Official Full Name
Factor VII
Background
Human factor VII is a single chain, vitamin K-dependent, plasma glycoprotein which is synthesized in the liver. Prior to secretion into the blood, post translational modification by a vitamin K-dependent carboxylase produces ten-carboxyglutamic acid (gla) residues located in the NH2-terminal portion of the molecule, which facilitate cell membrane binding. Factor VII is proteolytically activated to the serine protease, factor VIIa, during coagulation. Factor VII can be activated by thrombin, factor IXa, factor Xa or factor XIIa. The activation results in cleavage of the single chain molecule on the COOH-terminal side of arginine-152, to produce an NH2-terminal derived light chain (Mr=20,000) and a COOH-terminal derived heavy chain (Mr=30,000) which remain covalently associated by a single disulfide bond. The light chain region contains the gla domain, as well as two growth factor domains which are homologous to human epidermal growth factor (EGF). A single β-hydroxyaspartic acid identified in factor VII is also located in the light chain region. The heavy chain region of factor VIIa contains the catalytic domain. Factor VIIa and the cofactor, tissue factor, may combine on negatively charged cell surfaces in a calcium dependent manner to form the extrinsic factor Xase enzyme complex. This enzyme complex catalyzes the conversion of both factor IX to factor IXa and factor X to factor Xa. The cDNA for factor VII has been isolated and the nucleotide sequence determined. Factor VII shares extensive sequence homology with other serine proteases including factor IX, factor X and protein C.
Human factor VII is purified using a combination of conventional techniques and immunoaffinity chromatography. The purified protein is supplied in 50% (vol/vol) glycerol/H2O and should be stored at -20°C. Purity is determined by SDS-PAGE analysis and activity is measured in a factor VII clotting assay.
Synonyms
Human Coagulation Factor VII; Factor VII
Introduction
Factor VII, also known as serum prothrombin conversion accelerator or proconvertin, is one of the essential blood clotting proteins in the human body, predominantly manufactured in the liver. The primary function of blood clotting proteins is to prevent excessive bleeding upon injury. Factor VII, along with its cofactor tissue factor, plays a pivotal role in the initiation of the coagulation cascade, thus facilitating the formation of blood clots. Any anomalies in the functioning or levels of Factor VII can result in serious bleeding disorders. Given this critical role, understanding Factor VII's structure, function, mechanism, applications, and clinical significance, is not only important for biological comprehension but also pivotal for diagnosing, treating, and managing diverse conditions associated with blood coagulation.
Structure
Factor VII is a large glycoprotein involving a complex and intricate structure. It is a single-chain protein, composed of 406 amino acids with a molecular weight of about 50,000 Da. The protein is divided into different function-oriented domains, namely, the gamma-carboxyglutamic acid (Gla) domain, two epidermal growth factor-like domains (EGF1 and EGF2), and the catalytic domain housing the active center of the protein. It's noteworthy that the Gla domain houses ten gamma-carboxyglutamic acid residues that enable the protein to bind to phospholipid surfaces, facilitating the activation of Factor VII.
Functions
Factor VII's function is predominantly related to its role in the blood clotting process. In the inactive state, Factor VII circulates in the blood plasma. But, upon vascular injury, Factor VII interacts with tissue factor (a membrane-bound protein) exposed at the injury site, getting converted into its active form, Factor VIIa. This activated Factor VII (Factor VIIa) triggers a cascade of reactions leading to clot formation preventing excessive bleeding.
Applications
In clinical applications, Factor VII plays a significant role. The quantified level of Factor VII in blood can act as an indicator of various disorders. Particularly, deficiencies in Factor VII can lead to rare bleeding disorders. Hence, recombinant Factor VIIa serves as a life-saving medication for patients with hemophilia or inhibitors to Factors VIII or IX. It's used to control and prevent bleeding episodes or as an operative cover. More recently, Factor VII has also been linked with cardiovascular diseases, implying its role beyond blood coagulation.
Mechanism
This mechanism of action is part of the extrinsic pathway of blood coagulation. Factor VIIa binds to tissue factor, forming a complex that activates Factor IX and Factor X. Activated Factor X, in association with Factor V, catalyzes the conversion of prothrombin to thrombin, which then stimulates the transformation of fibrinogen into fibrin, forming a stable blood clot.
Clinical Significance
The clinical significance of Factor VII is equally paramount. Low levels (Factor VII deficiency) can lead to mild to severe bleeding complications. Conversely, elevated levels of Factor VII are associated with an increased risk of thromboembolic events, such as stroke or myocardial infarction. Therefore, levels of Factor VII play a crucial role in the diagnosis, prognosis, and treatment strategies of such disorders.
Conclusion
Factor VII is instrumental in the functioning of the blood clotting cascade, marking it as a pivotal determinant in the realm of haemostatic disorders. The multifaceted significance of Factor VII lies not only in its intricate structural makeup and fundamental mechanisms but also in its varied clinical implications. Understanding the role of Factor VII can contribute significantly to advancements in healthcare, primarily regarding diagnosis, prognosis, and therapeutic design for conditions related to coagulation and beyond.
