Factor VIII, also known as anti-haemophilic factor (AHF), is an essential blood-clotting protein consisting of 2332 residues isolated from Homo sapiens, whose gene is located on the X chromosome.
Factor VIII is produced in the liver (in liver sinusoidal cells) and outside (in endothelial cells) and acts in the intrinsic pathway of blood coagulation. It is actually a plasma glycoprotein whose deficiency or absence causes a bleeding disorder: haemophilia A.
Factor VIII is much studied in order to find cure to haemophilia A, also written as HEMA.
History
1937: first use of the factor VIII (known at this period as “Antihemophilic Globulin”) to cure the blood coagulation disorder of haemophilia patients thanks to the discovery of F.H.L Patek and A.J Taylor. [10]
1964: Usual utilisation of concentrated factor VIII to treat haemophilia.
1984: Factor VIII was first characterized by scientists at Genentech
Function
Factor VIII plays a central role in blood coagulation.
The Factor VIII is an inactive form.
Factor VIII circulates in the bloodstream in this inactive form, bound to another molecule called von Willebrand factor, until an injury that damages blood vessels occurs.
Indeed, in plasma, factor VIII exists in two forms: free or in the factor VIII / von Willebrand factor complex. Complex form is the main form and exists at a level of 0.1 µg/ml because factor VIII is stabilized by von Willebrand factor, while in its free state, it is rapidly cleaved by protease serines. [8]
In response to injury, coagulation factor VIII is activated and separates from von Willebrand factor. The active form is called Factor VIIIa and is obtained by a proteolytic cleavage of the B-domain of Factor VIII by thrombin.
Factor VIIIa is a non-covalent dimer in a metal-linked (probably calcium) complex.
Factor VIIIa is the catalyst for the activation reaction of factor X (to factor Xa) by activated factor IXa in the presence of calcium ion and phospholipids.
The factor X activation reaction by factor IXa is accelerated approximately 200,000 times when factor VIII interacts with factor IXa.
Then, no longer protected by von Willebrand factor, factor VIIIa is proteolytically inactivated and quickly cleared from the blood stream, whereas, factor Xa becomes able (with the help of other factors) to stop the bleeding by forming a blood clot.
Structure
Primary Structure
In humans, factor VIII is encoded by the F8 gene. [2] This gene maps on the most distal band of the long arm of the X-chromosome (region Xq28). It is 186kb in size (0.1% of the whole size of the chromosome) and contains 26 exons. [4]
Secondary Structure
Factor VIII protein is composed of six globular domains: A1-A2-B-A3-C1-C2 and contains one Ca2+ and two Cu2+ ions. It has a molecular weight of 330kDa. [1]
The three A domains are homologous to the A domains of the copper-binding protein ceruloplasmin. Together, they form a triangular heterotrimer where the A1 and A3 domains serve as the base and interact with the C2 and C1 domains, respectively. [9]
The C domains belong to the phospholipid-binding discoidin domain family. They are adjacent at the base of the triangular heterotrimer. Moreover, C1 and C2 domains are structurally homologous and reveal membrane binding features. Indeed, each C domain projects three β-hairpin loops containing hydrophobic and basic residues toward the same plane. These loops likely contribute to the interaction of factor VIII with the phospholipid bilayer. [9]
Factor VIIIa is obtained by cleavage and release of the B domain. Although active factor VIII can be formed from cleavage at Arg372 and Arg1689, fully active factor VIII is generated by three cleavage events involving Arg372, Arg740, and Arg1689. [9]
The two chain that result are a heavy and a light chains.
The heavy chain has a various size (90/120kDa) and is composed of 754 amino acids. It consists of the A1-A2 domains. The A1 and A2 domains each consist of two connected β barrels.
The light chain has a molecular weight of 80kDa and is composed of 684 amino acids. It contains two domains: a unique A domain of 371 amino acids and a duplicated C domain of 153 amino acids and 160 amino acids. [3] These domains are arranged as follows A3-C1-C2. [8]
It is composed of 42 % irregular structure, 36 % β-strands, and 22 % α-helix. [3]
The C1 and C2 domains are defined by a distorted β barrel, while A3, as A1 and A2, is composed of two connected β barrels.
This chain also contains of the major binding site of von Willebrand Factor at its N-terminus.
Both chains are no covalently associated through to a calcium ion to form the active heterodimers. [3] This complex is the pro-coagulant factor VIIIa.
Such an association is indispensable for the functioning of the factor VIII.
Ligands
Alpha-D-mannose, calcium ion (Ca2+), copper ion (Cu2+) and N-acetl-D-glucosamine are the four ligands the factor VIII is able to bind.
In factor VIII there are two copper ions and their binding sites are internally within the A1 and the A3 domain, but also a single calcium ion, whose binding site was located in the A1 domain.
Disease
Haemophilia is a genetic disorder characterized by a permanent tendency to haemorrhage because of a lack of blood coagulation.
There are different types of haemophilia: A or B, caused by a deficiency of two different factors.
Haemophilia A, also written as HEMA, is four times as common as haemophilia B. [7]
It is caused by a deficiency of factor VIII.
This deficiency in factor VIII clotting activity results in prolonged oozing after injuries, tooth extractions, or surgery, and delayed or recurrent bleeding prior to complete wound healing. [6]
Although haemophilia A is usually an inherited disease and therefore runs in families, about one-third of people with the disease are caused by a spontaneous mutation. [5]
Inheritance:
Haemophilia A is inherited in an X-linked recessive manner:
Females inherit two X chromosomes, one from their mother and one from their father (XX). Males inherit an X chromosome from their mother and a Y chromosome from their father (XY). This means that if a son inherits an X chromosome carrying haemophilia from his mother, he will have haemophilia. By contrast, daughters have two X chromosomes, even if they inherit the haemophilia gene from their mother, they inherit a healthy X chromosome from their father and as a results they are only carrier but not affected.
Thus, because of recessivity, men only are affected by this disease and women are carrier that may pass the gene on to their children (50% chance of transmitting it in each pregnancy). [7]
The risk for boys to carry the disease therefore depends on the carrier status of the mother because affected males transmit the pathogenic variant to all of their daughters and none of their sons. [6]
Haemophilia A can be mild, moderate, or severe, depending on the level of Factor VIII clotting activity:
• Severe haemophilia A: factor VIII’s proportion in the blood ≤ 1%
• Moderate haemophilia A: 1% ≤ factor VIII’s proportion in the blood ≤ 5%
• Mild haemophilia A: 6% ≤ factor VIII’s proportion in the blood ≤ 40% [6]
The major treatment of the bleeding disorder associated with haemophilia A is the infusion of factor VIII, which leads to the correction of hemostasis.
Relevance
Haemophilia occurs in approximately 1 in 5,000 live births but is severe in approximately 60% of cases. [7]
The main medication to treat haemophilia A is concentrated factor VIII product, called clotting factor or simply factor. Getting this simply factor is therefore a major concern for haemophilia-affected people.
Nowadays, recombinant coagulation factor VIII products, which are developed in a lab through the use of DNA technology, may preclude the use of human-derived pools of donor-sourced plasm. [7]
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