View source for Thrombin

{{Short description|Enzyme involved in blood coagulation in humans}}
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[[File:Coagulation full.svg|thumb|360px|alt=Schematic diagram of the blood coagulation and [[protein C]] pathways. In the blood coagulation pathway, thrombin acts to convert factor XI to XIa, VIII to VIIIa V to Va, fibrinogen to fibrin. In addition, thrombin promotes platelet activation and aggregation via activation of protease-activated receptors on the cell membrane of the platelet. Thrombin also cross over into the protein C pathway by converting protein C into APC. APC in turn converts factor V into Vi, and VIIIa into VIIIi. Finally APC activates PAR-1 and EPCR.|Role of thrombin in the blood coagulation cascade]]

'''Prothrombin''' ('''coagulation factor II''') is encoded in the human by the F2-gene. It is [[Proteolysis|proteolytically]] cleaved during the [[Coagulation#Coagulation cascade|clotting process]] by the [[prothrombinase]] enzyme complex to form thrombin. 

'''Thrombin''' ('''Factor IIa''') ({{EC number|3.4.21.5}}, fibrose, thrombase, thrombofort, topical, thrombin-C, tropostasin, activated blood-coagulation factor II, E thrombin, beta-thrombin, gamma-thrombin) is a [[serine protease]], that converts fibrinogen into strands of insoluble [[fibrin]], as well as catalyzing many other coagulation-related reactions.<ref name="pmid3474786">{{cite journal | vauthors = Royle NJ, Irwin DM, Koschinsky ML, MacGillivray RT, Hamerton JL |title = Human genes encoding prothrombin and ceruloplasmin map to 11p11-q12 and 3q21-24, respectively |journal = Somatic Cell and Molecular Genetics |volume = 13 |issue = 3 |pages = 285–92 |date = May 1987 |pmid = 3474786 |doi = 10.1007/BF01535211 |s2cid = 45686258 }}</ref><ref name="pmid2825773">{{cite journal |vauthors = Degen SJ, Davie EW |title = Nucleotide sequence of the gene for human prothrombin |journal = Biochemistry |volume = 26 |issue = 19 |pages = 6165–77 |date = September 1987 |pmid = 2825773 |doi = 10.1021/bi00393a033 }}</ref>

==History==
After the description of fibrinogen and fibrin, [[Alexander Schmidt (physiologist)|Alexander Schmidt]] hypothesised the existence of an enzyme that converts fibrinogen into fibrin in 1872.<ref>{{cite journal|author=Schmidt A|year=1872|title=Neue Untersuchungen ueber die Fasserstoffesgerinnung|journal=Pflügers Archiv für die gesamte Physiologie|volume=6|pages=413–538|doi=10.1007/BF01612263|s2cid=37273997}}</ref>

Prothrombin was discovered by [[Cornelis Adrianus Pekelharing|Pekelharing]] in 1894.<ref>{{cite book | vauthors = Kaushansky K, Lichtman M, Prchal J, Levi M, Press O, Burns L, Caligiuri M |title=Williams Hematology |date=2015 |publisher=McGraw-Hill |page=1918 |isbn=9780071833011}}</ref><ref>{{cite book | vauthors = Quick AJ |title=Hemorrhagic Diseases |date=1957 |publisher=Lea and Febiger |location=Philadelphia |pages=451–490 |oclc=599096191}}</ref><ref>{{cite journal | vauthors = Morawitz P |title=Die Chemie der Blutgerinnung |journal=Ergeb Physiol |date=1905 |volume=4 |pages=307–422|doi=10.1007/BF02321003 |s2cid=84003009 }}</ref>

==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 co-translationally modified in a [[vitamin K]]-dependent reaction that converts 10-12 [[glutamic acid]]s in the N terminus of the molecule to [[gamma-carboxyglutamic acid]] (Gla).<ref name="pmid22649613">{{cite journal | vauthors = Knorre DG, Kudryashova NV, Godovikova TS | title = Chemical and functional aspects of posttranslational modification of proteins | journal = Acta Naturae | volume = 1 | issue = 3 | pages = 29–51 | date = October 2009 | pmid = 22649613 | pmc = 3347534 | doi = 10.32607/20758251-2009-1-3-29-51 }}</ref> In the presence of calcium, the Gla residues promote the binding of prothrombin to phospholipid bilayers. 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.<ref>{{cite journal | vauthors = Andrew M, Paes B, Milner R, Johnston M, Mitchell L, Tollefsen DM, Powers P | title = Development of the human coagulation system in the full-term infant | journal = Blood | volume = 70 | issue = 1 | pages = 165–72 | date = July 1987 | pmid = 3593964 | doi = 10.1182/blood.V70.1.165.165 | doi-access = free }}</ref>

