Factor VII

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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 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 gammacarboxyglutamic 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

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3-6 hours Molecular weight . Activation The major proportion of factor VII circulates in plasma in zymogen form.com/article/209585-overview vitamin K back to the reduced form.000) linked via a single disulfide bond (Cys 135 to Cys 262).6 ng/mL in healthy individuals. 2 dari 8 3/16/2013 6:16 AM . factor Xa. has the highest potential to activate factor VII. Plasma factor VII levels also increase with age and are higher in females and in persons with hypertriglyceridemia. The mean plasma concentration is 3. Resulting factor VIIa consists of an NH2-derived light chain (relative molecular mass. Note the image below. Warfarin inhibits the activity of vitamin K epoxide reductase and prevents recycling of vitamin K back to the reduced form.[2] Properties of factor VII Factor VII is coded by the gene on band 13q34. Conversion of factor VII to factor VIIa is catalyzed by a number of proteases. have very low concentrations of circulating factor VIIa and achieve normal levels of VIIa within a few hours of infusion of purified factor IX. which is the tissue factor in the presence of calcium (autocatalysis). IX. prothrombin.Tissue factor Substrate . 2 epidermal growth factor domains Cofactor . Hence.Factor VII http://emedicine.medscape. Factor VIIa can be detected in plasma by a sensitive assay using a recombinant soluble form of tissue factor.5 mg/mL. This complex converts prothrombin to thrombin. or warfarin therapy.Amino-terminal (light chain) Gla domain.5 h) compared with other activated coagulation factors. A strong contribution of the factor VII genotype to factor VII levels has been demonstrated. factor VIIIa. and factor XIIa.50. The rate of factor X activation by this pathway (extrinsic) is approximately 50 times slower than the rate achieved by factor IXa. factor IXa. Comparison of these proteins has shown that factor Xa. in association with phospholipids. thus interfering with the synthesis of factor VII and other vitamin K–dependent factors. and activation of this form results in cleavage of the peptide bond between arginine 152 and isoleucine 153. vitamin K deficiency. and different factor VII genotypes can result in up to several-fold differences in mean factor VII levels. Patients with hemophilia B (factor IX deficiency). as in liver failure.Synthesized in the liver and circulates in the plasma as a zymogen Half-life . Factor Xa formed by both enzyme complexes binds to membrane-bound factor Va to produce the prothrombinase complex. including thrombin. and X. which results in the formation of fibrin clots.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. when a problem with synthesis occurs. closely located to the gene for factor X (F10). 4] Factor VII has the shortest half-life of all procoagulant factors (3-6 h). factors VII. 20. This reaction may be initiated by a small amount of preexisting 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 plasma concentration of factor VII is 0.[2. and calcium ions (intrinsic pathway). factor XIa.000 Structure . while the heavy chain contains the catalytic domain. phospholipid. followed by a decrease in other vitamin K–dependent factors. carboxy-terminal (heavy chain) catalytic domain. and the plasma levels are determined by genetic and environmental factors. enhancing the enzymatic activity of factor VIIa. The half-life of factor VIIa is relatively long (2. 30. unlike patients with hemophilia A (factor VIII deficiency). Factor VII levels are elevated during pregnancy in healthy females. Mutations of carboxylase can lead to low levels of all the gamma-carboxyglutamic acid domain-containing factors (ie. the factor VII level first decreases in the plasma.000) and a COOH terminal–derived heavy chain (relative molecular mass. protein C). A summary of the structure and properties of coagulation factor VII is as follows: Synthesis and localization . Rapid activation also occurs when factor VII is combined with its cofactor. The light chain contains the membrane-binding Gla domain. Warfarin poisoning can be reversed by administering vitamin K. 5] Factor IXa is responsible for basal levels of plasma factor VIIa in healthy individuals.[3.

