Factor VIII
Encyclopedia
Factor VIII is an essential blood clot
ting factor also known as anti-hemophilic factor (AHF). In humans, Factor VIII is encoded by the F8 gene
. Defects in this gene results in hemophilia A, a well known recessive X-linked coagulation disorder.
Factor VIII participates in blood coagulation; it is a cofactor for factor IX
a which, in the presence of Ca+2 and phospholipid
s 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.
Patients with high levels of Factor VIII are at increased risk for deep venous thrombosis and pulmonary embolism
.
(Xq28). The gene for factor VIII presents an interesting primary structure, as another gene is embedded in one of its introns.
procofactor
. It has been found to be synthesized and released into the bloodstream by the vascular, glomerular, and tubular endothelium
, and the sinusoidal cells of the liver
, though there is still considerable ambiguity as to what the primary site of release in humans is. In the circulating blood, it is mainly bound to von Willebrand factor
to form a stable complex. Upon activation by thrombin
, (Factor IIa), it dissociates from the complex to interact with Factor IX
a in the coagulation cascade. It is a cofactor to Factor IX
a in the activation of Factor X
, which, in turn, with its cofactor Factor V
a, activates more thrombin. Thrombin cleaves fibrin
ogen into fibrin
which polymer
izes and crosslinks (using Factor XIII
) into a blood clot.
No longer protected by vWF, activated FVIII is proteolytically
inactivated in the process (most prominently by activated Protein C
and Factor IX
a) and quickly cleared from the blood stream.
Factor VIII is not affected by liver disease. In fact, levels usually are elevated in such instances.
), or alternatively recombinant
FVIII can be given to hemophiliacs to restore 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 hepatitis B and C
and 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.
sparked controversy by continuing to sell contaminated factor VIII
after new heat-treated versions were available.
Batches of this product that were tainted with HIV - to the knowledge of both Bayer and the US government and the FDA - were pulled from US markets and sold to Asian, Latin American, and some European countries, protecting the companies' monetary profits but infecting thousands with HIV.
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.
Thrombus
A thrombus , or blood clot, is the final product of the blood coagulation step in hemostasis. It is achieved via the aggregation of platelets that form a platelet plug, and the activation of the humoral coagulation system...
ting factor also known as anti-hemophilic factor (AHF). In humans, Factor VIII is encoded by the F8 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. Defects in this gene results in hemophilia A, a well known recessive X-linked coagulation disorder.
Factor VIII participates in blood coagulation; it is a cofactor for factor IX
Factor IX
Factor IX is one of the serine proteases of the coagulation system; it belongs to peptidase family S1. Deficiency of this protein causes hemophilia B. It was discovered in 1952 after a young boy named Stephen Christmas was found to be lacking this exact factor, leading to...
a which, in the presence of Ca+2 and phospholipid
Phospholipid
Phospholipids are a class of lipids that are a major component of all cell membranes as they can form lipid bilayers. Most phospholipids contain a diglyceride, a phosphate group, and a simple organic molecule such as choline; one exception to this rule is sphingomyelin, which is derived from...
s forms a complex that converts factor X
Factor X
Factor X, also known by the eponym Stuart-Prower factor or as prothrombinase, is an enzyme of the coagulation cascade. It is a serine endopeptidase .-Physiology:...
to the activated form Xa. The Factor VIII gene produces two alternatively spliced transcripts. Transcript variant 1 encodes a large glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
, isoform a, which circulates in plasma and associates with von Willebrand factor
Von Willebrand factor
von Willebrand factor is a blood glycoprotein involved in hemostasis. It is deficient or defective in von Willebrand disease and is involved in a large number of other diseases, including thrombotic thrombocytopenic purpura, Heyde's syndrome, and possibly hemolytic-uremic syndrome...
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.
Patients with high levels of Factor VIII are at increased risk for deep venous thrombosis and pulmonary embolism
Pulmonary embolism
Pulmonary embolism is a blockage of the main artery of the lung or one of its branches by a substance that has travelled from elsewhere in the body through the bloodstream . Usually this is due to embolism of a thrombus from the deep veins in the legs, a process termed venous thromboembolism...
.
Genetics
The gene for Factor VIII is located on the X chromosomeX chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
(Xq28). The gene for factor VIII presents an interesting primary structure, as another gene is embedded in one of its introns.
Physiology
FVIII is a glycoproteinGlycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
procofactor
Cofactor (biochemistry)
A cofactor is a non-protein chemical compound that is bound to a protein and is required for the protein's biological activity. These proteins are commonly enzymes, and cofactors can be considered "helper molecules" that assist in biochemical transformations....
. It has been found to be synthesized and released into the bloodstream by the vascular, glomerular, and tubular endothelium
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...
, and the sinusoidal cells of the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
, though there is still considerable ambiguity as to what the primary site of release in humans is. In the circulating blood, it is mainly bound to von Willebrand factor
Von Willebrand factor
von Willebrand factor is a blood glycoprotein involved in hemostasis. It is deficient or defective in von Willebrand disease and is involved in a large number of other diseases, including thrombotic thrombocytopenic purpura, Heyde's syndrome, and possibly hemolytic-uremic syndrome...
to form a stable complex. Upon activation by thrombin
Thrombin
Thrombin is a "trypsin-like" serine protease protein that in humans is encoded by the F2 gene. Prothrombin is proteolytically cleaved to form thrombin in the first step of the coagulation cascade, which ultimately results in the stemming of blood loss...
