WordNet
- a protein in blood plasma that is the inactive precursor of thrombin (同)factor_II
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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2012/09/18 08:46:25」(JST)
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| Coagulation factor II (thrombin) | |||||||||||||
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The structure of human thrombin in complex with the inhibitor hirudin.[1] |
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| Identifiers | |||||||||||||
| Symbols | F2; PT; RPRGL2; THPH1 | ||||||||||||
| External IDs | OMIM: 176930 MGI: 88380 HomoloGene: 426 ChEMBL: 204 GeneCards: F2 Gene | ||||||||||||
| EC number | 3.4.21.5 | ||||||||||||
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| RNA expression pattern | |||||||||||||
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| Orthologs | |||||||||||||
| Species | Human | Mouse | |||||||||||
| Entrez | 2147 | 14061 | |||||||||||
| Ensembl | ENSG00000180210 | ENSMUSG00000027249 | |||||||||||
| UniProt | P00734 | P19221 | |||||||||||
| RefSeq (mRNA) | NM_000506.3 | NM_010168.2 | |||||||||||
| RefSeq (protein) | NP_000497.1 | NP_034298.1 | |||||||||||
| Location (UCSC) | Chr 11: 46.74 – 46.76 Mb |
Chr 2: 91.63 – 91.64 Mb |
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| PubMed search | [1] | [2] | |||||||||||
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Role of thrombin in the blood coagulation cascade
Thrombin is a "trypsin-like" serine protease protein that in humans is encoded by the F2 gene.[2][3] Prothrombin (coagulation factor II) is proteolytically cleaved to form thrombin in the coagulation cascade, which ultimately results in the stemming of blood loss. Thrombin in turn acts as a serine protease that converts soluble fibrinogen into insoluble strands of fibrin, as well as catalyzing many other coagulation-related reactions.
Contents
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History
After the description of fibrinogen and fibrin, Alexander Schmidt hypothesised the existence of an enzyme that converts fibrinogen into fibrin in 1872.[4]
Physiology
Synthesis
Thrombin is produced by the enzymatic cleavage of two sites on prothrombin by activated Factor X (Xa). The activity of factor Xa is greatly enhanced by binding to activated Factor V (Va), termed the prothrombinase complex. 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). In the presence of calcium, the Gla residues promote the binding of prothrombin 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.
In human adults, the normal blood level of antithrombin activity has been measured to be around 1.1 units/mL. Newborn levels of thrombin steadily increase after birth to reach normal adult levels, from a level of around 0.5 units/mL 1 day after birth, to a level of around 0.9 units/mL after 6 months of life.[5]
Mechanism of action
In the blood coagulation pathway, thrombin acts to convert factor XI to XIa, VIII to VIIIa, V to Va, and fibrinogen to fibrin.
Factor XIIIa[clarification needed] is a transglutaminase that catalyzes the formation of covalent bonds between lysine and glutamine residues in fibrin. The covalent bonds increase the stability of the fibrin clot. Thrombin interacts with thrombomodulin.[6][7]
As part of its activity in the coagulation cascade, thrombin also promotes platelet activation and aggregation via activation of protease-activated receptors on the cell membrane of the platelet.
Negative feedback
Thrombin bound to thrombomodulin activates protein C, an inhibitor of the coagulation cascade. The activation of protein C is greatly enhanced following the binding of thrombin to thrombomodulin, an integral membrane protein expressed by endothelial cells. Activated protein C inactivates factors Va and VIIIa. Binding of activated protein C to protein S leads to a modest increase in its activity. Thrombin is also inactivated by antithrombin, a serine protease inhibitor.
Protein
Anchoring of bovine prothrombin to the membrane through its Gla domain.[8]
The molecular weight of prothrombin is approximately 72,000 Da. The catalytic domain is released from prothrombin fragment 1.2 to create the active enzyme thrombin, which has a molecular weight of 36,000 Da.