===Mechanism of action===
In the blood coagulation pathway, thrombin acts to convert [[factor XI]] to XIa, [[factor VIII|VIII]] to VIIIa, [[factor V|V]] to Va, [[fibrinogen]] to [[fibrin]], and [[factor XIII|XIII]] to XIIIa. In the conversion of fibrinogen into fibrin, thrombin catalyzes the cleavage of [[fibrinopeptide A|fibrinopeptides A]] and [[fibrinopeptide B|B]] from the respective [[fibrinogen alpha chain|Aα]] and [[fibrinogen beta chain|Bβ]] chains of fibrinogen to form fibrin monomers.<ref name="pmid22759629">{{cite journal | vauthors = Wolberg AS | title = Determinants of fibrin formation, structure, and function | journal = Curr Opin Hematol | volume = 19 | issue = 5 | pages = 349–56 | date = September 2012 | pmid = 22759629 | doi = 10.1097/MOH.0b013e32835673c2 | s2cid = 11358104 | url = }}</ref>

[[Factor XIIIa]] 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 [[Protein-protein interaction|interacts]] with [[thrombomodulin]].<ref name="pmid8663147">{{cite journal | vauthors = Bajzar L, Morser J, Nesheim M | title = TAFI, or plasma procarboxypeptidase B, couples the coagulation and fibrinolytic cascades through the thrombin-thrombomodulin complex | journal = The Journal of Biological Chemistry | volume = 271 | issue = 28 | pages = 16603–8 | date = July 1996 | pmid = 8663147 | doi = 10.1074/jbc.271.28.16603 | doi-access = free }}</ref><ref name="pmid2544585">{{cite journal | vauthors = Jakubowski HV, Owen WG | title = Macromolecular specificity determinants on thrombin for fibrinogen and thrombomodulin | journal = The Journal of Biological Chemistry | volume = 264 | issue = 19 | pages = 11117–21 | date = July 1989 | doi = 10.1016/S0021-9258(18)60437-5 | pmid = 2544585 | doi-access = free }}</ref>

As part of its activity in the coagulation cascade, thrombin also promotes [[platelet]] activation and aggregation via activation of [[protease-activated receptor]]s 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 [[serpin|serine protease inhibitor]].

==Structure==
[[Image:1nl2_opm.png|thumb|Anchoring of bovine prothrombin to the membrane through its [[Gla domain]].<ref name="pmid12923575">{{PDB|1nl2}}; {{cite journal | vauthors = Huang M, Rigby AC, Morelli X, Grant MA, Huang G, Furie B, Seaton B, Furie BC | title = Structural basis of membrane binding by Gla domains of vitamin K-dependent proteins | journal = Nature Structural Biology | volume = 10 | issue = 9 | pages = 751–6 | date = September 2003 | pmid = 12923575 | doi = 10.1038/nsb971 | s2cid = 7751100 }}</ref>]]

The molecular weight of prothrombin is approximately 72,000 [[atomic mass unit|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.

Prothrombin is composed of four domains; an N-terminal [[Gla domain]], two [[kringle domain]]s and a C-terminal [[trypsin]]-like [[serine protease]] domain.
[[Factor Xa]] with [[factor V]] as a cofactor leads to cleavage of the Gla and two Kringle domains (forming together a fragment called fragment 1.2) and leave thrombin, consisting solely of the serine protease domain.<ref>{{cite journal | vauthors = Davie EW, Kulman JD | title = An overview of the structure and function of thrombin | journal = Seminars in Thrombosis and Hemostasis | volume = 32 | pages = 3–15 | date = April 2006 | issue = Suppl 1 | pmid = 16673262 | doi = 10.1055/s-2006-939550 | s2cid = 36616995 }}</ref>

As is the case for all [[serine protease]]s, [[prothrombin]] is converted to active thrombin by proteolysis of an internal peptide bond, exposing a new N-terminal Ile-NH3. The historic model of activation of serine proteases involves insertion of this newly formed N-terminus of the heavy chain into the [[Beta barrel|β-barrel]] promoting the correct conformation of the catalytic residues.<ref>{{Cite journal| vauthors = Huber R, Bode W |date=1978-03-01|title=Structural basis of the activation and action of trypsin|journal=Accounts of Chemical Research|volume=11|issue=3|pages=114–122|doi=10.1021/ar50123a006|issn=0001-4842}}</ref> Contrary to crystal structures of active thrombin, hydrogen-deuterium exchange mass spectrometry studies indicate that this N-terminal Ile-NH3 does not become inserted into the β-barrel in the apo form of thrombin. However, binding of the active fragment of [[thrombomodulin]] appears to allosterically promote the active conformation of thrombin by inserting this N-terminal region.<ref>{{cite journal | vauthors = Handley LD, Treuheit NA, Venkatesh VJ, Komives EA | title = Thrombomodulin Binding Selects the Catalytically Active Form of Thrombin | journal = Biochemistry | volume = 54 | issue = 43 | pages = 6650–8 | date = November 2015 | pmid = 26468766 | pmc = 4697735 | doi = 10.1021/acs.biochem.5b00825 }}</ref>

