View source for Factor V

{{Short description|Mammalian protein found in humans}}
{{About|the coagulation protein|the software company|Factor 5|Factor V (NAD+)|chocolate agar}}
{{Infobox_gene}}

'''Coagulation factor V''' ('''Factor V'''), also less commonly known as '''proaccelerin''' or '''labile factor''', is a [[protein]] involved in [[coagulation]], encoded, in humans, by ''F5'' [[gene]].<ref name="Medline2024">{{cite web |title=F5 gene: MedlinePlus Genetics |url=https://medlineplus.gov/genetics/gene/f5/ |website=medlineplus.gov |access-date=9 May 2024 |language=en}}</ref> In contrast to most other coagulation factors, it is not enzymatically active but functions as a [[cofactor (biochemistry)|cofactor]].<ref name="Medline2024" /> Factor V deficiency leads to predisposition for [[hemorrhage]], while some mutations (most notably [[factor V Leiden]]) predispose for [[thrombosis]].

==Genetics==
The [[gene]] for factor V is located on the [[first chromosome]] (1q24). It is genomically related to the family of [[multicopper oxidase]]s, and is homologous to [[coagulation factor VIII]]. 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 [[homology (biology)|homologous]] to the A domains of the copper-binding protein [[ceruloplasmin]], and form a triangular as in that protein. A copper ion is bound in the A1-A3 interface, and A3 interacts with the plasma.<ref>{{cite journal | vauthors = Villoutreix BO, [[Björn Dahlbäck|Dahlbäck B]] | title = Structural investigation of the A domains of human blood coagulation factor V by molecular modeling | journal = Protein Science | volume = 7 | issue = 6 | pages = 1317–25 | date = June 1998 | pmid = 9655335 | doi = 10.1002/pro.5560070607 | pmc=2144041}}</ref>

The C domains belong to the  [[phospholipid]]-binding [[discoidin domain]] family (unrelated to [[C2 domain]]), and the C2 domain mediates membrane binding. The B domain [[C-terminus]] acts as a [[cofactor (biochemistry)|cofactor]] for the [[anticoagulant]] [[protein C]] activation by [[protein S]].<ref name = "Thorelli1998">{{cite journal | vauthors = Thorelli E, Kaufman RJ, Dahlbäck B | title = The C-terminal region of the factor V B-domain is crucial for the anticoagulant activity of factor V | journal = The Journal of Biological Chemistry | volume = 273 | issue = 26 | pages = 16140–45 | date = June 1998 | pmid = 9632668 | doi=10.1074/jbc.273.26.16140| doi-access = free }}</ref>
<ref>{{cite journal | vauthors = Macedo-Ribeiro S, Bode W, Huber R, Quinn-Allen MA, Kim SW, Ortel TL, Bourenkov GP, Bartunik HD, Stubbs MT, Kane WH, Fuentes-Prior P | title = Crystal structures of the membrane-binding C2 domain of human coagulation factor V | journal = Nature | volume = 402 | issue = 6760 | pages = 434–39 | date = November 1999 | pmid = 10586886 | doi = 10.1038/46594 | bibcode = 1999Natur.402..434M | s2cid = 4393638 }}</ref>

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.<ref name="Thorelli1998" />

==Physiology==
Factor V is produced by [[megakaryocytes]], which produce platelets and platelet-derived factor V, and hepatocytes, which produce plasma-derived factor V.<ref>{{cite book | vauthors = Lam W, Moosavi L | chapter = Physiology, Factor V |date=18 July 2022 | title = StatPearls |publisher=StatPearls Publishing | pmid = 31334957 | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK544237/ |access-date=7 February 2022 }}</ref> The molecule circulates in plasma as a single-chain molecule with a plasma half-life of 12–36 hours.<ref name="HuangKoerper2008">{{cite journal | vauthors = Huang JN, Koerper MA | title = Factor V deficiency: a concise review | journal = Haemophilia | volume = 14 | issue = 6 | pages = 1164–69 | date = November 2008 | pmid = 19141156 | doi = 10.1111/j.1365-2516.2008.01785.x | doi-access = free }}</ref>

Factor V is able to bind to activated [[platelet]]s and is activated by [[thrombin]]. 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 in biology|calcium]]. The thereby activated factor V (now called FVa) is a cofactor of the [[prothrombinase]] complex: The activated [[factor X]] (FXa) enzyme requires calcium and activated factor V (FVa) to convert prothrombin to [[thrombin]] on the cell surface membrane.

