View source for Factor VII

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{{Short description|Mammalian protein found in humans}}
{{Lead rewrite|date=April 2024|reason=More than half of the lead is about recent pharmaceuticals, not the natural protein.}}
{{Infobox gene}}

'''Coagulation factor VII''' ({{EC number|3.4.21.21}}, formerly known as '''proconvertin''') is a [[protein]] involved in [[coagulation]] and, in humans, is encoded by [[gene]] ''F7''.  It is an [[enzyme]] of the [[serine protease]] class. Once bound to [[tissue factor]] released from damaged tissues, it is converted to '''factor VIIa''' (or ''blood-coagulation factor VIIa'', ''activated blood coagulation factor VII''), which in turn activates [[factor IX]] and [[factor X]].

Using [[genetic recombination]] a [[recombinant factor VIIa]] (eptacog alfa) (trade names include NovoSeven) has been approved by the [[FDA]] for the control of bleeding in [[hemophilia]].<ref name="ERH">{{cite journal | vauthors = Biron-Andreani C, Schved JF | title = Eptacog beta: a novel recombinant human factor VIIa for the treatment of hemophilia A and B with inhibitors | journal = Expert Review of Hematology | volume = 12 | issue = 1 | pages = 21–28 | date = January 2019 | pmid = 30577721 | doi = 10.1080/17474086.2019.1560259 | s2cid = 58538425 }}</ref> It is sometimes used unlicensed in severe uncontrollable bleeding, although there have been safety concerns. A [[biosimilar]] form of recombinant activated factor VII (AryoSeven) is also available, but does not play any considerable role in the market.

In April 2020, the US FDA approved a new rFVIIa product, eptacog beta (SEVENFACT), the first [[bypassing agent]] (BPA) approved in more than 2 decades. As an rFVIIa product, eptacog beta works in a complex with tissue factor to activate factor X to Xa, thereby bypassing FVIII and FIX. The activation of Factor X to Xa initiates the coagulation cascade’s common pathway, leading to clot formation at the site of hemorrhage. Activated FVII binds to endothelial protein C receptor (EPCR), which enhances hemostasis.14 One study showed that eptacog beta binds to EPCR with 25% to 30% more affinity than eptacog alfa, displacing protein C from EPCR binding sites and downregulating activated protein C generation, contributing to its hemostatic effect.

== Physiology ==

The main role of factor VII (FVII) is to initiate the process of coagulation in conjunction with [[tissue factor]] (TF/factor III). Tissue factor is found on the outside of blood vessels - normally not exposed to the bloodstream. Upon vessel injury, tissue factor is exposed to the blood and circulating factor VII. Once bound to TF, FVII is activated to FVIIa by different proteases, among which are [[thrombin]] (factor IIa), factor Xa, IXa, XIIa, and the FVIIa-TF complex itself. The complex of factor VIIa with TF catalyzes the conversion of factor IX and factor X into the active proteases, factor IXa and factor Xa, respectively.<ref>{{cite journal | vauthors = Wajima T, Isbister GK, Duffull SB | title = A comprehensive model for the humoral coagulation network in humans | journal = Clinical Pharmacology and Therapeutics | volume = 86 | issue = 3 | pages = 290–298 | date = September 2009 | pmid = 19516255 | doi = 10.1038/clpt.2009.87 | s2cid = 205121835 }}</ref>

The action of the factor is impeded by [[tissue factor pathway inhibitor]] (TFPI), which is released almost immediately after initiation of coagulation. Factor VII, which was discovered around 1950, is [[vitamin K]]-dependent and produced in the [[liver]]. Use of [[warfarin]] or similar [[anticoagulant]]s decreases hepatic synthesis of FVII.{{Citation needed|date=October 2019}}

A coagulation [[enzyme cascade]] may begin with a few molecules of factor XII and culminate in the activation of millions of times more [[fibrin]] molecules.<ref>{{cite journal | vauthors = Zhang Q, Bhattacharya S, Andersen ME | title = Ultrasensitive response motifs: basic amplifiers in molecular signalling networks | journal = Open Biology | volume = 3 | issue = 4 | pages = 130031 | date = April 2013 | pmid = 23615029 | pmc = 3718334 | doi = 10.1098/rsob.130031 }}</ref>

== Structure ==
{{See also|Factor_IX#Domain_architecture}}
Factor VII shares a common domain architecture with factors [[factor IX|IX]] and [[factor X|X]].

