Factor VII (EC3.4.21.21, blood-coagulation factor VIIa, activated blood coagulation factor VII, formerly known as proconvertin) is one of the proteins that causes blood to clot in the coagulation cascade. It is an enzyme of the serine protease class. A recombinant form of human factor VIIa (eptacog alfa [activated], NovoSeven) has U.S. Food and Drug Administration approval for uncontrolled bleeding in hemophilia patients. 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.
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.[1]
The action of the factor is impeded by tissue factor pathway inhibitor (TFPI), which is released almost immediately after initiation of coagulation. Factor VII is vitamin K dependent; it is produced in the liver. Use of warfarin or similar anticoagulants decreases hepatic synthesis of FVII.
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 ([2])
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,[3][4] but its role in this setting is controversial with insufficient evidence to support its use outside of clinical trials.[5] The first report of its use in hemorrhage was in an Israeli soldier with uncontrollable bleeding in 1999.[6] Risks of its use include an increase in arterial thrombosis.[5]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.[7]
Recombinant human factor VII while initially looking promising in intracerebral hemorrhage failed to show benefit following further study and this is no longer recommended.[8][9]
↑Wajima T, Isbister GK, Duffull SB (September 2009). "A comprehensive model for the humoral coagulation network in humans". Clinical Pharmacology and Therapeutics. 86 (3): 290–8. doi:10.1038/clpt.2009.87. PMID19516255.
↑Sustained correction of FVII deficiency in dogs using AAV-mediated expression of zymogen FVII PMID26702064
↑Roberts HR, Monroe DM, White GC (December 2004). "The use of recombinant factor VIIa in the treatment of bleeding disorders". Blood. 104 (13): 3858–64. doi:10.1182/blood-2004-06-2223. PMID15328151.
↑Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN, Skolnick BE, Steiner T (February 2005). "Recombinant activated factor VII for acute intracerebral hemorrhage". The New England Journal of Medicine. 352 (8): 777–85. doi:10.1056/NEJMoa042991. PMID15728810.
↑Carlsson K, Freskgård PO, Persson E, Carlsson U, Svensson M (June 2003). "Probing the interface between factor Xa and tissue factor in the quaternary complex tissue factor-factor VIIa-factor Xa-tissue factor pathway inhibitor". European Journal of Biochemistry. 270 (12): 2576–82. doi:10.1046/j.1432-1033.2003.03625.x. PMID12787023.
↑Zhang E, St Charles R, Tulinsky A (February 1999). "Structure of extracellular tissue factor complexed with factor VIIa inhibited with a BPTI mutant". Journal of Molecular Biology. 285 (5): 2089–104. doi:10.1006/jmbi.1998.2452. PMID9925787.
Further reading
Broze GJ, Majerus PW (February 1980). "Purification and properties of human coagulation factor VII". The Journal of Biological Chemistry. 255 (4): 1242–7. PMID7354023.
Versteeg HH, Peppelenbosch MP, Spek CA (December 2001). "The pleiotropic effects of tissue factor: a possible role for factor VIIa-induced intracellular signalling?". Thrombosis and Haemostasis. 86 (6): 1353–9. PMID11776298.
1bf9: N-TERMINAL EGF-LIKE DOMAIN FROM HUMAN FACTOR VII, NMR, 23 STRUCTURES
PDB 1cvw EBI.jpg
1cvw: CRYSTAL STRUCTURE OF ACTIVE SITE-INHIBITED HUMAN COAGULATION FACTOR VIIA (DES-GLA)
PDB 1dan EBI.jpg
1dan: COMPLEX OF ACTIVE SITE INHIBITED HUMAN BLOOD COAGULATION FACTOR VIIA WITH HUMAN RECOMBINANT SOLUBLE TISSUE FACTOR
PDB 1dva EBI.jpg