==Gene==
There are an estimated 30 people in the world that have been diagnosed with the congenital form of Factor II deficiency,<ref name="pmid7792730">{{cite journal | vauthors = Degen SJ, McDowell SA, Sparks LM, Scharrer I | title = Prothrombin Frankfurt: a dysfunctional prothrombin characterized by substitution of Glu-466 by Ala | journal = Thrombosis and Haemostasis | volume = 73 | issue = 2 | pages = 203–9 | date = February 1995 | pmid = 7792730 | doi =  10.1055/s-0038-1653751| s2cid = 20144699 }}</ref> which should not be confused with the [[prothrombin G20210A]] mutation, which is also called the factor II mutation. Prothrombin G20210A is congenital.<ref name="pmid15262854">{{cite journal | vauthors = Varga EA, Moll S | title = Cardiology patient pages. Prothrombin 20210 mutation (factor II mutation) | journal = Circulation | volume = 110 | issue = 3 | pages = e15–8 | date = July 2004 | pmid = 15262854 | doi = 10.1161/01.CIR.0000135582.53444.87 | doi-access = free }}</ref>

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.<ref>{{cite journal | vauthors = Bernstein CN, Sargent M, Vos HL, Rosendaal FR | title = Mutations in clotting factors and inflammatory bowel disease | journal = The American Journal of Gastroenterology | volume = 102 | issue = 2 | pages = 338–43 | date = February 2007 | pmid = 17156138 | doi = 10.1111/j.1572-0241.2006.00974.x | s2cid = 19895315 }}</ref>

==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 [[Antibody|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.<ref name="pmid19228706">{{cite journal | vauthors = Borissoff JI, Spronk HM, Heeneman S, ten Cate H | title = Is thrombin a key player in the 'coagulation-atherogenesis' maze? | journal = Cardiovascular Research | volume = 82 | issue = 3 | pages = 392–403 | date = June 2009 | pmid = 19228706 | doi = 10.1093/cvr/cvp066 | doi-access = free }}</ref><ref name="pmid20697022">{{cite journal | vauthors = Borissoff JI, Heeneman S, Kilinç E, Kassák P, Van Oerle R, Winckers K, Govers-Riemslag JW, Hamulyák K, Hackeng TM, Daemen MJ, ten Cate H, Spronk HM | title = Early atherosclerosis exhibits an enhanced procoagulant state | journal = Circulation | volume = 122 | issue = 8 | pages = 821–30 | date = August 2010 | pmid = 20697022 | doi = 10.1161/CIRCULATIONAHA.109.907121 | doi-access = free }}</ref><ref name="pmid21542745">{{cite journal | vauthors = Borissoff JI, Spronk HM, ten Cate H | title = The hemostatic system as a modulator of atherosclerosis | journal = The New England Journal of Medicine | volume = 364 | issue = 18 | pages = 1746–60 | date = May 2011 | pmid = 21542745 | doi = 10.1056/NEJMra1011670 }}</ref>

Thrombin is implicated in the physiology of [[blood clot]]s. Its presence indicates the existence of a clot. In 2013 a system for detecting the presence of thrombin was developed in mice. It combines peptide-coated [[iron oxide]] attached to "reporter chemicals". When a peptide binds to a thrombin molecule, the report is released and appears in the [[urine]] where it can be detected. Human testing has not been conducted.<ref>{{cite news|author=Economist|url=https://www.economist.com/blogs/babbage/2013/11/nanomedicine |title=Nanomedicine: Particle physiology |newspaper=The Economist |date=2013-11-05 |access-date=2013-12-15}}</ref>