factor VII (Verona) is associated with an abnormal form of factor VII. Factor IXa along with factor VIIIa results in formation of more factor Xa. which is thus considered a mild mutation. this was found to be the most common type of mutation in Europe. These data appear to indicate that patients with activated factor VII levels greater than 50% are less likely to have a definitive F7 mutation. and 7%.[6] This is partly because different F7 mutations express different levels of coagulant activity. Ala294Val. 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. Intrinsic and extrinsic pathways of coagulation. and splice-site abnormalities have also been identified. Factor Xa along with factor Va converts prothrombin to thrombin. less than 1%.[6] In the same study. Cys135Arg. Eight polymorphisms within F7 are known.[6] Factor VII activity is influenced by mutations of F7 and by allelic polymorphic variations of the gene. indicating that loss of protease function is the most common cause of the clinical phenotype. Most described mutations are missense mutations. factor V. Very small amounts of thrombin formed during this initiation phase of thrombin generation subsequently activate platelets. Factor VII coagulant activities measured in the laboratory are not well correlated with bleeding manifestations. and IVS4+1G>A were associated with factor VII activities of 8%. Phe4Leu. Factor VII deficiency To date. wherein the bulk of the thrombin is generated.[6] The donor splice mutation in intron 7 (IVS7+7) was first described in Italy.404delC was first described by Arbini et al in Polish patients and by Bernardi et al in Italian patients. an insertion polymorphism of the promoter. small deletions.[7] According to Herrmann et al.404delC. Ala244Val. although polymorphisms of the F7 gene can be detected in these patients. Both qualitative and quantitative forms of factor VII deficiency have been noted. data concerning the pathophysiology are limited.[8] 3 dari 8 3/16/2013 6:16 AM . Approximately two thirds of the mutations seem to affect the protease domain. Because factor VII deficiency is a rare disease. Factor VII Padua 2 is a double-heterozygote condition associated with abnormal coagulation test results with only ox brain thromboplastin. Factor VII activities ranging from 75-80% were found in heterozygous patients with donor splice mutation IVS7+7. 1-4%. Ala294Val and Ala294Val. Tissue factor pathway inhibitor targets factor VIIa/tissue factor/factor Xa product complex and principally serves to regulate the initiation phase of the reaction. less than 1%. 3%. respectively. The antithrombin III/heparin complex plays a major role in the inhibition of all vitamin K–dependent proteases except factor VIIa. factor VII activity levels are variable when assayed in the presence of tissue factor obtained from different species. the Arg353Gln polymorphism of exon 8) influence the level of factor VII activities. fewer than 200 cases of true factor VII deficiency have been reported. 3 of which (ie.com/article/209585-overview Factor VII. 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. Additionally.medscape. a repeat polymorphism within intron 7. Nonsense mutations. Approximately 30 different mutations have been identified since the isolation of the factor VII gene (F7). homozygous conditions to mutations Val (-17) Ile. Factor VII Padua I has been described in one kindred with an abnormal rabbit brain prothrombin time (PT) but a normal ox brain PT. and kindreds with heterozygosity for this type have been reported. This leads to the propagation phase. and factor XI. The initiation and propagation phases of the coagulation system are differentially regulated by the inhibitors. factor VIII. Factor VII/tissue factor complex activates factor IX and factor X.Factor VII http://emedicine.

