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Factor V (pronounced factor five) is a
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, respo ...
of the
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 ...
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. Deficiency leads to predisposition for
hemorrhage Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, vag ...
, while some mutations (most notably
factor V Leiden Factor V Leiden (rs6025 or ''F5'' p.R506Q) is a variant (mutated form) of human factor V (one of several substances that helps blood clot), which causes an increase in blood clotting (hypercoagulability). Due to this mutation, protein C, an anticoa ...
) predispose for
thrombosis Thrombosis (from Ancient Greek "clotting") is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (thro ...
.


Genetics

The
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 ba ...
for factor V is located on the first chromosome (1q24). It is genomically related to the family of
multicopper oxidase In molecular biology, multicopper oxidases are enzymes which oxidise their substrate by accepting electrons at a mononuclear copper centre and transferring them to a trinuclear copper centre; dioxygen binds to the trinuclear centre and, follo ...
s, and is homologous to coagulation
factor VIII Factor VIII (FVIII) is an essential blood-clotting protein, also known as anti-hemophilic factor (AHF). In humans, factor VIII is encoded by the ''F8'' gene. Defects in this gene result in hemophilia A, a recessive X-linked coagulation disorder. ...
. The gene spans 70 kb, consists of 25 exons, and the resulting protein has a relative molecular mass of approximately 330kDa.


Structure

Factor V protein consists of six domains: A1-A2-B-A3-C1-C2. The A domains are homologous to the A domains of the copper-binding protein
ceruloplasmin Ceruloplasmin (or caeruloplasmin) is a ferroxidase enzyme that in humans is encoded by the ''CP'' gene. Ceruloplasmin is the major copper-carrying protein in the blood, and in addition plays a role in iron metabolism. It was first described in 194 ...
, and form a triangular as in that protein. A copper ion is bound in the A1-A3 interface, and A3 interacts with the plasma. The C domains belong to the
phospholipid Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...
-binding
discoidin domain Discoidin domain (also known as F5/8 type C domain, or C2-like domain) is major protein domain of many blood coagulation factors. Blood coagulation factors V and VIII contain a C-terminal, twice repeated, domain of about 150 amino acids, whic ...
family (unrelated to
C2 domain A C2 domain is a protein structural domain involved in targeting proteins to cell membranes. The typical version (PKC-C2) has a beta-sandwich composed of 8 beta sheet, β-strands that co-ordinates two or three calcium ions, which bind in a cavity ...
), and the C2 domain mediates membrane binding. The B domain
C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
acts as a cofactor for the
anticoagulant Anticoagulants, commonly known as blood thinners, are chemical substances that prevent or reduce coagulation of blood, prolonging the clotting time. Some of them occur naturally in blood-eating animals such as leeches and mosquitoes, where the ...
protein C Protein C, also known as autoprothrombin IIA and blood coagulation factor XIX, is a zymogen, that is, an inactive enzyme. The activated form plays an important role in regulating anticoagulation, inflammation, and apoptosis, cell death and ...
activation by
protein S Protein S (also known as PROS) is a vitamin K-dependent plasma glycoprotein synthesized in the liver. In the circulation, Protein S exists in two forms: a free form and a complex form bound to complement protein C4b-binding protein (C4BP). In huma ...
. Activation of factor V to factor Va is done by cleavage and release of the B domain, after which the protein no longer assists in activating protein C. 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 Va.