Gene
The thrombin (prothrombin) gene is located on the eleventh chromosome (11p11-q12).[2]
There are an estimated 30 people in the world that have been diagnosed with the congenital form of Factor II deficiency,[9] which should not be confused with the prothrombin G20210A mutation, which is also called the factor II mutation. Prothrombin G20210A is congenital.[10]
Prothrombin G20210A is not usually accompanied by other factor mutations (i.e., the most common is factor V Leiden). The gene may be inherited heterozygous (1 pair), or much more rarely, homozygous (2 pairs), 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 G20210A or factor V Leiden mutation have been contradicted by research.[11]
Role in disease
Activation of prothrombin is crucial in physiological and pathological coagulation. Various rare diseases involving prothrombin have been described (e.g., hypoprothrombinemia). Anti-prothrombin antibodies in autoimmune disease may be a factor in the formation of the lupus anticoagulant also known as (antiphospholipid syndrome). Hyperprothrombinemia can be caused by the G20210A mutation.
Thrombin, a potent vasoconstrictor and mitogen, is implicated as a major factor in vasospasm following subarachnoid hemorrhage. Blood from a ruptured cerebral aneurysm clots around a cerebral artery, releasing thrombin. This can induce an acute and prolonged narrowing of the blood vessel, potentially resulting in cerebral ischemia and infarction (stroke).
Beyond its key role in the dynamic process of thrombus formation, thrombin has a pronounced pro-inflammatory character, which may influence the onset and progression of atherosclerosis. Acting via its specific cell membrane receptors (protease activated receptors: PAR-1, PAR-3 and PAR-4), which are abundantly expressed in all arterial vessel wall constituents, thrombin has the potential to exert pro-atherogenic actions such as inflammation, leukocyte recruitment into the atherosclerotic plaque, enhanced oxidative stress, migration and proliferation of vascular smooth muscle cells, apoptosis and angiogenesis.[12][13][14]
Applications
Research tool
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. 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.
Medicine and surgery
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. Indications include intractable bleeding due to warfarin.
Manipulation of prothrombin is central to the mode of action of most anticoagulants. Warfarin and related drugs inhibit vitamin K-dependent carboxylation of several coagulation factors, including prothrombin. Heparin increases the affinity of antithrombin to thrombin (as well as factor Xa). The direct thrombin inhibitors, a newer class of medication, directly inhibit thrombin by binding to its active site.
Recombinant thrombin is available as a powder for reconstitution into aqueous solution. It can be applied topically during surgery, as an aid to hemostasis. It can be useful for controlling minor bleeding from capillaries and small venules, but ineffective and not indicated for massive or brisk arterial bleeding.[15][16][17] It is marketed by ZymoGenetics in the US under the trade name Recothrom.
Food production
Thrombin is sold under the brand name Fibrimex for use as a binding agent for meat. The thrombin in Fibrimex derives from pigs or bovine blood.[18] According to the manufacturer it can be used to produce new kinds of mixed meats (for example combining beef and fish seamlessly). The manufacturer also states that it can be used to combine whole muscle meat, form and portion these thus cutting down on production costs without a loss in quality.[19]
General secretary Jan Bertoft of Sveriges Konsumenter (The Consumer Coalition of Sweden) has stated that "there is danger of misleading the consumers since there is no way to tell this reconstituted meat from real meat"[18]
See also
- The Proteolysis Map
- Fibrin glue
References
- ^ PDB 2C93; Howard N, Abell C, Blakemore W, Chessari G, Congreve M, Howard S, Jhoti H, Murray CW, Seavers LC, van Montfort RL (February 2006). "Application of fragment screening and fragment linking to the discovery of novel thrombin inhibitors". J. Med. Chem. 49 (4): 1346–55. doi:10.1021/jm050850v. PMID 16480269.
- ^ a b Royle NJ, Irwin DM, Koschinsky ML, MacGillivray RT, Hamerton JL (May 1987). "Human genes encoding prothrombin and ceruloplasmin map to 11p11-q12 and 3q21-24, respectively". Somat. Cell Mol. Genet. 13 (3): 285–92. doi:10.1007/BF01535211. PMID 3474786.
- ^ Degen SJ, Davie EW (September 1987). "Nucleotide sequence of the gene for human prothrombin". Biochemistry 26 (19): 6165–77. doi:10.1021/bi00393a033. PMID 2825773.