Because the association between increased factor VII levels and cardiovascular disease is controversial. are observed in Gujaratis (25%) and Dravidian Indians (29%) compared with northern Europeans (9%) and Japanese (3%). but their measurement in healthy subjects did not seem to be beneficial beyond more established risk factors. hence. factor VII:c levels were elevated in patients who had coronary events. Severe factor VII deficiencies (< 1%) result in bleeding disorders indistinguishable from severe hemophilia A or hemophilia B. Acquired factor VII deficiency has also been reported to occur spontaneously or with other conditions. a prospective study of hemostatic factors and the prevalence of coronary heart disease. this deficiency does not offer protection against deep venous thrombosis. 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. WBCs. Mortality/Morbidity Morbidity and mortality rates vary with the severity of the factor deficiency. 10.medscape. a missense Ala244Val mutation is responsible for frequent occurrences of disease.[1] Prevalence is estimated to be 1 case per 500. and von Willebrand factor were identified as risk factors associated with coronary heart disease. In the Prospective Cardiovascular Munster study. The results of the Survival of Myocardial Infarction Long-Term Evaluation study (ie.[12] Venous thromboembolism has been reported in patients with factor VII deficiency. and aplastic anemia.com/article/209585-overview A detailed database of mutations is available at the MRC Haemostasis & Thrombosis Database Resource Site. factor VIII.000 persons in the general population. Another prospective study. the Edinburgh Artery Study. 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. after multiple logistic regression analysis.[13] Acquired factor VII deficiency from inhibitors is very rare.Factor VII http://emedicine. but. The highest frequencies of the polymorphism. an Arg353Gln substitution. Dubin-Johnson syndrome and Rotor syndrome are associated with a high prevalence of factor VII deficiency. factor VII:c was not identified as an independent risk factor for coronary events. Epidemiology Frequency International Hereditary factor VII deficiency is a rare autosomal recessive bleeding disorder first described by Alexander et al in 1951. Cases have been reported with the deficiency occurring in association with drugs such as cephalosporins. whether elevated factor VII levels should be taken into account in the presence of additional risk factors when assessing cardiovascular risk remains unclear.[9] The Atherosclerosis Risk in Communities Study. also failed to confirm factor VII as an independent predictor of coronary disease. Among Iranian and Moroccan Jews. In this study. sepsis. only elevated levels of fibrinogen. and with interleukin-2 therapy and antithymocyte globulin therapy. Race Specific mutations and polymorphisms are known to occur in some populations. and oral anticoagulants. such as myeloma.[14] 4 dari 8 3/16/2013 6:16 AM . penicillins. resulting in decreases in factor VII levels.[3. 11] Neither factor VII:c levels nor F7 polymorphisms have been associated with cerebrovascular disease. showed no association of coronary disease with factor VII. This study showed that elevated factor VII levels were related to fatal myocardial infarctions but not to nonfatal myocardial infarctions.

Department of Medicine. Specialty Editor Board Paul Schick.Factor VII http://emedicine. Medscape Drug Reference Disclosure: Medscape Salary Employment Ronald A Sacher. Francisco J Hernandez-Ilizaliturri. MD is a member of the following medical societies: American Association of Physicians of Indian Origin and American Society of Hematology Disclosure: Nothing to disclose. University of Buffalo State University of New York School of Medicine and Biomedical Sciences Francisco J Hernandez-Ilizaliturri. Lankenau Hospital Paul Schick. MD Emeritus Professor. BCh. MD Assistant Professor. MD Associate Professor of Medicine. and New York Academy of Sciences Disclosure: Nothing to disclose. Roswell Park Cancer Institute. Department of Immunology. MB. Michigan State University Ganapathy S Krishnan. Assistant Professor of Immunology. Internal Medicine and Pathology. Veterans Affairs Medical Center of Buffalo Jeyanthi Ramanarayanan. Hoxworth Blood 5 dari 8 3/16/2013 6:16 AM . Drexel University College of Medicine. Department of Hematology and Oncology. Jefferson Medical College of Thomas Jefferson University. University of Nebraska Medical Center College of Pharmacy. Editor-in-Chief. MD is a member of the following medical societies: American Association for Cancer Research and American Society of Hematology Disclosure: Nothing to disclose. Research Professor. American Society of Hematology. FRCPC Professor. Adjunct Professor of Medicine. PharmD. Coauthor(s) Ganapathy S Krishnan. Medical Oncology. PhD Adjunct Assistant Professor. MBBS is a member of the following medical societies: American Society of Hematology Disclosure: Nothing to disclose. Department of Internal Medicine. Francisco Talavera. Department of Internal Medicine. MD is a member of the following medical societies: American College of Physicians. Contributor Information and Disclosures Author Jeyanthi Ramanarayanan.com/article/209585-overview Sex Factor VII deficiency has no reported predilection for either sex.medscape. MBBS Fellow. Age Factor VII deficiency has no reported predilection for any particular age group. Director. International Society on Thrombosis and Haemostasis. MD. American Heart Association.

