Thrombin (activated Factor II [IIa]) is a coagulation protein that has many effects in the coagulation cascade. The Human Genome Organisation (HUGO is an organization involved in the Human Genome Project, a project about mapping the human genome The Mouse Genome Informatics (MGI website is run by The Jackson Laboratory. HomoloGene, a tool of the National Center for Biotechnology Information (NCBI is a system for automated detection of homologs (similarity attributable to descent The Entrez Global Query Cross-Database Search System is a powerful Federated search engine or Web portal that allows users to search many discrete Health sciences Ensembl is a joint scientific project between the European Bioinformatics Institute and the Wellcome Trust Sanger Institute, which was launched in 1999 in response to the imminent UniProt is the uni versal prot ein resource a central repository of Protein data created by combining Swiss-Prot, TrEMBL PubMed is a free search engine for accessing the MEDLINE database of citations and abstracts of biomedical research articles Coagulation is a complex process by which Blood forms Clots It is an important part of Hemostasis (the cessation of blood loss from a damaged vessel whereby Coagulation is a complex process by which Blood forms Clots It is an important part of Hemostasis (the cessation of blood loss from a damaged vessel whereby It is a serine protease (EC 3.4.21.5) that converts soluble fibrinogen into insoluble strands of fibrin, as well as catalyzing many other coagulation-related reactions. Serine proteases or serine endopeptidases (newer name are Proteases ( Enzymes that cut Peptide bonds in Proteins in which one of This article is about the Enzyme Commission codes For the European Commission system for coding chemicals see EC-No. Fibrin (also called Factor Ia) is a Protein involved in the clotting of blood Fibrin (also called Factor Ia) is a Protein involved in the clotting of blood
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Genetics
The prothrombin gene is located on the eleventh chromosome (11p11-q12). History See also History of genetics The existence of genes was first suggested by Gregor Mendel (1822-1884 who in the 1860s studied inheritance A chromosome is an organized structure of DNA and Protein that is found in cells. The molecular weight of prothrombin is approximately 72000mol-1; in contrast, the molecular weight of thrombin is 36000mol-1. Once activated, the catalytic domain of prothrombin is released from prothrombin fragment 1. 2. There are an estimated 30 people in the world that have been diagnosed with the congenital form of Factor II deficiency (Degen, 1995)[3], which should not be confused with a mutation of prothrombin. The prothrombin gene mutation is called Factor II mutation. Factor II mutation is congenital. [4] The Factor II mutated gene is not usually accompanied by other factor mutations (i. e. the most common is Factor V Leiden). The gene may be inherited heterozygous, or much more rarely, homozygous, and is not related to gender or blood type. Homozygous mutations increase the risk of thrombosis more than heterozygous mutations, but the relative increased risk is not well documented. Other potential risks for thrombosis, such as oral contraceptives may be additive. The previously reported relationship of inflammatory bowel disease (i. e. Crohn's disease or Ulcerative Colitis) and prothrombin mutation or Factor V Leiden mutation have been contradicted by research. [5]
Physiology
Generation
Thrombin is produced by the enzymatic cleavage of two sites on prothrombin by activated Factor X (Xa). Vitamin K-dependent carboxylation/gamma-carboxyglutamic (GLA domain is a Protein domain that contains post-translational modifications ofmany glutamate residues by Factor X, also known by the Eponym Stuart-Prower factor or as thrombokinase, is an Enzyme ( of the coagulation cascade. The activity of factor Xa is greatly enhanced by binding to activated Factor V (Va), termed the prothrombinase complex. Factor V is a Protein of the Coagulation system rarely referred to as proaccelerin or labile factor. Prothrombin is produced in the liver and is post-translationally modified in a vitamin K-dependent reaction that converts ten glutamic acids on prothrombin to gamma-carboxyglutamic acid (Gla). Vitamin K (K from "Koagulations-Vitamin" in German Danish Swedish and Norwegian denotes a group of Lipophilic, Hydrophobic Vitamins that In the presence of calcium, the Gla residues promote the binding of thrombin to phospholipid bilayers (see the picture). Deficiency of vitamin K or administration of the anticoagulant warfarin inhibits the production of gamma-carboxyglutamic acid residues, slowing the activation of the coagulation cascade. Warfarin (also known under the brand names Coumadin, Jantoven, Marevan, and Waran) is an Anticoagulant.
In human beings the level prothrombin in the blood stream increases after birth and typically peaks on the 8th day after which the prothrombin level lowers to normal levels. [1]
Action
Thrombin converts fibrinogen to an active form that assembles into fibrin. Thrombin also activates factor XI, factor V, and factor VIII. Factor XI or plasma thromboplastin antecedent is one of the Enzymes of the coagulation cascade. Factor V is a Protein of the Coagulation system rarely referred to as proaccelerin or labile factor. Factor VIII (FVIII is an essential Clotting factor A deficiency of FVIII causes Hemophilia A, a bleeding disorder This positive feedback accelerates the production of thrombin.