Physiology

Factor V synthesis occurs in the liver, principally. The molecule circulates in plasma as a single-chain molecule with a plasma half-life of 12–36 hours. Factor V is able to bind to activated
platelet Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...
s and is activated by
thrombin Thrombin (, ''fibrinogenase'', ''thrombase'', ''thrombofort'', ''topical'', ''thrombin-C'', ''tropostasin'', ''activated blood-coagulation factor II'', ''blood-coagulation factor IIa'', ''factor IIa'', ''E thrombin'', ''beta-thrombin'', ''gamma- ...
. On activation, factor V is spliced in two chains (heavy and light chain with molecular masses of 110000 and 73000, respectively) which are noncovalently bound to each other by
calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to ...
. The thereby activated factor V (now called FVa) is a cofactor of the
prothrombinase The prothrombinase complex consists of the serine protease, Factor Xa, and the protein cofactor, Factor Va. The complex assembles on negatively charged phospholipid membranes in the presence of calcium ions. The prothrombinase complex catalyzes the ...
complex: The activated
factor X Factor X, also known by the eponym Stuart–Prower factor, is an enzyme () of the coagulation cascade. It is a serine endopeptidase (protease group S1, PA clan). Factor X is synthesized in the liver and requires vitamin K for its synthesis. Fac ...
(FXa) enzyme requires calcium and activated factor V (FVa) to convert prothrombin to
thrombin Thrombin (, ''fibrinogenase'', ''thrombase'', ''thrombofort'', ''topical'', ''thrombin-C'', ''tropostasin'', ''activated blood-coagulation factor II'', ''blood-coagulation factor IIa'', ''factor IIa'', ''E thrombin'', ''beta-thrombin'', ''gamma- ...
on the cell surface membrane. Factor Va is degraded by
activated protein C Protein C, also known as autoprothrombin IIA and blood coagulation factor XIX, is a zymogen, that is, an inactive enzyme. The activated form plays an important role in regulating anticoagulation, inflammation, and cell death and maintaining ...
, one of the principal physiological inhibitors of coagulation. In the presence of
thrombomodulin Thrombomodulin (TM), CD141 or BDCA-3 is an integral membrane protein expressed on the surface of endothelial cells and serves as a cofactor for thrombin. It reduces blood coagulation by converting thrombin to an anticoagulant enzyme from a procoa ...
, thrombin acts to decrease clotting by activating protein C; therefore, the concentration and action of protein C are important determinants in the negative feedback loop through which thrombin limits its own activation.


Role in disease

Various hereditary disorders of factor V are known. Deficiency is associated with a rare mild form of
hemophilia Haemophilia, or hemophilia (), is a mostly inherited genetic disorder that impairs the body's ability to make blood clots, a process needed to stop bleeding. This results in people bleeding for a longer time after an injury, easy bruising, ...
(termed parahemophilia or Owren parahemophilia), the incidence of which is about 1:1,000,000. It inherits in an
autosomal 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 and t ...
fashion. There exists a bleeding tendency associated with the genetic up‐regulation of FV‐short, a minor splicing isoform of FV. This abnormal bleeding tendency occurs in east Texas bleeding disorder, Amsterdam bleeding disorder, and a third and more extreme example described in 2021 by Karen L. Zimowski ''et al.'' Other
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
s of factor V are associated with
venous thrombosis Venous thrombosis is blockage of a vein caused by a thrombus (blood clot). A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off (embolizes) and flows to the lungs to ...
. They are the most common hereditary causes for
thrombophilia Thrombophilia (sometimes called hypercoagulability or a prothrombotic state) is an abnormality of blood coagulation that increases the risk of thrombosis (blood clots in blood vessels). Such abnormalities can be identified in 50% of people who ...
(a tendency to form
blood clot A thrombus (plural thrombi), colloquially called a blood clot, is the final product of the blood coagulation step in hemostasis. There are two components to a thrombus: aggregated platelets and red blood cells that form a plug, and a mesh of c ...
s). The most common one of these,
factor V Leiden Factor V Leiden (rs6025 or ''F5'' p.R506Q) is a variant (mutated form) of human factor V (one of several substances that helps blood clot), which causes an increase in blood clotting (hypercoagulability). Due to this mutation, protein C, an anticoa ...
, is due to the replacement of an
arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the am ...
residue with
glutamine Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral, ...
at amino acid position 506 (R506Q). All prothrombotic factor V mutations (factor V Leiden, factor V Cambridge, factor V Hong Kong) make it resistant to cleavage by activated protein C ("APC resistance"). It therefore remains active and increases the rate of thrombin generation.