== Genetics ==

The [[gene]] for factor VII is located on [[chromosome 13]] (13q34).

== Role in disease ==
{{main|Factor VII deficiency}}
[[Factor VII deficiency]] (congenital proconvertin deficiency) is rare and inherited recessively.  It presents as a hemophilia-like bleeding disorder.  It is treated with recombinant factor VIIa (NovoSeven or [[AryoSeven]]). Gene therapy approaches for treating FVII deficiency are very promising (<ref>{{cite journal | vauthors = Marcos-Contreras OA, Smith SM, Bellinger DA, Raymer RA, Merricks E, Faella A, Pavani G, Zhou S, Nichols TC, High KA, Margaritis P | display-authors = 6 | title = Sustained correction of FVII deficiency in dogs using AAV-mediated expression of zymogen FVII | journal = Blood | volume = 127 | issue = 5 | pages = 565–571 | date = February 2016 | pmid = 26702064 | pmc = 4742547 | doi = 10.1182/blood-2015-09-671420 }}</ref>)

== Medical uses ==

[[Recombinant factor VIIa]], marketed under the trade names ''AryoSeven'' and ''NovoSeven'', is used for people with [[hemophilia]] (with [[Factor VIII]] or [[Factor IX|IX]] deficiency) who have developed antibodies against replacement coagulation factor.

It has also been used in the setting of uncontrollable hemorrhage,<ref>{{cite journal | vauthors = Roberts HR, Monroe DM, White GC | title = The use of recombinant factor VIIa in the treatment of bleeding disorders | journal = Blood | volume = 104 | issue = 13 | pages = 3858–3864 | date = December 2004 | pmid = 15328151 | doi = 10.1182/blood-2004-06-2223 | doi-access = free }}</ref><ref>{{Cite web |url=https://www.mcdonaldworley.com/xarelto-lawsuit.php |title=Uncontrolled Bleeding and Injury Lawsuit Claims |access-date=2015-08-26 |archive-url=https://web.archive.org/web/20160616163010/https://www.mcdonaldworley.com/xarelto-lawsuit.php |archive-date=2016-06-16 |url-status=dead }}</ref> but its role in this setting is controversial with insufficient evidence to support its use outside of clinical trials.<ref name=Cochrane2012>{{cite journal | vauthors = Simpson E, Lin Y, Stanworth S, Birchall J, Doree C, Hyde C | title = Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia | journal = The Cochrane Database of Systematic Reviews | volume = 3 | issue = 3 | pages = CD005011 | date = March 2012 | pmid = 22419303 | doi = 10.1002/14651858.CD005011.pub4 | hdl-access = free | hdl = 10871/13808 }}</ref> The first report of its use in hemorrhage was in an [[Israel]]i soldier with uncontrollable bleeding in 1999.<ref>{{cite journal | vauthors = Kenet G, Walden R, Eldad A, Martinowitz U | title = Treatment of traumatic bleeding with recombinant factor VIIa | journal = Lancet | volume = 354 | issue = 9193 | pages = 1879 | date = November 1999 | pmid = 10584732 | doi = 10.1016/S0140-6736(99)05155-7 | s2cid = 23159895 }}</ref> Risks of its use include an increase in arterial thrombosis.<ref name=Cochrane2012/> However, animal studies have not shown complications as seen in humans, in fact same of the studies show a better prognosis. In the military settings it is used as an off label intervention in complications related to disseminated intravascular coagulation related haemorrhage caused by penetrating trauma.<ref>{{cite journal | vauthors = Hodgetts TJ, Kirkman E, Mahoney PF, Russell R, Thomas R, Midwinter M | title = UK defence medical services guidance for the use of recombinant factor VIIa (rFVIIa) in the deployed military setting | journal = Journal of the Royal Army Medical Corps | volume = 153 | issue = 4 | pages = 307–309 | date = December 2007 | pmid = 18619169 | doi = 10.1136/jramc-153-04-18 | s2cid = 10776054 }}</ref>