==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 [[anticoagulant]]s. [[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 X]]a). The [[direct thrombin inhibitor]]s, 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 [[topical]]ly 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.<ref name="pmid17660072">{{cite journal | vauthors = Chapman WC, Singla N, Genyk Y, McNeil JW, Renkens KL, Reynolds TC, Murphy A, Weaver FA | title = A phase 3, randomized, double-blind comparative study of the efficacy and safety of topical recombinant human thrombin and bovine thrombin in surgical hemostasis | journal = Journal of the American College of Surgeons | volume = 205 | issue = 2 | pages = 256–65 | date = August 2007 | pmid = 17660072 | doi = 10.1016/j.jamcollsurg.2007.03.020 }}</ref><ref name="pmid19651065">{{cite journal | vauthors = Singla NK, Ballard JL, Moneta G, Randleman CD, Renkens KL, Alexander WA | title = A phase 3b, open-label, single-group immunogenicity and safety study of topical recombinant thrombin in surgical hemostasis | journal = Journal of the American College of Surgeons | volume = 209 | issue = 1 | pages = 68–74 | date = July 2009 | pmid = 19651065 | doi = 10.1016/j.jamcollsurg.2009.03.016 }}</ref><ref name="pmid19349898">{{cite journal | vauthors = Greenhalgh DG, Gamelli RL, Collins J, Sood R, Mozingo DW, Gray TE, Alexander WA | title = Recombinant thrombin: safety and immunogenicity in burn wound excision and grafting | journal = Journal of Burn Care & Research | volume = 30 | issue = 3 | pages = 371–9 | year = 2009 | pmid = 19349898 | doi = 10.1097/BCR.0b013e3181a28979 | s2cid = 3678462 }}</ref>

===Food production===
Thrombin, combined with [[fibrinogen]], is sold under the brand name Fibrimex for use as a binding agent for meat. Both proteins in Fibrimex derives from [[porcine]] or [[bovine]] blood.<ref name="dn">{{cite web|url=https://www.dn.se/nyheter/politik/sverige-rostade-ja-till-kottklister/|title=Sverige röstade ja till köttklister|work=Dagens Nyheter |trans-title=Sweden voted in favor of the meat paste|language=sv|date=2010-02-09|access-date=2010-10-17}}</ref> 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.<ref name="url_Fibrimex">{{cite web|url=https://www.sonac.biz/markets/food-ingredient-supplier/qconnect-fresh-meat-binding/fibrimexr/|title=Welcome to Fibrimex|work=Fibrimex website|publisher=Sonac|access-date=2019-02-28}}</ref>

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".<ref name="dn" />

== See also ==
* [[Cerastocytin]]
* [[Fibrin glue]]
* [[Fibrinogen]]
* [[PA clan]] of proteases
* [[The Proteolysis Map]]
* [[Thrombin generation assay]]

