Factor VIII (FVIII) is an essential
blood-clotting
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
, also known as anti-hemophilic factor (AHF). In humans, factor VIII is encoded by the ''F8''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
.
Defects in this gene result in
hemophilia A, a
recessive
In genetics, dominance is the phenomenon of one variant ( allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant an ...
X-linked coagulation disorder.
Factor VIII is produced in liver 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.
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
blood coagulation
Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism o ...
; 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
Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glyco ...
, 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.
There is a
formulation as a medication that is on the
WHO Model List of Essential Medicines
The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health ...
, the most important medications needed in a basic
health system
Health, according to the World Health Organization, is "a state of complete physical, mental and social well-being and not merely the absence of disease and infirmity".World Health Organization. (2006)''Constitution of the World Health Organi ...
.
Genetics
Factor VIII was first characterized in 1984 by scientists at Genentech. The gene for factor VIII is located on the
X chromosome
The X chromosome is one of the two sex-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO sex ...
(Xq28). The gene for factor VIII presents an interesting primary structure, as another gene (''
F8A1
40-kDa huntingtin-associated protein is a protein that in humans is encoded by the ''F8A1'', ''F8A2'', and ''F8A3'' genes.
''F8A1'' is contained entirely within intron 22 of the factor VIII gene; spans less than 2 kb, and is transcribed in the ...
'') 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
Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glyco ...
pro
cofactor. 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
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the ve ...
, and the
sinusoidal cells of the
liver
The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...
.
Hemophilia A has been corrected by liver
transplantation.
Transplanting
hepatocyte
A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass.
These cells are involved in:
* Protein synthesis
* Protein storage
* Transformation of carbohydrates
* Synthesis of cholesterol, ...
s 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 (factor IIa), it dissociates from the complex to interact with
factor IXa in the
coagulation cascade
Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechani ...
. 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
fibrin
Fibrin (also called Factor Ia) is a fibrous, non-globular protein involved in the clotting of blood. It is formed by the action of the protease thrombin on fibrinogen, which causes it to polymerize. The polymerized fibrin, together with pl ...
ogen into
fibrin
Fibrin (also called Factor Ia) is a fibrous, non-globular protein involved in the clotting of blood. It is formed by the action of the protease thrombin on fibrinogen, which causes it to polymerize. The polymerized fibrin, together with pl ...
which
polymer
A polymer (; Greek '' poly-'', "many" + '' -mer'', "part")
is a substance or material consisting of very large molecules called macromolecules, composed of many repeating subunits. Due to their broad spectrum of properties, both synthetic a ...
izes and crosslinks (using
factor XIII) into a blood clot.
The factor VIII protein has a
half-life
Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable ...
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 (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.
Medical use
FVIII concentrated from donated blood plasma, or alternatively
recombinant FVIIa can be given to
hemophiliacs to restore
hemostasis
In biology, hemostasis or haemostasis is a process to prevent and stop bleeding, meaning to keep blood within a damaged blood vessel (the opposite of hemostasis is hemorrhage). It is the first stage of wound healing. This involves coagulatio ...
.
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.
Immunostain target
Factor VIII related antigen is used as a target for
immunohistochemistry
Immunohistochemistry (IHC) is the most common application of immunostaining. It involves the process of selectively identifying antigens (proteins) in cells of a tissue section by exploiting the principle of antibodies binding specifically to ant ...
, where endothelial cells, megakaryocytes, platelets and mast cells normally stain positive.
Contamination scandal
In the 1980s, some pharmaceutical companies such as
Baxter International
Baxter International Inc. is an American multinational healthcare company with headquarters in Deerfield, Illinois.
The company primarily focuses on products to treat kidney disease, and other chronic and acute medical conditions. The company ...
and
Bayer
Bayer AG (, commonly pronounced ; ) is a German multinational pharmaceutical and biotechnology company and one of the largest pharmaceutical companies in the world. Headquartered in Leverkusen, Bayer's areas of business include pharmaceutic ...
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.
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
(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.
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.
See also
*
Ralph Kekwick
*
Frances Rotblat
*
Edward Shanbrom
*
Edward Tuddenham
*
Ryan White
References
Further reading
*
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*
External links
GeneReviews/NCBI/NIH/UW entry on Hemophilia AThe Coagulation Factor VIII Protein*
*
{{Coagulation
Acute-phase proteins
Recombinant proteins
Coagulation system
Wyeth brands
Pfizer brands
Cofactors