American Society of Nephrology. American College of Clinical Pharmacology. Mar 2005. FASN is a member of the following medical societies: American College of Physicians. American Society for Clinical Pathology. Blood Coagul Fibrinolysis. American Society of Clinical Oncology. and Royal College of Physicians and Surgeons of Canada Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching. Lichtman MA. Pinotti M. Roberts HR. BCh.30(6):596-608. DO. Laurian Y. Auberger K. 6 dari 8 3/16/2013 6:16 AM . 8. References 1. [Medline]. Wulff K. National Kidney Foundation. Ruddock V. 4. Talecris Honoraria Board membership Rebecca J Schmidt. West Virginia University School of Medicine Rebecca J Schmidt. Jun 1 2000.com/article/209585-overview Center. American Federation for Medical Research. Mitchell MJ. Mitchell J. Stirling Y. et al. and New York Academy of Sciences Disclosure: Nothing to disclose. DO. et al. Department of Medicine. Patel R.32 Suppl 1:37-40. Jefferson Medical College of Thomas Jefferson University Emmanuel C Besa. Jun 1951. Atherosclerosis . American Medical Association. 6. Girelli D.Factor VII http://emedicine. Molecular biology and biochemistry of the coagulation factors and pathways of hemostasis. [Medline]. Herrmann FH. May 1992. Hum Genet. American Society of Hematology. 6th ed.16(2):91-5. Seligsohn U. Lane A. Molecular biology and clinical manifestation of hereditary factor VIIdeficiency. MB. Kimmel Cancer Center. eds. R Goldstein and G Landwehr. Modulation of factor VII levels by intron 7 polymorphisms: population and in vitro studies. American Society of Hematology. Hoffman M. Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation. and long-term incidence ofischaemic heart disease in the Northwick Park Heart Study. Molecular analysis of factor VII deficiency in Italy: a frequent mutation(FVII Lazio) in a repeated intronic region. [Medline].26(4):393-400. The significance of published polymorphisms in 14 cases of mild factor VII deficiency. NY: McGraw-Hill. FRCPC is a member of the following medical societies: American Association for the Advancement of Science. Pathophysiol Haemost Thromb. Cutler JA. 3. Lancet. FACP.92(5):446-50. 2001. [Medline]. Section of Nephrology. 2000. [Medline]. 5.342(8879):1076-9. et al. Meade TW. American Clinical and Climatological Association. Monroe DM.95(11):3423-8. [Medline]. Fibrinolytic activity. et al. Bernardi F. Alexander B. Kipps TJ. Blood. 2. Gemmati D. clotting factors. American Association of Blood Banks. 2001:1409-34. MD Professor. CooK CD. Coller BS. FASN Professor of Medicine. Section Chief. 2002. Genetic and environmental determinants of factor VII coagulant activity in ethnic groups at differing risk of coronary heart disease. 9. MD. FACP. Semin Thromb Hemost. Toso R. Treatment of bleeding in patients with platelet disorders: is there a place for recombinant factor VIIa?. In: Beutler E. Congenital SPCA deficiency: a hitherto unrecognized coagulation defect with hemorrhage rectified by serum and serum fractions. Department of Medicine. J Clin Invest. International Society on Thrombosis and Haemostasis. University of Cincinnati Academic Health Center Ronald A Sacher. Oct 30 1993. College of American Pathologists. Savidge GF.medscape. MD is a member of the following medical societies: American Association for Cancer Education. [Medline]. Renal Physicians Association. Nov 1993. International Society of Nephrology. Patracchini P. New York. et al. Cruickshank JK.94(1):43-50. International Society of Blood Transfusion. William's Hematology . 7. and West Virginia State Medical Association Disclosure: Renal Ventures Ownership interest Other Chief Editor Emmanuel C Besa. [Medline].

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