eMedicine Specialties > Hematology > Coagulation, Hemostasis, and Disorders
Factor VII
Updated: Feb 14, 2008
Introduction
Background
Blood coagulation is a series of reactions in which plasma zymogens are converted into active enzymes. The final event of these reactions is the formation of an insoluble fibrin clot. These coagulant reactions are regulated by a number of stimulatory and inhibitory mechanisms. Thus, coagulation is a finely regulated system that maintains blood in a fluid phase but can rapidly respond to injury for the formation of clots. Factor VII is a vitamin K–dependent serine protease glycoprotein (also known as stable factor or proconvertin) with a pivotal role in hemostasis and coagulation. Other vitamin K–dependent factors include prothrombin, factors IX and X, and proteins C and S.
The discovery of vitamin K–dependent factors evolved slowly, after the initial identification of the role of prothrombin in blood clotting 100 years ago. In 1951, Alexander and colleagues identified factor VII as the key initiator of coagulation when they reported the first case of factor VII deficiency in a child and called it serum prothrombin conversion accelerator deficiency.1
Tissue factor is an intrinsic membrane glycoprotein that is normally not exposed on the surface of intact blood vessels. When the vascular lumen is damaged, tissue factor is exposed and then binds to the small amounts of circulating factors VIIa and VII. This facilitates conversion of factor VII to factor VIIa. Factor VIIa bound to tissue factor in the presence of calcium and phospholipids facilitates the conversion of factor IX to factor IXa and factor X to factor Xa. Coagulation has traditionally been considered to occur via extrinsic and intrinsic pathways. Although this division is useful for understanding in vitro laboratory coagulation tests, no such division occurs in vivo because the tissue factor VIIa complex is a potent activator of factor IX and factor X.
Pathophysiology
Protein structure
Factor VII is synthesized in the liver and secreted as a single-chain glycoprotein of 48 kd. All vitamin K–dependent coagulation zymogens share a similar protein domain structure consisting of an amino-terminal gamma-carboxyglutamic acid (Gla) domain with 9-12 residues, carboxy-terminal serine protease domain (catalytic domain), and 2 epidermal growth factor–like domains. The mature protein is generated by cleavage of the Arg-Ala bond. The Gla domain is responsible for the interaction of the protein with lipid membranes.
The epidermal growth factor domain has a calcium ion binding site that to some degree mediates interaction with the tissue factor exposed at the site of vessel injury. Factor VII is now converted to factor VIIa. Gamma-glutamyl carboxylase catalyzes carboxylation of Gla residues in the amino-terminal portion of the molecule. The carboxylase is dependent on a reduced form of vitamin K for its action. Whenever each glutamyl residue is carboxylated, the reduced vitamin K is converted to the epoxide form. Vitamin K epoxide reductase is required to convert the epoxide form of vitamin K back to the reduced form.
Warfarin inhibits the activity of vitamin K epoxide reductase and prevents recycling of vitamin K back to the reduced form, thus interfering with the synthesis of factor VII and other vitamin K–dependent factors. Warfarin poisoning can be reversed by administering vitamin K. Mutations of carboxylase can lead to low levels of all the gamma-carboxyglutamic acid domain-containing factors (ie, prothrombin; factors VII, IX, and X; protein C).2
Properties of factor VII
Factor VII is coded by the gene on band 13q34, closely located to the gene for factor X (F10). The plasma concentration of factor VII is 0.5 mg/mL, and the plasma levels are determined by genetic and environmental factors.3,4 Factor VII has the shortest half-life of all procoagulant factors (3-6 h). Hence, when a problem with synthesis occurs, as in liver failure, vitamin K deficiency, or warfarin therapy, the factor VII level first decreases in the plasma, followed by a decrease in other vitamin K–dependent factors.
Factor VII levels are elevated during pregnancy in healthy females. Plasma factor VII levels also increase with age and are higher in females and in persons with hypertriglyceridemia. A strong contribution of the factor VII genotype to factor VII levels has been demonstrated, and different factor VII genotypes can result in up to several-fold differences in mean factor VII levels.
Activation
The major proportion of factor VII circulates in plasma in zymogen form, and activation of this form results in cleavage of the peptide bond between arginine 152 and isoleucine 153. Resulting factor VIIa consists of an NH2-derived light chain (relative molecular mass, 20,000) and a COOH terminal–derived heavy chain (relative molecular mass, 30,000) linked via a single disulfide bond (Cys 135 to Cys 262). The light chain contains the membrane-binding Gla domain, while the heavy chain contains the catalytic domain.
