Factor VII

{{Lead rewrite|date=April 2024|reason=More than half of the lead is about recent pharmaceuticals, not the natural protein.}}

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.{{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 }} 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.{{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 }}

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 anticoagulants 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.{{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 }}

Structure

Factor VII shares a common domain architecture with factors IX and X.

Genetics

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

Role in disease

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 ({{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 }})

Medical uses

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

It has also been used in the setting of uncontrollable hemorrhage,{{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 }}{{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 }} but its role in this setting is controversial with insufficient evidence to support its use outside of clinical trials.{{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 }} The first report of its use in hemorrhage was in an Israeli soldier with uncontrollable bleeding in 1999.{{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 }} Risks of its use include an increase in arterial thrombosis. 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.{{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 }}

Recombinant human factor VII while initially looking promising in intracerebral hemorrhage failed to show benefit following further study and this is no longer recommended.{{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 }}{{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 }}

Interactions

Factor VII has been shown to interact with tissue factor and endothelial protein C receptor.{{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 }}{{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 }}

References

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/]

Category:Coagulation system

Category:EC 3.4.21

Category:Peripheral membrane proteins