Factor XIII is also activated by thrombin. Factor XIII or fibrin stabilizing factor is an Enzyme ( of the blood coagulation system that crosslinks Fibrin. Factor XIIIa is a transglutaminase that catalyzes the formation of covalent bonds between lysine and glutamine residues in fibrin. Transglutaminases are a family of Enzymes ( that Catalyze the formation of a Covalent bond between a free amine group (e The covalent bonds increase the stability of the fibrin clot.
Platelets
In addition to its activity in the coagulation cascades, thrombin also promotes platelet activation, via activation of protease-activated receptors on the platelet. Platelets, or Thrombocytes, are small cytoplasmic bodies derived from cells They circulate in the Blood of Mammals and are involved Protease-activated receptor s are a subfamily of related G protein-coupled receptors that are activated by cleavage of part of their extracellular domain
Negative feedback
Thrombin activates protein C, an inhibitor of the coagulation cascade. Protein C is a major physiological Anticoagulant. It is a Vitamin K -dependent Serine protease Enzyme ( that is activated by Thrombin The activation of protein C is greatly enhanced following the binding of thrombin to thrombomodulin, an integral membrane protein expressed by endothelial cells. Thrombomodulin, CD 141 or BDCA-3 is an Integral membrane protein expressed on the surface of endothelial cells The endothelium is the thin layer of cells that line the interior surface of Blood vessels forming an interface between circulating Blood in the Activated protein C inactivates factors Va and VIIIa. Binding of activated protein C to protein S leads to a modest increase in its activity.
Role in disease
Activation of prothrombin is crucial in physiological and pathological coagulation. Various rare diseases involving prothrombin have been described (e. g. , hypoprothrombinemia). Hypoprothrombinemia is a blood disorder in which a deficiency of prothrombin ( Factor II) results in impaired blood clotting, leading to an increased physiological Anti-thrombin antibodies in autoimmune disease may be a factor in the formation of the lupus anticoagulant. Anti-thrombin antibodies are autoantibodies directed against Thrombin that may constitute a fraction of Lupus anticoagulant and are seen an increased levels in Autoimmune diseases arise from an overactive Immune response of the body against substances and tissues normally present in the body Lupus anticoagulant (also known as lupus antibody, LA, or lupus inhibitors) is a medical phenomenon where autoantibodies bind to Phospholipids
Prothrombin 20210a mutation
Substitution of adenine for guanine at position 20210 of the prothrombin gene, known as the prothrombin 20210a mutation, prothrombin 20210 mutation and, less precise, just factor II mutation,[2][3] leads to hypercoagulability and may be a factor that contributes to infertility. Adenine is a Purine with a variety of roles in Biochemistry including Cellular respiration, in the form of both the energy-rich Adenosine Guanine is one of the five main Nucleobases found in the Nucleic acids DNA and RNA, the others being Adenine, Cytosine, Thrombophilia is the propensity to develop Thrombosis (blood clots due to an abnormality in the system of Coagulation. Female infertility|Male infertility Infertility primarily refers to the biological inability of a Man or a Woman to contribute to conception. Its prevalence is thought to be approximately 2% in caucasians and 0. 5% in blacks. [3]
Position 20210 falls outside of the reading frame for the protein and is thought to play a role in promoting prothrombin production; the substitution leads to high levels of prothrombin. In Biology, a reading frame is a contiguous and non-overlapping set of three- Nucleotide Codons in DNA or RNA. In Biology, a promoter is a region of DNA that facilitates the transcription of a particular Gene. [4]
Biotechnology
Due to its high proteolytic specificity, thrombin is a valuable biochemical tool. The thrombin cleavage site (Leu-Val-Pro-Arg-Gly-Ser) is commonly included in linker regions of recombinant fusion protein constructs. Fusion proteins, also known as chimeric proteins, are proteins created through the joining of two or more Genes which originally coded for separate proteins Following purification of the fusion protein, thrombin can be used to selectively cleave between the Arginine and Glycine residues of the cleavage site, effectively removing the purification tag from the protein of interest with a high degree of specificity. Protein tags are peptide sequences genetically grafted onto a recombinant protein
Pharmacology
Prothrombin complex concentrate and fresh frozen plasma are prothrombin-rich coagulation factor preparations that can be used to correct deficiencies (usually due to medication) of prothrombin. Prothrombin Complex Concentrate (PCC is a combination of blood Clotting factors II VII IX and X Fresh Frozen Plasma ( FFP) is defined as the fluid portion of one unit of Human blood that has been centrifuged separated and frozen solid at -18° C (or colder Indications include intractable bleeding due to warfarin. Warfarin (also known under the brand names Coumadin, Jantoven, Marevan, and Waran) is an Anticoagulant.