History

Until the discovery of factor V, coagulation was regarded as a product of four factors:
calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to ...
(IV) and thrombokinase (III) together acting on
prothrombin Thrombin (, ''fibrinogenase'', ''thrombase'', ''thrombofort'', ''topical'', ''thrombin-C'', ''tropostasin'', ''activated blood-coagulation factor II'', ''blood-coagulation factor IIa'', ''factor IIa'', ''E thrombin'', ''beta-thrombin'', ''gamma- ...
(II) to produce
fibrinogen Fibrinogen (factor I) is a glycoprotein complex, produced in the liver, that circulates in the blood of all vertebrates. During tissue and vascular injury, it is converted enzymatically by thrombin to fibrin and then to a fibrin-based blood clo ...
(I); this model had been outlined by
Paul Morawitz Paul Oskar Morawitz (April 3, 1879 in St. Petersburg – July 1, 1936) was a German internist and physiologist whose most important work was in studying the coagulation of blood. After completing his medical studies at Leipzig (in 1901) he comp ...
in 1905. The suggestion that an additional factor might exist was made by (1905–1990), a
Norwegian Norwegian, Norwayan, or Norsk may refer to: *Something of, from, or related to Norway, a country in northwestern Europe *Norwegians, both a nation and an ethnic group native to Norway *Demographics of Norway *The Norwegian language, including the ...
physician, during his investigations into the bleeding tendency of a lady called Mary (1914–2002). She had suffered from
nosebleeds A nosebleed, also known as epistaxis, is bleeding from the nose. Blood can flow down into the stomach, and cause nausea and vomiting. In more severe cases, blood may come out of both nostrils. Rarely, bleeding may be so significant that low bloo ...
and
menorrhagia Heavy menstrual bleeding (HMB), previously known as menorrhagia or hypermenorrhea, is a menstrual period with excessively heavy flow. It is a type of abnormal uterine bleeding Abnormal uterine bleeding (AUB), also known as (AVB) or as atypical ...
(excessive menstrual blood loss) for most her life, and was found to have a prolonged
prothrombin time The prothrombin time (PT) – along with its derived measures of prothrombin ratio (PR) and international normalized ratio (INR) – is an assay for evaluating the ''extrinsic'' pathway and common pathway of coagulation. This blood test is als ...
, suggesting either
vitamin K Vitamin K refers to structurally similar, fat-soluble vitamers found in foods and marketed as dietary supplements. The human body requires vitamin K for post-synthesis modification of certain proteins that are required for blood coagulation ...
deficiency or
chronic liver disease Chronic liver disease in the clinical context is a disease process of the liver that involves a process of progressive destruction and regeneration of the liver parenchyma leading to fibrosis and cirrhosis. "Chronic liver disease" refers to disease ...
leading to prothrombin deficiency. However, neither were the case, and Owren demonstrated this by correcting the abnormality with plasma from which prothrombin had been removed. Using Mary's serum as index, he found that the "missing" factor, which he labeled V (I–IV having been used in Morawitz' model), had particular characteristics. Most investigations were performed during the
Second World War World War II or the Second World War, often abbreviated as WWII or WW2, was a world war that lasted from 1939 to 1945. It involved the vast majority of the world's countries—including all of the great powers—forming two opposin ...
, and while Owren published his results in Norway in 1944, he could not publish them internationally until the war was over. They appeared finally in ''
The Lancet ''The Lancet'' is a weekly peer-reviewed general medical journal and one of the oldest of its kind. It is also the world's highest-impact academic journal. It was founded in England in 1823. The journal publishes original research articles, ...
'' in 1947. The possibility of an extra coagulation factor was initially resisted on methodological grounds by Drs Armand Quick and Walter Seegers, both world authorities in coagulation. Confirmatory studies from other groups led to their final approval several years later. Owren initially felt that factor V (labile factor or proaccelerin) activated another factor, which he named VI. VI was the factor that accelerated the conversion from prothrombin to thrombin. It was later discovered that factor V was "converted" (activated) by thrombin itself, and later still that factor VI was simply the activated form of factor V. The complete amino acid sequence of the protein was published in 1987. In 1994
factor V Leiden Factor V Leiden (rs6025 or ''F5'' p.R506Q) is a variant (mutated form) of human factor V (one of several substances that helps blood clot), which causes an increase in blood clotting (hypercoagulability). Due to this mutation, protein C, an anticoa ...
, resistant to inactivation by
protein C Protein C, also known as autoprothrombin IIA and blood coagulation factor XIX, is a zymogen, that is, an inactive enzyme. The activated form plays an important role in regulating anticoagulation, inflammation, and apoptosis, cell death and ...
, was described; this abnormality is the most common genetic cause for
thrombosis Thrombosis (from Ancient Greek "clotting") is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (thro ...
.


Interactions

Factor V has been shown to
interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with
Protein S Protein S (also known as PROS) is a vitamin K-dependent plasma glycoprotein synthesized in the liver. In the circulation, Protein S exists in two forms: a free form and a complex form bound to complement protein C4b-binding protein (C4BP). In huma ...
.


References


Further reading

* * * * * * * *


External links


The Coagulation Factor V Protein
* {{Coagulation Coagulation system