Factor Va is degraded by [[protein C|activated protein C]], one of the principal physiological inhibitors of coagulation. In the presence of [[thrombomodulin]], 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]] (termed parahemophilia or Owren parahemophilia), the incidence of which is about 1:1,000,000. It inherits in an [[autosomal recessive]] 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.''<ref>{{cite journal | vauthors = Castoldi E | title = F5-Atlanta: Factor V-short strikes again | journal = Journal of Thrombosis and Haemostasis | volume = 19 | issue = 7 | pages = 1638–1640 | date = July 2021 | pmid = 34176223 | pmc = 8362210 | doi = 10.1111/jth.15351 }}</ref>

Other [[mutation]]s of factor V are associated with [[venous thrombosis]]. They are the most common hereditary causes for [[thrombophilia]] (a tendency to form [[blood clot]]s). The most common one of these, [[factor V Leiden]], is due to the replacement of an [[arginine]] residue with [[glutamine]] 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]] (IV) and thrombokinase (III) together acting on [[prothrombin]] (II) to produce [[fibrinogen]] (I); this model had been outlined by [[Paul Morawitz]] in 1905.<ref name=Stormorken>{{cite journal | vauthors = Stormorken H | title = The discovery of factor V: a tricky clotting factor | journal = Journal of Thrombosis and Haemostasis | volume = 1 | issue = 2 | pages = 206–13 | date = February 2003 | pmid = 12871488 | doi = 10.1046/j.1538-7836.2003.00043.x | authorlink = Helge Stormorken | doi-access = free }}</ref>

The suggestion that an additional factor might exist was made by {{ill|Paul Owren|no}} (1905–1990), a [[Norway|Norwegian]] physician, during his investigations into the bleeding tendency of a lady called Mary (1914–2002). She had suffered from [[epistaxis|nosebleeds]] and [[menorrhagia]] (excessive menstrual blood loss) for most her life, and was found to have a prolonged [[prothrombin time]], suggesting either [[vitamin K]] deficiency or [[chronic liver 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 [[World War II|Second World War]], 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]]'' in 1947.<ref name=Stormorken/><ref>{{cite journal | vauthors = Owren PA | title = Parahaemophilia; haemorrhagic diathesis due to absence of a previously unknown clotting factor | journal = Lancet | volume = 1 | issue = 6449 | pages = 446–48 | date = April 1947 | pmid = 20293060 | doi = 10.1016/S0140-6736(47)91941-7 }}</ref>

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.<ref name=Stormorken/>

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.<ref name=Stormorken/>

The complete amino acid sequence of the protein was published in 1987.<ref>{{cite journal | vauthors = Jenny RJ, Pittman DD, Toole JJ, Kriz RW, Aldape RA, Hewick RM, Kaufman RJ, Mann KG | title = Complete cDNA and derived amino acid sequence of human factor V | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 84 | issue = 14 | pages = 4846–50 | date = July 1987 | pmid = 3110773 | pmc = 305202 | doi = 10.1073/pnas.84.14.4846 | bibcode = 1987PNAS...84.4846J | doi-access = free }}</ref> In 1994 [[factor V Leiden]], resistant to inactivation by [[protein C]], was described; this abnormality is the most common genetic cause for [[thrombosis]].<ref>{{cite journal | vauthors = Bertina RM, Koeleman BP, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA, Reitsma PH | title = Mutation in blood coagulation factor V associated with resistance to activated protein C | journal = Nature | volume = 369 | issue = 6475 | pages = 64–67 | date = May 1994 | pmid = 8164741 | doi = 10.1038/369064a0 | bibcode = 1994Natur.369...64B | s2cid = 4314040 }}</ref>