- ^ Schmidt A (1872). "Neue Untersuchungen ueber die Fasserstoffesgerinnung". Pflüger's Archiv für die gesamte Physiologie 6: 413–538. doi:10.1007/BF01612263.
- ^ Andrew M, Paes B et al. (1987). "Development of the human coagulation system in the full-term infant". Blood 70 (1): 165–172. PMID 3593964.
- ^ Bajzar L, Morser J, Nesheim M (July 1996). "TAFI, or plasma procarboxypeptidase B, couples the coagulation and fibrinolytic cascades through the thrombin-thrombomodulin complex". J. Biol. Chem. 271 (28): 16603–8. doi:10.1074/jbc.271.28.16603. PMID 8663147.
- ^ Jakubowski HV, Owen WG (July 1989). "Macromolecular specificity determinants on thrombin for fibrinogen and thrombomodulin". J. Biol. Chem. 264 (19): 11117–21. PMID 2544585.
- ^ PDB 1nl2; Huang M, Rigby AC, Morelli X, Grant MA, Huang G, Furie B, Seaton B, Furie BC (September 2003). "Structural basis of membrane binding by Gla domains of vitamin K-dependent proteins". Nat. Struct. Biol. 10 (9): 751–6. doi:10.1038/nsb971. PMID 12923575.
- ^ Degen SJ, McDowell SA, Sparks LM, Scharrer I (February 1995). "Prothrombin Frankfurt: a dysfunctional prothrombin characterized by substitution of Glu-466 by Ala". Thromb. Haemost. 73 (2): 203–9. PMID 7792730.
- ^ Varga EA, Moll S (July 2004). "Cardiology patient pages. Prothrombin 20210 mutation (factor II mutation)". Circulation 110 (3): e15–8. doi:10.1161/01.CIR.0000135582.53444.87. PMID 15262854.
- ^ Bernstein CN, Sargent M, et al. (2007). "Mutations in clotting factors and inflammatory bowel disease". Am. J. Gastroenterol. 102 (2): 338–343. doi:10.1111/j.1572-0241.2006.00974.x. PMID 17156138.
- ^ Borissoff JI, Spronk HM, Heeneman S, ten Cate H. Is thrombin a key player in the 'coagulation-atherogenesis' maze? Cardiovasc Res. 2009;82(3):392-403. PMID19228706.http://cardiovascres.oxfordjournals.org/content/82/3/392.long
- ^ Borissoff JI, Heeneman S, Kilinc E, Kassak P, Van Oerle R, Winckers K, Govers-Riemslag JW, Hamulyak K, Hackeng TM, Daemen MJ, ten Cate H, Spronk HM. Early atherosclerosis exhibits an enhanced procoagulant state. Circulation. 2010;122(8):821-830. PMID20697022. http://circ.ahajournals.org/cgi/content/full/122/8/821
- ^ Borissoff JI, Spronk HM, ten Cate H. The hemostatic system as a modulator of atherosclerosis. N Engl J Med. 2011;364(18):1746-1760. PMID21542745. http://www.nejm.org/doi/full/10.1056/NEJMra1011670
- ^ Chapman WC, Singla N, Genyk Y, McNeil JW, Renkens KL, Reynolds TC, Murphy A, Weaver FA (August 2007). "A phase 3, randomized, double-blind comparative study of the efficacy and safety of topical recombinant human thrombin and bovine thrombin in surgical hemostasis". J. Am. Coll. Surg. 205 (2): 256–65. doi:10.1016/j.jamcollsurg.2007.03.020. PMID 17660072.
- ^ Singla NK, Ballard JL, Moneta G, Randleman CD, Renkens KL, Alexander WA (July 2009). "A phase 3b, open-label, single-group immunogenicity and safety study of topical recombinant thrombin in surgical hemostasis". J. Am. Coll. Surg. 209 (1): 68–74. doi:10.1016/j.jamcollsurg.2009.03.016. PMID 19651065.
- ^ Greenhalgh DG, Gamelli RL, Collins J, Sood R, Mozingo DW, Gray TE, Alexander WA (2009). "Recombinant thrombin: safety and immunogenicity in burn wound excision and grafting". J Burn Care Res 30 (3): 371–9. doi:10.1097/BCR.0b013e3181a28979. PMID 19349898.
