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Thrombin (EC188.8.131.52, fibrinogenase, thrombase, thrombofort, topical, thrombin-C, tropostasin, activated blood-coagulation factor II, blood-coagulation factor IIa, factor IIa, E thrombin, beta-thrombin, gamma-thrombin) is a serine protease that in humans is encoded by the F2gene.23Prothrombin (coagulation factor II) is proteolytically cleaved to form thrombin in the coagulation cascade, which ultimately results in the reduction 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.
After the description of fibrinogen and fibrin, Alexander Schmidt hypothesised the existence of an enzyme that converts fibrinogen into fibrin in 1872.4
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
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.
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.
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. Structurally, it is a member of the large PA clan of proteases.
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
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.121314
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.
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.151617
Thrombin is sold under the brand name Fibrimex for use as a binding agent for meat. The thrombin in Fibrimex derives from porcine 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 Swedish Consumers' Association has stated that "there is danger of misleading the consumers since there is no way to tell this reconstituted meat from real meat"18
^PDB2C93; 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. PMID16480269.
^Schmidt A (1872). "Neue Untersuchungen ueber die Fasserstoffesgerinnung". Pflüger's Archiv für die gesamte Physiologie6: 413–538. doi:10.1007/BF01612263.
^Andrew M, Paes B et al. (1987). "Development of the human coagulation system in the full-term infant". Blood70 (1): 165–172. PMID3593964.
^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. PMID8663147.
^Jakubowski HV, Owen WG (July 1989). "Macromolecular specificity determinants on thrombin for fibrinogen and thrombomodulin". J. Biol. Chem.264 (19): 11117–21. PMID2544585.
^PDB1nl2; 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. PMID12923575.
^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. PMID7792730.
^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. PMID17660072.
^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. PMID19651065.
^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 Res30 (3): 371–9. doi:10.1097/BCR.0b013e3181a28979. PMID19349898.