Factor VII is the most sensitive of the vitamin K-dependent clotting factors. The mechanism of action is tissue factor-dependent activation of factors Xa and IXa on the surfaces of activated platelets. Factor Xa leads to the generation of thrombin and hemostasis, by converting fibrinogen to fibrin. This process is limited to the site of injury, since the exposure of the subendothelial matrix tissue factor plays a role in the action of recombinant factor VIIa, thus reducing the risk of thromboembolic events.
Recombinant activated factor VII (factor VIIa) is indicated for patients with inhibitors of coagulation factors VIII and IX. It has also been used with good results preoperatively, in patients with severe thrombocytopenia, and in the treatment of life-threatening bleeding, including bleeding related to anticoagulant therapy or liver failure. The utility of recombinant factor VIIa in correcting prothrombin time has been demonstrated in three neonates with hepatic failure who underwent liver biopsy and central venous catheter placement.
A disadvantage of recombinant factor VIIa is the need for frequent administration, due to its short half-life, around 2.7 hours with a clearance of 0.5 ml/kg/minute. Clearance is even faster in patients under 15 years of age. In one child, the half-life was not longer than 1 hour.
In general, factor VII is well tolerated, with an incidence of non-serious adverse events of 3.6%. The most frequently reported adverse events are hypertension, skin reactions, fever, headache, epistaxis, reduced plasma fibrinogen, and prolonged prothrombin time. Animal studies and case reports have suggested that recombinant factor VIIa should lower the INR in patients taking oral anticoagulants and also has a hemostatic effect.
Regulation of production and activity
The concentration of factor VII in plasma, compared to other vitamin K-dependent clotting factors, is extremely low (0.5 μg ml – 1 or 10 nM). Limited steady-state FVII mRNA levels in the liver are responsible for the low mean plasma FVII concentration. The liver is believed to be the complete source of FVII in plasma since the expression of FVII mRNA is restricted to the liver. FVII can be synthesized locally (extrahepatically) in a limited number of cells under special circumstances, such as alveolar macrophages in interstitial lung diseases and smooth muscle cells in human atherosclerotic vessels.
The human FVII gene spans 13 kb and is located on chromosome 13, only 2.8 kb 5 ‘from the factor X gene. As in the promoters of many other clotting factor genes, the FVII promoter lacks a TATA box, a sequence present in approximately 80% of eukaryotic RNA polymerase II promoters. A major transcriptional start site is identified at -51. The first 185 bp 5 ‘of the transcription start site is sufficient to confer maximum promoter activity. A liver-enriched transcription factor, hepatocyte nuclear factor 4 (HNF-4), and a ubiquitous transcription factor, Sp1, which have been shown to bind within the first 108 bp of the FVII promoter region, play a fundamental role in the promoter of FVII activity.
ARP1, an orphan nuclear hormone receptor, interacts with two regions of the 5 ‘flanking region of FVII, the HNF-4 binding region (-77 to -47) and the nuclear hormone response region (-237 to – 200). The binding of ARP1 represses the transcriptional activation of the FVII gene. FVII expression can also be modulated by interactions that occur outside the HNF-4 and Sp1 binding region of the promoter.
A decanucleotide insert polymorphism at -323 is shown to reduce the expression of the FVII gene. The decanucleotide insert polymorphism correlates with lower FVII antigen and lower coagulant activity. In contrast to decanucleotide insertion, a base substitution at -402 (G → A) is associated with increased FVII expression.
Once the liver secretes FVII into the circulating blood, its activity is regulated by a variety of mechanisms; among them the activation of FVII by cleavage of the peptide bond between Arg 152 and Ile 153, and the allosteric influences exerted by the cofactor TF, substrates and inhibitors play predominant roles.
Activation of the FVII zymogen to the FVIIa enzyme is highly dependent on TF. Upon activation, the structure of FVII undergoes conformational changes that form the substrate-binding cleft. However, the conformational change in FVIIa is incomplete until it binds to TF. Therefore, FVIIa only exists only in a partially active form and is driven to the active enzyme under the influence of TF.
Factor VII deficiency
Factor VII has the shortest half-life of all clotting factors, estimated at 6 hours. Factor VII deficiency is a rare autosomal recessive disorder. The severity of the bleeding diathesis does not correlate with factor VII levels. Many individuals have factor VII mutations but are asymptomatic and seek medical attention as a result of isolated prolongation of PT.
Much more common than an inherited factor VII deficiency is an acquired factor VII deficiency. Due to the extraordinarily short half-life of factor VII, liver failure, vitamin K deprivation, or oral anticoagulant toxicity first manifest as factor VII deficiency with an isolated increased PT value.