Recombinant human factor VII while initially looking promising in [[intracerebral hemorrhage]] failed to show benefit following further study and this is no longer recommended.<ref>{{cite journal | vauthors = Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN, Skolnick BE, Steiner T | display-authors = 6 | title = Recombinant activated factor VII for acute intracerebral hemorrhage | journal = The New England Journal of Medicine | volume = 352 | issue = 8 | pages = 777–785 | date = February 2005 | pmid = 15728810 | doi = 10.1056/NEJMoa042991 | author1-link = Stephan A. Mayer | doi-access = free }}</ref><ref>{{cite journal | vauthors = Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN, Skolnick BE, Steiner T | display-authors = 6 | title = Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage | journal = The New England Journal of Medicine | volume = 358 | issue = 20 | pages = 2127–2137 | date = May 2008 | pmid = 18480205 | doi = 10.1056/NEJMoa0707534 | hdl-access = free | hdl = 10067/688040151162165141 }}</ref>

== Interactions ==

Factor VII has been shown to [[Protein-protein interaction|interact]] with [[tissue factor]] and endothelial protein C receptor.<ref name=pmid12787023>{{cite journal | vauthors = Carlsson K, Freskgård PO, Persson E, Carlsson U, Svensson M | title = Probing the interface between factor Xa and tissue factor in the quaternary complex tissue factor-factor VIIa-factor Xa-tissue factor pathway inhibitor | journal = European Journal of Biochemistry | volume = 270 | issue = 12 | pages = 2576–2582 | date = June 2003 | pmid = 12787023 | doi = 10.1046/j.1432-1033.2003.03625.x | doi-access = free }}</ref><ref name=pmid9925787>{{cite journal | vauthors = Zhang E, St Charles R, Tulinsky A | title = Structure of extracellular tissue factor complexed with factor VIIa inhibited with a BPTI mutant | journal = Journal of Molecular Biology | volume = 285 | issue = 5 | pages = 2089–2104 | date = February 1999 | pmid = 9925787 | doi = 10.1006/jmbi.1998.2452 }}</ref>
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== References ==
{{Reflist|33em}}

== Further reading ==
{{Refbegin|33em}}
* {{cite journal | vauthors = Broze GJ, Majerus PW | title = Purification and properties of human coagulation factor VII | journal = The Journal of Biological Chemistry | volume = 255 | issue = 4 | pages = 1242–1247 | date = February 1980 | pmid = 7354023 | doi = 10.1016/S0021-9258(19)86020-9 | doi-access = free }}
* {{cite journal | vauthors = Versteeg HH, Peppelenbosch MP, Spek CA | title = The pleiotropic effects of tissue factor: a possible role for factor VIIa-induced intracellular signalling? | journal = Thrombosis and Haemostasis | volume = 86 | issue = 6 | pages = 1353–1359 | date = December 2001 | pmid = 11776298 | doi = 10.1055/s-0037-1616734 | s2cid = 10976556 }}
* {{cite journal | vauthors = Golino P | title = The inhibitors of the tissue factor:factor VII pathway | journal = Thrombosis Research | volume = 106 | issue = 3 | pages = V257–V265 | date = May 2002 | pmid = 12356487 | doi = 10.1016/S0049-3848(02)00079-8 }}
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== External links ==
* [http://www.novosevenrt.com/ Official website]
* The [[MEROPS]] online database for peptidases and their inhibitors: [http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=S01.215 S01.215] {{Webarchive|url=https://web.archive.org/web/20200529050240/https://www.ebi.ac.uk/merops/ |date=2020-05-29 }}
* CHES - Comprehensive Health Education Services LLC - Factor VII treatment and awareness [http://www.comphealthed.com/]

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{{DEFAULTSORT:Factor Vii}}
[[Category:Coagulation system]]
[[Category:EC 3.4.21]]
[[Category:Peripheral membrane proteins]]