, (Factor IIa), it dissociates from the complex to interact with Factor IX
Factor IX
Factor IX is one of the serine proteases of the coagulation system; it belongs to peptidase family S1. Deficiency of this protein causes hemophilia B. It was discovered in 1952 after a young boy named Stephen Christmas was found to be lacking this exact factor, leading to...
a in the coagulation cascade. It is a cofactor to Factor IX
Factor IX
Factor IX is one of the serine proteases of the coagulation system; it belongs to peptidase family S1. Deficiency of this protein causes hemophilia B. It was discovered in 1952 after a young boy named Stephen Christmas was found to be lacking this exact factor, leading to...
a in the activation of Factor X
Factor X
Factor X, also known by the eponym Stuart-Prower factor or as prothrombinase, is an enzyme of the coagulation cascade. It is a serine endopeptidase .-Physiology:...
, which, in turn, with its cofactor Factor V
Factor V
Factor V is a protein of the coagulation system, rarely referred to as proaccelerin or labile factor. In contrast to most other coagulation factors, it is not enzymatically active but functions as a cofactor...
a, activates more thrombin. Thrombin cleaves fibrin
Fibrin
Fibrin is a fibrous, non-globular protein involved in the clotting of blood. It is a fibrillar protein that is polymerised to form a "mesh" that forms a hemostatic plug or clot over a wound site....
ogen into fibrin
Fibrin
Fibrin is a fibrous, non-globular protein involved in the clotting of blood. It is a fibrillar protein that is polymerised to form a "mesh" that forms a hemostatic plug or clot over a wound site....
which polymer
Polymer
A polymer is a large molecule composed of repeating structural units. These subunits are typically connected by covalent chemical bonds...
izes and crosslinks (using Factor XIII
Factor XIII
Factor XIII or fibrin stabilizing factor is an enzyme of the blood coagulation system that crosslinks fibrin.- Function :Factor XIII is a transglutaminase that circulates in the plasma as a heterotetramer of two catalytic A subunits and two carrier B subunits...
) into a blood clot.
No longer protected by vWF, activated FVIII is proteolytically
Proteolysis
Proteolysis is the directed degradation of proteins by cellular enzymes called proteases or by intramolecular digestion.-Purposes:Proteolysis is used by the cell for several purposes...
inactivated in the process (most prominently by activated Protein C
Protein C
Protein C, also known as autoprothrombin IIA and blood coagulation factor XIV, is a zymogenic protein, the activated form of which plays an important role in regulating blood clotting, inflammation, cell death and maintaining the permeability of blood vessel walls in humans and other animals...
and Factor IX
Factor IX
Factor IX is one of the serine proteases of the coagulation system; it belongs to peptidase family S1. Deficiency of this protein causes hemophilia B. It was discovered in 1952 after a young boy named Stephen Christmas was found to be lacking this exact factor, leading to...
a) 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 (AafactAafact
Aafact is a monoclonal purified factor VIII concentrate. It consists of a protein fraction prepared from fresh-frozen human plasma. It is used in cases of acute haemorrhage, pre-operative and post-operative treatment and prophylaxis in haemophilia A patients and in patients with an acquired...
), or alternatively recombinant
Recombinant DNA
Recombinant DNA molecules are DNA sequences that result from the use of laboratory methods to bring together genetic material from multiple sources, creating sequences that would not otherwise be found in biological organisms...
FVIII can be given to hemophiliacs to restore hemostasis
Hemostasis
Hemostasis or haemostasis is a process which causes bleeding to stop, meaning to keep blood within a damaged blood vessel . Most of the time this includes blood changing from a liquid to a solid state. Intact blood vessels are central to moderating blood's tendency to clot...
.
The transfer of a plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
byproduct into the blood stream of a patient with hemophilia often led to the transmission of diseases such as hepatitis B and C
Hepatitis C
Hepatitis C is an infectious disease primarily affecting the liver, caused by the hepatitis C virus . The infection is often asymptomatic, but chronic infection can lead to scarring of the liver and ultimately to cirrhosis, which is generally apparent after many years...
and HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
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 BayerBayer
Bayer AG is a chemical and pharmaceutical company founded in Barmen , Germany in 1863. It is headquartered in Leverkusen, North Rhine-Westphalia, Germany and well known for its original brand of aspirin.-History:...
sparked controversy by continuing to sell contaminated factor VIII
Contaminated haemophilia blood products
Contaminated hemophilia blood products were a serious public health problem in the late 1970s through 1985. These products caused large numbers of haemophiliacs to become infected with HIV and hepatitis C...
after new heat-treated versions were available.
Batches of this product that were tainted with HIV - to the knowledge of both Bayer and the US government and the FDA - were pulled from US markets and sold to Asian, Latin American, and some European countries, protecting the companies' monetary profits but infecting thousands with HIV.
In the early 1990s, pharmaceutical companies began to produce recombinant
Recombinant DNA
Recombinant DNA molecules are DNA sequences that result from the use of laboratory methods to bring together genetic material from multiple sources, creating sequences that would not otherwise be found in biological organisms...
synthesized factor products, which now prevent nearly all forms of disease transmission during replacement therapy.
See also
- Ryan WhiteRyan WhiteRyan Wayne White was an American teenager from Kokomo, Indiana, who became a national poster child for HIV/AIDS in the United States, after being expelled from middle school because of his infection. A hemophiliac, he became infected with HIV from a contaminated blood treatment and, when diagnosed...
- Contaminated haemophilia blood products