Rapid activation also occurs when factor VII is combined with its cofactor, which is the tissue factor in the presence of calcium (autocatalysis). This reaction may be initiated by a small amount of preexisting factor VIIa. Conversion of factor VII to factor VIIa is catalyzed by a number of proteases, including thrombin, factor IXa, factor Xa, factor XIa, and factor XIIa. Comparison of these proteins has shown that factor Xa, in association with phospholipids, has the highest potential to activate factor VII.2,5
Factor IXa is responsible for basal levels of plasma factor VIIa in healthy individuals. Patients with hemophilia B (factor IX deficiency), unlike patients with hemophilia A (factor VIII deficiency), have very low concentrations of circulating factor VIIa and achieve normal levels of VIIa within a few hours of infusion of purified factor IX.
Factor VIIa can be detected in plasma by a sensitive assay using a recombinant soluble form of tissue factor. The mean plasma concentration is 3.6 ng/mL in healthy individuals. The half-life of factor VIIa is relatively long (2.5 h) compared with other activated coagulation factors.
Summary of structure and properties of coagulation factor VII
- Synthesis and localization - Synthesized in the liver and circulates in the plasma as a zymogen
- Half-life - 3-6 hours
- Molecular weight - 50,000
- Structure - Amino-terminal (light chain) Gla domain, carboxy-terminal (heavy chain) catalytic domain, 2 epidermal growth factor domains
- Cofactor - Tissue factor
- Substrate - Factor VIIa/tissue factor complex activates factors X and IX
Role of factor VII in coagulation and coagulation pathways
The association of factor VIIa with tissue factor enhances the proteolytic activity by (1) bringing the binding sites for both the substrate (factors X and IX) and the enzyme (VIIa) into closer proximity and by (2) inducing a conformational change, enhancing the enzymatic activity of factor VIIa.
The factor VIIa/tissue factor complex formed as a result of binding of small amounts of preexistent plasma factor VIIa activates factor X and factor IX. The rate of factor X activation by this pathway (extrinsic) is approximately 50 times slower than the rate achieved by factor IXa, factor VIIIa, phospholipid, and calcium ions (intrinsic pathway). Factor Xa formed by both enzyme complexes binds to membrane-bound factor Va to produce the prothrombinase complex. This complex converts prothrombin to thrombin, which results in the formation of fibrin clots.
Inhibition of the extrinsic pathway of coagulation
Activation of factor X by the factor VIIa–tissue factor complex results in the interaction of factor Xa with factor Va to form a prothrombinase complex. Very small amounts of thrombin formed during this initiation phase of thrombin generation subsequently activate platelets, factor VIII, factor V, and factor XI. This leads to the propagation phase, wherein the bulk of the thrombin is generated. The initiation and propagation phases of the coagulation system are differentially regulated by the inhibitors. Tissue factor pathway inhibitor targets factor VIIa/tissue factor/factor Xa product complex and principally serves to regulate the initiation phase of the reaction.
The antithrombin III/heparin complex plays a major role in the inhibition of all vitamin K–dependent proteases except factor VIIa.
Factor VII deficiency
To date, fewer than 200 cases of true factor VII deficiency have been reported. Because factor VII deficiency is a rare disease, data concerning the pathophysiology are limited. Both qualitative and quantitative forms of factor VII deficiency have been noted. Factor VII Padua I has been described in one kindred with an abnormal rabbit brain prothrombin time (PT) but a normal ox brain PT; factor VII (Verona) is associated with an abnormal form of factor VII, and kindreds with heterozygosity for this type have been reported. Factor VII Padua 2 is a double-heterozygote condition associated with abnormal coagulation test results with only ox brain thromboplastin.
Approximately 30 different mutations have been identified since the isolation of the factor VII gene (F7). Most described mutations are missense mutations. Nonsense mutations, small deletions, and splice-site abnormalities have also been identified.
Factor VII coagulant activities measured in the laboratory are not well correlated with bleeding manifestations.6 This is partly because different F7 mutations express different levels of coagulant activity. Additionally, factor VII activity levels are variable when assayed in the presence of tissue factor obtained from different species.