- ^ a b "Sverige röstade ja till köttklister [Sweden voted in favor of the meat paste]" (in Swedish). Dagens Nyheter. 2010-02-09. http://www.dn.se/nyheter/politik/sverige-rostade-ja-till-kottklister-1.1042136. Retrieved 2010-10-17.
- ^ "Welcome to Fibrimex". Fibrimex website. FX Technology. http://www.fibrimex.com. Retrieved 2010-10-17.
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:10.1042/BST0300173. 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:10.1042/BST0300211. PMID 12023853.
- Firth SM, Baxter RC (2003). "Cellular actions of the insulin-like growth factor binding proteins". Endocr. Rev 23 (6): 824–54. doi:10.1210/er.2001-0033. 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:10.1161/01.ATV.0000099880.09014.7D. 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:10.1023/B:THRO.0000011370.80989.7b. PMID 14739624.
- Tsopanoglou NE, Maragoudakis ME (2004). "Role of thrombin in angiogenesis and tumor progression". Semin. Thromb. Hemost 30 (1): 63–9. doi:10.1055/s-2004-822971. PMID 15034798.
- Bode W (2007). "Structure and interaction modes of thrombin". Blood Cells Mol. Dis 36 (2): 122–30. doi:10.1016/j.bcmd.2005.12.027. PMID 16480903.
- Wolberg AS (2007). "Thrombin generation and fibrin clot structure". Blood Rev 21 (3): 131–42. doi:10.1016/j.blre.2006.11.001. PMID 17208341.
- Degen S: Prothrombin. In: High K, Roberts H, eds. Molecular Basis of Thrombosis and Hemostasis. New York, NY: Marcel Dekker; 1995:75.
External links
- The MEROPS online database for peptidases and their inhibitors: S01.217
- GeneReviews/NCBI/NIH/UW entry on Prothrombin Thrombophilia
- [3] Anti-coagulation & proteases by The Proteolysis Map-animation
- [4] PMAP: The Proteolysis Map/Thrombin
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UpToDate Contents
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- 1. Prothrombin gene mutation: Thrombotic risk and diagnosis
- 2. 凝固検査の臨床使用 clinical use of coagulation tests
- 3. 肝臓の合成能の検査（アルブミン、凝固因子、プロトロンビン時間など） tests of the livers biosynthetic capacity eg albumin coagulation factors prothrombin time
- 4. 出血性素因を有する成人患者へのアプローチ approach to the adult patient with a bleeding diathesis
- 5. 肝疾患患者における凝固異常 coagulation abnormalities in patients with liver disease
English Journal
- Acute and sub-chronic oral toxicity profiles of lipopeptides from Bacillus mojavensis A21 and evaluation of their in vitro anticoagulant activity.
- Ben Ayed H1, Nasri R2, Jemil N2, Ben Amor I3, Gargouri J3, Hmidet N2, Nasri M2.
- Chemico-biological interactions.Chem Biol Interact.2015 Jul 5;236:1-6. doi: 10.1016/j.cbi.2015.04.018. Epub 2015 Apr 24.
- The aim of the present study was to evaluate the acute and sub-chronic toxicity of lipopeptides mixture produced by Bacillus mojavensis A21 as well as their in vitro anticoagulant activity. A21 lipopeptides was given to mice at single dose from 75mg to 1000mg/kg body weight (bw). The median lethal d
- PMID 25912554
- Hemostatic resuscitation in postpartum hemorrhage - a supplement to surgery.
- Ekelund K1, Hanke G1, Stensballe J2,3, Wikkelsøe A4, Albrechtsen CK1, Afshari A1.
- Acta obstetricia et gynecologica Scandinavica.Acta Obstet Gynecol Scand.2015 Jul;94(7):680-92. doi: 10.1111/aogs.12607. Epub 2015 Mar 5.