== Interactions ==

Factor V has been shown to [[Protein-protein interaction|interact]] with [[Protein S]].<ref name=pmid10593904>{{cite journal | vauthors = Heeb MJ, Kojima Y, Rosing J, Tans G, Griffin JH | title = C-terminal residues 621–635 of protein S are essential for binding to factor Va | journal = The Journal of Biological Chemistry | volume = 274 | issue = 51 | pages = 36187–92 | date = December 1999 | pmid = 10593904 | doi = 10.1074/jbc.274.51.36187 | doi-access = free }}</ref><ref name=pmid8428962>{{cite journal | vauthors = Heeb MJ, Mesters RM, Tans G, Rosing J, Griffin JH | title = Binding of protein S to factor Va associated with inhibition of prothrombinase that is independent of activated protein C | journal = The Journal of Biological Chemistry | volume = 268 | issue = 4 | pages = 2872–77 | date = February 1993 | doi = 10.1016/S0021-9258(18)53854-0 | pmid = 8428962 | doi-access = free }}</ref>

== References ==
{{Reflist|33em}}

== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Nicolaes GA, [[Björn Dahlbäck|Dahlbäck B]] | title = Factor V and thrombotic disease: description of a janus-faced protein | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 22 | issue = 4 | pages = 530–38 | date = April 2002 | pmid = 11950687 | doi = 10.1161/01.ATV.0000012665.51263.B7 | doi-access = free }}
* {{cite journal | vauthors = Segers K, Dahlbäck B, Nicolaes GA | title = Coagulation factor V and thrombophilia: background and mechanisms | journal = Thrombosis and Haemostasis | volume = 98 | issue = 3 | pages = 530–42 | date = September 2007 | pmid = 17849041 | doi = 10.1160/th07-02-0150 | s2cid = 29406966 }}
* {{cite journal | vauthors = Hooper WC, De Staercke C | title = The relationship between FV Leiden and pulmonary embolism | journal = Respiratory Research | volume = 3 | issue = 1 | pages = 8 | year = 2006 | pmid = 11806843 | pmc = 64819 | doi = 10.1186/rr180 | doi-access = free }}
* {{cite journal | vauthors = Schrijver I, Houissa-Kastally R, Jones CD, Garcia KC, Zehnder JL | title = Novel factor V C2-domain mutation (R2074H) in two families with factor V deficiency and bleeding | journal = Thrombosis and Haemostasis | volume = 87 | issue = 2 | pages = 294–99 | date = February 2002 | pmid = 11858490 | doi =  10.1055/s-0037-1612988| s2cid = 4818866 | url = http://pdfs.semanticscholar.org/e5db/02b52d800c71a430815119c6f8c832d34353.pdf | archive-url = https://web.archive.org/web/20190307192832/http://pdfs.semanticscholar.org/e5db/02b52d800c71a430815119c6f8c832d34353.pdf | url-status = dead | archive-date = 2019-03-07 }}
* {{cite journal | vauthors = Mann KG, Kalafatis M | title = Factor V: a combination of Dr Jekyll and Mr Hyde | journal = Blood | volume = 101 | issue = 1 | pages = 20–30 | date = January 2003 | pmid = 12393635 | doi = 10.1182/blood-2002-01-0290 | s2cid = 8885302 | doi-access = free }}
* {{cite journal | vauthors = Duga S, Asselta R, Tenchini ML | title = Coagulation factor V | journal = The International Journal of Biochemistry & Cell Biology | volume = 36 | issue = 8 | pages = 1393–99 | date = August 2004 | pmid = 15147718 | doi = 10.1016/j.biocel.2003.08.002 | s2cid = 27193482 }}
* {{cite journal | vauthors = Andreassi MG, Botto N, Maffei S | title = Factor V Leiden, prothrombin G20210A substitution and hormone therapy: indications for molecular screening | journal = Clinical Chemistry and Laboratory Medicine | volume = 44 | issue = 5 | pages = 514–21 | year = 2006 | pmid = 16681418 | doi = 10.1515/CCLM.2006.103 | s2cid = 34399027 }}
* {{cite journal | vauthors = Du X | title = Signaling and regulation of the platelet glycoprotein Ib-IX-V complex | journal = Current Opinion in Hematology | volume = 14 | issue = 3 | pages = 262–69 | date = May 2007 | pmid = 17414217 | doi = 10.1097/MOH.0b013e3280dce51a | s2cid = 39904506 }}
{{refend}}

== External links ==
* {{usurped|1=[https://archive.today/20130128114235/http://macromoleculeinsights.com/coagulationfactorv.php The Coagulation Factor V Protein]}}
* {{PDBe-KB2|P12259|Coagulation factor V}}

{{PDB Gallery|geneid=2153}}
{{Coagulation}}

[[Category:Coagulation system]]