Thrombin


Thrombin
Coagulation factor II (thrombin)

The structure of human thrombin in complex with the inhibitor hirudin.[1]
Identifiers
Symbols F2; PT
External IDs OMIM176930 MGI88380 HomoloGene426 GeneCards: F2 Gene
EC number 3.4.21.5
RNA expression pattern
PBB GE F2 205754 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 2147 14061
Ensembl ENSG00000180210 ENSMUSG00000027249
UniProt P00734 Q3TJ94
RefSeq (mRNA) NM_000506 NM_010168
RefSeq (protein) NP_000497 NP_034298
Location (UCSC) Chr 11:
46.7 – 46.72 Mb
Chr 2:
91.43 – 91.44 Mb
PubMed search [1] [2]
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 first step of 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

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 a mutation of prothrombin. The prothrombin gene mutation is called Factor II mutation. Factor II mutation is congenital.[10]

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 (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 mutation 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 a mutation at 20210a.

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 scrap meat into whole steaks that can then be sold to a higher price, thus cutting down on production costs.[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

  1. ^ 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. 
  2. ^ 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. 
  3. ^ 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. 
  4. ^ Schmidt A (1872). "Neue Untersuchungen ueber die Fasserstoffesgerinnung". Pflüger's Archiv für die gesamte Physiologie 6: 413–538. doi:10.1007/BF01612263. 
  5. ^ 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. 
  6. ^ 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. 
  7. ^ Jakubowski HV, Owen WG (July 1989). "Macromolecular specificity determinants on thrombin for fibrinogen and thrombomodulin". J. Biol. Chem. 264 (19): 11117–21. PMID 2544585. 
  8. ^ 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. 
  9. ^ 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. 
  10. ^ 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. 
  11. ^ 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. 
  12. ^ 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
  13. ^ 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
  14. ^ 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
  15. ^ 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. 
  16. ^ 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. 
  17. ^ 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. 
  18. ^ 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. 
  19. ^ "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


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Look at other dictionaries:

  • Thrombin — Vorhandene Strukturdaten: siehe UniProt Eintrag …   Deutsch Wikipedia

  • Thrombin — Throm bin, n. [See {Thrombus}.] (Biochem.) The enzyme which converts fibrinogen into fibrin. [Webster 1913 Suppl. +PJC] [1913 Webster] …   The Collaborative International Dictionary of English

  • thrombin — thrombin. См. тромбин. (Источник: «Англо русский толковый словарь генетических терминов». Арефьев В.А., Лисовенко Л.А., Москва: Изд во ВНИРО, 1995 г.) …   Молекулярная биология и генетика. Толковый словарь.

  • Thrombīn — Thrombīn, s. Fibrin …   Meyers Großes Konversations-Lexikon

  • Thrombin — Thrombin, Serinprotease, die die reversible Umwandlung von Fibrinogen in Fibrin bewirkt, indem sie Fibrinogen in Peptide, Kohlenhydrate und Fibrinmonomere, die polymerisieren, zerlegt; wird aus dem in der Leber unter Mitwirkung von Vitamin K… …   Deutsch wörterbuch der biologie

  • thrombin — [thräm′bin] n. [ THROMB(US) + IN1] the enzyme of the blood, formed from prothrombin, that causes clotting by converting fibrinogen to fibrin …   English World dictionary

  • Thrombin — A key clot promoter, thrombin is an enzyme that presides over the conversion of a substance called fibrinogen to fibrin, the right stuff for a clot. * * * 1. An enzyme (proteinase), formed in shed blood, that converts fibrinogen into fibrin by… …   Medical dictionary

  • Thrombin — trombinas statusas T sritis ekologija ir aplinkotyra apibrėžtis Hidrolazių klasės fermentas – kraujo krešėjimo reakcijos fermentas, fibrinogeną verčiantis fibrinu. atitikmenys: angl. prothrombin; thrombin; thrombosin vok. Thrombin, n;… …   Ekologijos terminų aiškinamasis žodynas

  • thrombin — trombinas statusas T sritis ekologija ir aplinkotyra apibrėžtis Hidrolazių klasės fermentas – kraujo krešėjimo reakcijos fermentas, fibrinogeną verčiantis fibrinu. atitikmenys: angl. prothrombin; thrombin; thrombosin vok. Thrombin, n;… …   Ekologijos terminų aiškinamasis žodynas

  • thrombin — Protease (34 kD) generated in blood clotting that acts on fibrinogen to produce fibrin. Consists of two chains, A and B, linked by a disulphide bond. B chain has sequence homology with pancreatic serine proteases: cleaves at Arg Gly. Thrombin is… …   Dictionary of molecular biology


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