Manipulation of prothrombin is central to the mode of action of most anticoagulants. An anticoagulant is a substance that prevents coagulation; that is it stops Blood from clotting Warfarin and related drugs inhibit vitamin K-dependent carboxylation of several coagulation factors, including prothrombin. Warfarin (also known under the brand names Coumadin, Jantoven, Marevan, and Waran) is an Anticoagulant. Vitamin K (K from "Koagulations-Vitamin" in German Danish Swedish and Norwegian denotes a group of Lipophilic, Hydrophobic Vitamins that Heparin increases the affinity of antithrombin to thrombin (as well as factor Xa). Heparin, a highly-sulfated Glycosaminoglycan, is widely used as an injectable Anticoagulant and has the highest negative Charge density of any known Antithrombin (AT is a small protein molecule that inactivates several enzymes of the Coagulation system Factor X, also known by the Eponym Stuart-Prower factor or as thrombokinase, is an Enzyme ( of the coagulation cascade. The direct thrombin inhibitors, a newer class of medication, directly inhibit thrombin by binding to its active site. Direct thrombin inhibitors (DTIs are a class of Medication that act as Anticoagulants (delaying blood clotting) by directly inhibiting the Enzyme
History
After the description of fibrinogen and fibrin, Alexander Schmidt hypothesised the existence of an enzyme that converts fibrinogen into fibrin in 1872. Fibrin (also called Factor Ia) is a Protein involved in the clotting of blood Alexander Schmidt ( 1831 - April 22, 1894) was a Physiologist who was born on the Island of Mohn which today is called Muhu, [5]
References
- ^ McMillen, S. I. (1984), None of These Diseases (Old Tappan, NJ: Revell)
- ^ Steen CJ. Factor II. eMedicine. com. URL: http://www.emedicine.com/med/topic3494.htm. Accessed on: March 11, 2007.
- ^ a b Varga E, Moll S (2004). "Cardiology patient pages. Prothrombin 20210 mutation (factor II mutation)". Circulation 110 (3): e15-8. PMID 15262854. Free Full Text.
- ^ Poort S, Rosendaal F, Reitsma P, Bertina R (1996). "A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis". Blood 88 (10): 3698-703. PMID 8916933.
- ^ Schmidt A (1872). "Neue Untersuchungen ueber die Fasserstoffesgerinnung". Pflüger's Archiv für die gesamte Physiologie 6: 413-538.
Further reading
- Esmon CT (1995). "Thrombomodulin as a model of molecular mechanisms that modulate protease specificity and function at the vessel surface. ". FASEB J. 9 (10): 946-55. PMID 7615164.
- Lenting PJ, van Mourik JA, Mertens K (1999). "The life cycle of coagulation factor VIII in view of its structure and function. ". Blood 92 (11): 3983-96. PMID 9834200.
- Plow EF, Cierniewski CS, Xiao Z, et al. (2002). "AlphaIIbbeta3 and its antagonism at the new millennium. ". Thromb. Haemost. 86 (1): 34-40. PMID 11487023.
- Maragoudakis ME, Tsopanoglou NE, Andriopoulou P (2002). "Mechanism of thrombin-induced angiogenesis. ". Biochem. Soc. Trans. 30 (2): 173-7. doi:. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 12023846.
- Howell DC, Laurent GJ, Chambers RC (2002). "Role of thrombin and its major cellular receptor, protease-activated receptor-1, in pulmonary fibrosis. ". Biochem. Soc. Trans. 30 (2): 211-6. doi:. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 12023853.
- Firth SM, Baxter RC (2003). "Cellular actions of the insulin-like growth factor binding proteins. ". Endocr. Rev. 23 (6): 824-54. PMID 12466191.
- Minami T, Sugiyama A, Wu SQ, et al. (2004). "Thrombin and phenotypic modulation of the endothelium. ". Arterioscler. Thromb. Vasc. Biol. 24 (1): 41-53. doi:. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 14551154.
- De Cristofaro R, De Candia E (2004). "Thrombin domains: structure, function and interaction with platelet receptors. ". J. Thromb. Thrombolysis 15 (3): 151-63. doi:. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 14739624.
- Tsopanoglou NE, Maragoudakis ME (2004). "Role of thrombin in angiogenesis and tumor progression. ". Semin. Thromb. Hemost. 30 (1): 63-9. doi:. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 15034798.
- Bode W (2007). "Structure and interaction modes of thrombin. ". Blood Cells Mol. Dis. 36 (2): 122-30. doi:. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 16480903.
- Wolberg AS (2007). "Thrombin generation and fibrin clot structure. ". Blood Rev. 21 (3): 131-42. doi:. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 17208341.
- Degen S: Prothrombin. In: High K, Roberts H, eds. Molecular Basis of Thrombosis and Hemostasis. New York, NY: Marcel Dekker; 1995:75.
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