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http://emedicine.medscape.com/article/209585-overview
Factor VII
Author: Jeyanthi Ramanarayanan, MD; Chief Editor: Emmanuel C Besa, MD more... Updated: May 19, 2011
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 Kdependent serine protease glycoprotein (also known as stable factor or proconvertin) with a pivotal role in hemostasis and coagulation. Other vitamin Kdependent factors include prothrombin, factors IX and X, and proteins C and S. The discovery of vitamin Kdependent 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 Kdependent coagulation zymogens share a similar protein domain structure consisting of an amino-terminal gammacarboxyglutamic acid (Gla) domain with 9-12 residues, carboxy-terminal serine protease domain (catalytic domain), and 2 epidermal growth factorlike 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
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Factor VII
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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 Kdependent 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]
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 terminalderived 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. A summary of the structure and properties of coagulation factor VII is as follows: 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
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Factor VII
http://emedicine.medscape.com/article/209585-overview
Factor VII. Intrinsic and extrinsic pathways of coagulation. Factor VII/tissue factor complex activates factor IX and factor X. Factor IXa along with factor VIIIa results in formation of more factor Xa. Factor Xa along with factor Va converts prothrombin to thrombin.
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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.
Epidemiology
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]
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Sex
Factor VII deficiency has no reported predilection for either sex.
Age
Factor VII deficiency has no reported predilection for any particular age group.
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Center, University of Cincinnati Academic Health Center Ronald A Sacher, MB, BCh, MD, FRCPC is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood Transfusion, International Society on Thrombosis and Haemostasis, and Royal College of Physicians and Surgeons of Canada Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; Talecris Honoraria Board membership Rebecca J Schmidt, DO, FACP, FASN Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine Rebecca J Schmidt, DO, FACP, FASN is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Nephrology, International Society of Nephrology, National Kidney Foundation, Renal Physicians Association, and West Virginia State Medical Association Disclosure: Renal Ventures Ownership interest Other Chief Editor Emmanuel C Besa, MD Professor, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Clinical Oncology, American Society of Hematology, and New York Academy of Sciences Disclosure: Nothing to disclose.
References
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