1dva: Crystal Structure of the Complex Between the Peptide Exosite Inhibitor E-76 and Coagulation Factor VIIA
PDB 1f7e EBI.jpg
1f7e: THE FIRST EGF-LIKE DOMAIN FROM HUMAN BLOOD COAGULATION FVII, NMR, 20 STRUCTURES
PDB 1f7m EBI.jpg
1f7m: THE FIRST EGF-LIKE DOMAIN FROM HUMAN BLOOD COAGULATION FVII, NMR, MINIMIZED AVERAGE STRUCTURE
PDB 1fak EBI.jpg
1fak: HUMAN TISSUE FACTOR COMPLEXED WITH COAGULATION FACTOR VIIA INHIBITED WITH A BPTI-MUTANT
PDB 1ff7 EBI.jpg
1ff7: THE FIRST EGF-LIKE DOMAIN FROM HUMAN BLOOD COAGULATION FVII (FUCOSYLATED AT SER-60), NMR, 20 STRUCTURES
PDB 1ffm EBI.jpg
1ffm: THE FIRST EGF-LIKE DOMAIN FROM HUMAN BLOOD COAGULATION FVII (FUCOSYLATED AT SER-60), NMR, MINIMIZED AVERAGE STRUCTURE
PDB 1j9c EBI.jpg
1j9c: Crystal Structure of tissue factor-factor VIIa complex
PDB 1jbu EBI.jpg
1jbu: Coagulation Factor VII Zymogen (EGF2/Protease) in Complex with Inhibitory Exosite Peptide A-183
PDB 1kli EBI.jpg
1kli: Cofactor-and substrate-assisted activation of factor VIIa
PDB 1klj EBI.jpg
1klj: Crystal structure of uninhibited factor VIIa
PDB 1o5d EBI.jpg
1o5d: Dissecting and Designing Inhibitor Selectivity Determinants at the S1 site Using an Artificial Ala190 Protease (Ala190 uPA)
PDB 1qfk EBI.jpg
1qfk: STRUCTURE OF HUMAN FACTOR VIIA AND ITS IMPLICATIONS FOR THE TRIGGERING OF BLOOD COAGULATION
PDB 1w0y EBI.jpg
1w0y: TF7A_3771 COMPLEX
PDB 1w2k EBI.jpg
1w2k: TF7A_4380 COMPLEX
PDB 1w7x EBI.jpg
1w7x: FACTOR7- 413 COMPLEX
PDB 1w8b EBI.jpg
1w8b: FACTOR7 - 413 COMPLEX
PDB 1wqv EBI.jpg
1wqv: Human Factor Viia-Tissue Factor Complexed with propylsulfonamide-D-Thr-Met-p-aminobenzamidine
PDB 1wss EBI.jpg
1wss: Human Factor Viia-Tissue Factor in Complex with peprid mimetic inhibitor that has two charge groups in P2 and P4
PDB 1wtg EBI.jpg
1wtg: Human Factor Viia-Tissue Factor Complexed with ethylsulfonamide-D-biphenylalanine-Gln-p-aminobenzamidine
PDB 1wun EBI.jpg
1wun: Human Factor Viia-Tissue Factor Complexed with ethylsulfonamide-D-Trp-Gln-p-aminobenzamidine
PDB 1wv7 EBI.jpg
1wv7: Human Factor Viia-Tissue Factor Complexed with ethylsulfonamide-D-5-propoxy-Trp-Gln-p-aminobenzamidine
PDB 1ygc EBI.jpg
1ygc: Short Factor VIIa with a small molecule inhibitor
PDB 1z6j EBI.jpg
1z6j: Crystal Structure of a ternary complex of Factor VIIa/Tissue Factor/Pyrazinone Inhibitor
PDB 2a2q EBI.jpg
2a2q: Complex of Active-site Inhibited Human Coagulation Factor VIIa with Human Soluble Tissue Factor in the Presence of Ca2+, Mg2+, Na+, and Zn2+
PDB 2aei EBI.jpg
2aei: Crystal structure of a ternary complex of factor VIIa/tissue factor and 2-[[6-[3-(aminoiminomethyl)phenoxy]-3,5-difluro-4-[(1-methyl-3-phenylpropyl)amino]-2-pyridinyl]oxy]-benzoic acid
PDB 2aer EBI.jpg
2aer: Crystal Structure of Benzamidine-Factor VIIa/Soluble Tissue Factor complex.
PDB 2b7d EBI.jpg
2b7d: Factor VIIa Inhibitors: Chemical Optimization, Preclinical Pharmacokinetics, Pharmacodynamics, and Efficacy in a Baboon Thrombosis Model
PDB 2b8o EBI.jpg
2b8o: Crystal Structure of Glu-Gly-Arg-Chloromethyl Ketone-Factor VIIa/Soluble Tissue Factor Complex
PDB 2bz6 EBI.jpg
2bz6: ORALLY AVAILABLE FACTOR7A INHIBITOR
PDB 2c4f EBI.jpg
2c4f: CRYSTAL STRUCTURE OF FACTOR VII.STF COMPLEXED WITH PD0297121
PDB 2f9b EBI.jpg
2f9b: Discovery of Novel Heterocyclic Factor VIIa Inhibitors
PDB 2fir EBI.jpg
2fir: Crystal structure of DFPR-VIIa/sTF
PDB 2flb EBI.jpg
2flb: Discovery of a Novel Hydroxy Pyrazole Based Factor IXa Inhibitor
PDB 2flr EBI.jpg
2flr: Novel 5-Azaindole Factor VIIa Inhibitors
PDB 2puq EBI.jpg
2puq: Crystal structure of active site inhibited coagulation factor VIIA in complex with soluble tissue factor