== References ==
{{Reflist|2}}

== Further reading ==
{{refbegin|2}}
* {{cite journal | vauthors = Esmon CT | title = Thrombomodulin as a model of molecular mechanisms that modulate protease specificity and function at the vessel surface | journal = FASEB Journal | volume = 9 | issue = 10 | pages = 946–55 | date = July 1995 | pmid = 7615164 | doi =  10.1096/fasebj.9.10.7615164| doi-access = free | s2cid = 19565674 }}
* {{cite journal | vauthors = Wu H, Zhang Z, Li Y, Zhao R, Li H, Song Y, Qi J, Wang J | title = Time course of upregulation of inflammatory mediators in the hemorrhagic brain in rats: correlation with brain edema | journal = Neurochemistry International | volume = 57 | issue = 3 | pages = 248–53 | date = October 2010 | pmid = 20541575 | doi = 10.1016/j.neuint.2010.06.002 | pmc=2910823}}
* {{cite journal | vauthors = Lenting PJ, van Mourik JA, Mertens K | title = The life cycle of coagulation factor VIII in view of its structure and function | journal = Blood | volume = 92 | issue = 11 | pages = 3983–96 | date = December 1998 | pmid = 9834200 | doi =  10.1182/blood.V92.11.3983}}
* {{cite journal | vauthors = Plow EF, Cierniewski CS, Xiao Z, Haas TA, Byzova TV | title = AlphaIIbbeta3 and its antagonism at the new millennium | journal = Thrombosis and Haemostasis | volume = 86 | issue = 1 | pages = 34–40 | date = July 2001 | pmid = 11487023 | doi =  10.1055/s-0037-1616198| s2cid = 74389210 }}
* {{cite journal | vauthors = Maragoudakis ME, Tsopanoglou NE, Andriopoulou P | title = Mechanism of thrombin-induced angiogenesis | journal = Biochemical Society Transactions | volume = 30 | issue = 2 | pages = 173–7 | date = April 2002 | pmid = 12023846 | doi = 10.1042/BST0300173 }}
* {{cite journal | vauthors = Howell DC, Laurent GJ, Chambers RC | title = Role of thrombin and its major cellular receptor, protease-activated receptor-1, in pulmonary fibrosis | journal = Biochemical Society Transactions | volume = 30 | issue = 2 | pages = 211–6 | date = April 2002 | pmid = 12023853 | doi = 10.1042/BST0300211 | s2cid = 32822567 }}
* {{cite journal | vauthors = Firth SM, Baxter RC | title = Cellular actions of the insulin-like growth factor binding proteins | journal = Endocrine Reviews | volume = 23 | issue = 6 | pages = 824–54 | date = December 2002 | pmid = 12466191 | doi = 10.1210/er.2001-0033 | doi-access = free }}
* {{cite journal | vauthors = Minami T, Sugiyama A, Wu SQ, Abid R, Kodama T, Aird WC | title = Thrombin and phenotypic modulation of the endothelium | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 24 | issue = 1 | pages = 41–53 | date = January 2004 | pmid = 14551154 | doi = 10.1161/01.ATV.0000099880.09014.7D | doi-access = free }}
* {{cite journal | vauthors = De Cristofaro R, De Candia E | title = Thrombin domains: structure, function and interaction with platelet receptors | journal = Journal of Thrombosis and Thrombolysis | volume = 15 | issue = 3 | pages = 151–63 | date = June 2003 | pmid = 14739624 | doi = 10.1023/B:THRO.0000011370.80989.7b }}
* {{cite journal | vauthors = Tsopanoglou NE, Maragoudakis ME | title = Role of thrombin in angiogenesis and tumor progression | journal = Seminars in Thrombosis and Hemostasis | volume = 30 | issue = 1 | pages = 63–9 | date = February 2004 | pmid = 15034798 | doi = 10.1055/s-2004-822971 | s2cid = 260320933 }}
* {{cite journal | vauthors = Bode W | title = Structure and interaction modes of thrombin | journal = Blood Cells, Molecules & Diseases | volume = 36 | issue = 2 | pages = 122–30 | year = 2007 | pmid = 16480903 | doi = 10.1016/j.bcmd.2005.12.027 | doi-access = free }}
* {{cite journal | vauthors = Wolberg AS | title = Thrombin generation and fibrin clot structure | journal = Blood Reviews | volume = 21 | issue = 3 | pages = 131–42 | date = May 2007 | pmid = 17208341 | doi = 10.1016/j.blre.2006.11.001 }}
* {{cite book |author-link=Sandra J. F. Degen |vauthors=Degen S |chapter=Prothrombin |veditors=High K, Roberts H |title=Molecular Basis of Thrombosis and Hemostasis |publisher=Marcel Dekker |year=1995 |page=75 |isbn=9780824795016}}
{{refend}}

== External links ==
* The [[MEROPS]] online database for peptidases and their inhibitors: [http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=S01.217 S01.217] {{Webarchive|url=https://web.archive.org/web/20190919021629/http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=S01.217 |date=2019-09-19 }}
* {{cite journal |first=Jody L. |last=Kujovich |title=Prothrombin Thrombophilia |url=https://www.ncbi.nlm.nih.gov/books/NBK1148/ |veditors=Adam MP, Ardinger HH, Pagon RA, ''et al.'' |journal=GeneReviews |publisher=University of Washington, Seattle |location=Seattle WA |date=February 2021 |id=NBK1148 |pmid=20301327}}
* {{YouTube|H_lVLYgls04|Anti-coagulation & proteases}} by [[The Proteolysis Map]]-animation
* [https://web.archive.org/web/20110727185915/http://www.proteolysis.org/proteases/m_summarypg/pmap.17563] PMAP: [[The Proteolysis Map]]/Thrombin
* [http://www.rcsb.org/pdb/101/motm.do?momID=25 Thrombin: RCSB PDB Molecule of the Month] {{Webarchive|url=https://web.archive.org/web/20131005173140/http://www.rcsb.org/pdb/101/motm.do?momID=25 |date=2013-10-05 }}
* [http://sbi.imim.es/web/files/projects/master/2010/Coagulation_serine_proteases/Prothrombin.html Prothrombin Structure]
* [https://www.ebi.ac.uk/pdbe/pdbe-kb/proteins/P00734 PDBe-KB] provides an overview of all the structure information available in the PDB for Human Thrombin.
* [https://www.ebi.ac.uk/pdbe/pdbe-kb/proteins/P19221 PDBe-KB] provides an overview of all the structure information available in the PDB for Mouse Thrombin.

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[[Category:Coagulation system]]
[[Category:Acute-phase proteins]]
[[Category:EC 3.4.21]]
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[[Category:Peripheral membrane proteins]]