Approximately two thirds of the mutations seem to affect the protease domain, indicating that loss of protease function is the most common cause of the clinical phenotype.6
The donor splice mutation in intron 7 (IVS7+7) was first described in Italy. Ala294Val and Ala294Val;404delC was first described by Arbini et al in Polish patients and by Bernardi et al in Italian patients.7 According to Herrmann et al, this was found to be the most common type of mutation in Europe.6 In the same study, homozygous conditions to mutations Val (-17) Ile, Phe4Leu, Cys135Arg, Ala244Val, Ala294Val;404delC, and IVS4+1G>A were associated with factor VII activities of 8%, less than 1%, 1-4%, 3%, less than 1%, and 7%, respectively. Factor VII activities ranging from 75-80% were found in heterozygous patients with donor splice mutation IVS7+7, which is thus considered a mild mutation.6
Factor VII activity is influenced by mutations of F7 and by allelic polymorphic variations of the gene. Eight polymorphisms within F7 are known, 3 of which (ie, an insertion polymorphism of the promoter, a repeat polymorphism within intron 7, the Arg353Gln polymorphism of exon 8) influence the level of factor VII activities. A recent analysis of 7 of the polymorphisms in 14 patients showed only a mild decrease (>50%) of factor VII levels in those without an identified mutation compared to those with an identified mutation. These data appear to indicate that patients with activated factor VII levels greater than 50% are less likely to have a definitive F7 mutation, although polymorphisms of the F7 gene can be detected in these patients.8
A detailed database of mutations is available at the MRC Haemostasis & Thrombosis Database Resource Site.
Increased factor VII plasma levels and associations with thrombotic disease
The Northwick Park Heart Study was a prospective study in which factor VII levels were found to be strongly associated with coronary risk. This study showed that elevated factor VII levels were related to fatal myocardial infarctions but not to nonfatal myocardial infarctions.9
The Atherosclerosis Risk in Communities Study, a prospective study of hemostatic factors and the prevalence of coronary heart disease, showed no association of coronary disease with factor VII. In this study, only elevated levels of fibrinogen, WBCs, factor VIII, and von Willebrand factor were identified as risk factors associated with coronary heart disease, but their measurement in healthy subjects did not seem to be beneficial beyond more established risk factors.
In the Prospective Cardiovascular Munster study, factor VII:c levels were elevated in patients who had coronary events, but, after multiple logistic regression analysis, factor VII:c was not identified as an independent risk factor for coronary events.
The results of the Survival of Myocardial Infarction Long-Term Evaluation study (ie, the largest published case-controlled study showing the relationship between genetic polymorphisms and disease) demonstrated that a genetic propensity to high factor VII levels is not associated with a risk for myocardial infarction.
Another prospective study, the Edinburgh Artery Study, also failed to confirm factor VII as an independent predictor of coronary disease.
Because the association between increased factor VII levels and cardiovascular disease is controversial, whether elevated factor VII levels should be taken into account in the presence of additional risk factors when assessing cardiovascular risk remains unclear.3,10,11
Neither factor VII:c levels nor F7 polymorphisms have been associated with cerebrovascular disease.12
Venous thromboembolism has been reported in patients with factor VII deficiency; hence, this deficiency does not offer protection against deep venous thrombosis.
Frequency
International
- Hereditary factor VII deficiency is a rare autosomal recessive bleeding disorder first described by Alexander et al in 1951.1 Prevalence is estimated to be 1 case per 500,000 persons in the general population. Dubin-Johnson syndrome and Rotor syndrome are associated with a high prevalence of factor VII deficiency.13
- Acquired factor VII deficiency from inhibitors is very rare. Cases have been reported with the deficiency occurring in association with drugs such as cephalosporins, penicillins, and oral anticoagulants. Acquired factor VII deficiency has also been reported to occur spontaneously or with other conditions, such as myeloma, sepsis, and aplastic anemia, and with interleukin-2 therapy and antithymocyte globulin therapy.
Mortality/Morbidity
Morbidity and mortality rates vary with the severity of the factor deficiency. Severe factor VII deficiencies (<1%) result in bleeding disorders indistinguishable from severe hemophilia A or hemophilia B.
Race
Specific mutations and polymorphisms are known to occur in some populations. Among Iranian and Moroccan Jews, a missense Ala244Val mutation is responsible for frequent occurrences of disease. The highest frequencies of the polymorphism, an Arg353Gln substitution, are observed in Gujaratis (25%) and Dravidian Indians (29%) compared with northern Europeans (9%) and Japanese (3%), resulting in decreases in factor VII levels.14
Sex
Factor VII deficiency has no reported predilection for either sex.