- BACKGROUND: Postpartum hemorrhage is a potentially life-threatening albeit preventable condition that persists as a leading cause of maternal death. Identification of safe and cost-effective hemostatic treatment options remains crucial as a supplement to surgery and uterotonic agents.OBJECTIVE: This
- PMID 25660118
- Is there any association between thrombosis and tissue factor pathway inhibitor levels in patients with vitamin d deficiency?
- Topaloglu O1, Arslan MS2, Karakose M2, Ucan B2, Ginis Z3, Cakir E2, Akkaymak ET2, Sahin M4, Ozbek M2, Cakal E2, Delibasi T2.
- Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis.Clin Appl Thromb Hemost.2015 Jul;21(5):428-33. doi: 10.1177/1076029613509477. Epub 2013 Nov 6.
- OBJECTIVE: The aim of this study was to evaluate the relationship between vitamin D levels and hemostatic factors like tissue factor pathway inhibitor (TFPI).METHODS: Patients who had 25-hydroxyvitamin D3 (25(OH)D3) levels measured were included. Coagulation and hemostatic parameters were evaluated.
- PMID 24203351
Japanese Journal
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- 中村 郁代,佐藤 美弥子,大向 香織,長沼 未加
- アプライド・セラピューティクス 11(0), 60-66, 2019
- ワルファリンは相互作用が多い薬剤であり、服用期間中のPT-INRのモニタリングが重要である。今回、心臓移植へのブリッジ（以下、BTT）として補助人工心臓（以下、VAD）を装着している患者1名について、薬剤師としてPT-INRモニタリングおよびVAD装着後のサポートを行ったので報告する。患者は、20XX年より当薬局へ来局し、20XX+12年に心臓移植を登録、その4ヶ月後にVADを装着したのち20XX …
- NAID 130007629766
- 後天性血友病A患者に対して凝固第Ⅶ因子補充療法を行うも重篤な抜歯後口腔咽頭喉頭血腫を生じた1例
- 武田 大介,小松原 秀紀,古森 孝英
- 日本口腔外科学会雑誌 65(1), 10-15, 2019
- … <p>Bypass therapy using recombinant activated factor Ⅶ (rFⅦa) or activated prothrombin complex concentrate (APCC) is effective for hemostatic treatment in acquired hemophilia A. …
- NAID 130007617131
- A Retrospective Analysis of the Effect of Tigecycline on Coagulation Function
- Leng Bing,Xue Yuan Chao,Zhang Wen,Gao Tian tian,Yan Gen quan,Tang Hui
- ＣＨＥＭＩＣＡＬ ＆ ＰＨＡＲＭＡＣＥＵＴＩＣＡＬ ＢＵＬＬＥＴＩＮ 67(3), 258-264, 2019
- … Coagulation parameters, including Fibrinogen (FIB) levels, prothrombin time (PT), activated partial thromboplastin time (aPTT), platelet count (PLT) and D-dimer, were evaluated in order to assess the impact of tigecycline treatment in these severely infected patients. …
- NAID 130007606832
Related Links
- prothrombin [pro-throm´bin] a glycoprotein present in the plasma that is converted into thrombin by extrinsic thromboplastin during the second stage of blood clotting; called also factor II. prothrombin consumption a clinical laboratory ...
- prothrombinとは。意味や和訳。[名詞] 〔生化学〕 プロトロンビン：血液凝固に関与する血漿けっしょうタンパク質；血漿中の因子によって活性化しトロンビンとなる；thrombogen ともいう.[語源]1898.PRO-1+THROMBIN - 80万項目以上 ...
Related Pictures
★リンクテーブル★
| リンク元 | 「プロトロンビン」 |
| 拡張検索 | 「prothrombinase」「hypoprothrombinemia」「prothrombin deficiency」「prothrombin time ratio」 |
「プロトロンビン」
- 英
- prothrombin
- 同
- 第II因子 factor II
- 関
- 血液凝固因子
概念
- 凝固系の共通経路に位置する
- 肝臓でビタミンK依存的に産生される
- Xa、Ca2+、V の作用によりプロトロンビンはトロンビンとなり、セリンプロテアーゼとして機能する。
- 分子量：72kDa
- 半減期：60-100hr
検査
- 基準値：(血漿)100-150 ug/ml
プロトロンビンが関与する検査値
「prothrombinase」