[10] 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 (by an as-yet-unknown mechanism) with another coagulation factor called factor IX. This interaction sets off a chain of additional chemical reactions that form a blood clot.[10]
Factor VIII participates inblood coagulation; it is a cofactor forfactor IXa, which, in the presence of Ca2+ andphospholipids, forms a complex that convertsfactor X to the activated form Xa. The factor VIII gene produces two alternatively spliced transcripts. Transcript variant 1 encodes a largeglycoprotein, 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.[11]
People with high levels of factor VIII are at increased risk fordeep vein thrombosis andpulmonary embolism.[12] Copper is a required cofactor for factor VIII and copper deficiency is known to increase the activity of factor VIII.[13]
In human, the F8 gene is located on theX chromosome at position q28.
Factor VIII was first characterized in 1984 by scientists at Genentech.[15] The gene for factor VIII is located on theX chromosome (Xq28). The gene for factor VIII presents an interesting primary structure, as another gene (F8A1) is embedded in one of itsintrons.[16]
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.[19]
No longer protected by vWF, activated FVIII isproteolytically inactivated in the process (most prominently by activatedprotein C andfactor 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.[23][24]
FVIII concentrated from donated blood plasma, or recombinant FVIII can be given tohemophiliacs to restorehemostasis. Bypassing agents such asrecombinant 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.[25]
Factor VIII related antigen is used as a target forimmunohistochemistry, where endothelial cells, megakaryocytes, platelets and mast cells normally stain positive.[26]
In the 1980s, some pharmaceutical companies such asBaxter International andBayer sparked controversy by continuing to sellcontaminated factor VIII after new heat-treated versions were available.[27] 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).[27]
Factor VIII was first discovered in 1937, but it was not until 1979 that its purification byEdward Tuddenham,Frances Rotblat and coworkers led to the molecular identification of the protein.[28][29]
^Truett MA, Blacher R, Burke RL, Caput D, Chu C, Dina D, et al. (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):333–349.doi:10.1089/dna.1985.4.333.PMID3935400.
^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.doi:10.1016/0888-7543(90)90512-S.PMID2110545.
^Macedo-Ribeiro S, Bode W, Huber R, Quinn-Allen MA, Kim SW, Ortel TL, et al. (November 1999). "Crystal structures of the membrane-binding C2 domain of human coagulation factor V".Nature.402 (6760):434–439.Bibcode:1999Natur.402..434M.doi:10.1038/46594.PMID10586886.S2CID4393638.
^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):267–275.doi:10.1160/th03-05-0310.PMID14961153.S2CID20091477.
^Rubin R, Leopold L (1998).Hematologic Pathophysiology. Madison, Conn: Fence Creek Publishing.ISBN1-889325-04-X.
^Tuddenham EG, Trabold NC, Collins JA, Hoyer LW (January 1979). "The properties of factor VIII coagulant activity prepared by immunoadsorbent chromatography".The Journal of Laboratory and Clinical Medicine.93 (1):40–53.PMID366050.
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):3983–3996.doi:10.1182/blood.V92.11.3983.PMID9834200.
Lavigne-Lissalde G, Schved JF, Granier C, Villard S (October 2005). "Anti-factor VIII antibodies: a 2005 update".Thrombosis and Haemostasis.94 (4):760–769.doi:10.1160/TH05-02-0118.PMID16270627.S2CID38533008.