Age
Factor VII deficiency has no reported predilection for any particular age group.
Clinical
History
Bleeding history is a crucial element in the evaluation of any patient with a hemorrhagic disorder. Of all factors evaluated, clinical history appears to be the best predictor of bleeding risk after hemostatic challenges in inherited FVII deficiencies.15 A bleeding disorder is considered likely when a bleeding tendency is discovered in one or more family members or when an abnormal coagulation assay result is obtained as a part of a routine examination or before surgery.
Knowing the mode of inheritance of hereditary disorders is important when eliciting the family history. Factor VII deficiency is an autosomal recessive disease, unlike hemophilia, which is an X-linked recessive disease.
- Only homozygote or compound heterozygote patients with factor VII deficiency are symptomatic. Heterozygotes who have partial factor VII deficiency may not exhibit hemorrhagic manifestations, even following trauma. In symptomatic patients, clinical phenotypes vary from mild to severe and do not necessarily correlate with factor VII levels. A multicenter European study of patients who are congenitally factor VII deficient showed that clinical symptoms did not vary with the frequency of functional polymorphisms and that homozygotes with the same mutation presented with striking differences in severity of bleeding.16
- Patients with factor VII levels of less than 1% frequently present with bleeding symptoms indistinguishable from those of persons with severe hemophilia A or hemophilia B. They may present with life-threatening intracerebral hemorrhage manifesting as headaches, seizures, or focal deficits or with recurrent hemarthrosis leading to severe arthropathy. Intracranial hemorrhage has been reported, especially in neonates after vaginal delivery.
- Unlike in hemophilia, hemarthrosis rarely occurs but may be precipitated by trauma. Patients should be asked about recurrent joint pain, swelling, and motion limitation. Hemarthrosis is sometimes heralded by an aura of mild discomfort that becomes progressively painful over a period of minutes to hours. In children, hemarthrosis usually occurs when the affected child begins to walk.
- Patients with factor VII levels of 5% or more have much milder disease characterized by epistaxis, gingival bleeding, menorrhagia, and easy bruising. In patients with mild disease, dental extractions, tonsillectomy, and procedures involving the urogenital tract are frequently associated with bleeding (due to local fibrinolysis), while surgical procedures such as laparotomy, herniorrhaphy, appendectomy, and hysterectomy are not. Postpartum hemorrhage is noted in patients with levels less than 10-20% of the reference range.
- Bleeding isolated to a single organ or system (eg, hematuria, hematemesis, hemoptysis) is less likely to be due to a hemostatic abnormality than to a local cause such as neoplasm or ulcer.
- A family history is particularly important when a hereditary factor deficiency is considered likely. A specific inquiry should be made about consanguinity. Population genetics information may be helpful; for example, a higher frequency of factor VII deficiency is observed in Iranian and Moroccan Jews.
- Drug history is important; drugs of concern may include hepatotoxic drugs, oral anticoagulants (eg, warfarin), and agents such as aspirin. Nutritional history is important to assess the likelihood of vitamin K deficiency. Rarely, drugs such as penicillins and cephalosporins have been associated with selective factor VII deficiency, but other antibiotics can cause vitamin K deficiency and consequently inhibit the synthesis of functional vitamin K-dependent factors, including factor VII.
Physical
Physical findings depend on the site and severity of bleeding.
- Hemarthrosis may lead to findings of joint swelling, motion limitation, and mild fever. If significant fever develops, infection should be considered. Repeated hemarthrosis leads to joint deformity complicated by muscle atrophy and contractures.
- Focal neurological deficits depend on the location of bleeding into the nervous system. Symptoms and signs of subdural hematoma may be delayed for weeks.
- Bruising and soft tissue bleeding may be observed with or without trauma. Large hematomas may expand locally and cause compression of adjacent organs, blood vessels, and nerves. Pharyngeal and retropharyngeal hematomas may enlarge and obstruct the airway.
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References
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Further Reading
Keywords
FVII, F7 gene, proconvertin, stable factor, serum prothrombin conversion accelerator, SPCA, autoprothrombin I, recombinant factor VIIa, rFVIIa, NovoSeven, coagulation, procoagulants, coagulation cascade, anticoagulant factors, Dubin-Johnson syndrome, Rotor syndrome, prothrombin conversion accelerator deficiency, coagulation disorder, blood disorder blood disease, hemophilia A, hemophilia, hemophilia B
