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| {{Infobox_Disease | | | __NOTOC__ |
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| | {{Antithrombin III}} |
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| | '''''For patient information, click <u>[[Antithrombin III (patient information)|here]]'''''</u>. |
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| '''''Synonyms and key words:''''' AT 3, AT III | |
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| ==Overview== | | ==Overview== |
| '''Antithrombin''' (AT) is a small protein molecule that inactivates several enzymes of the [[coagulation]] system. It is a [[glycoprotein]] produced by the [[liver]] and consists of 432 amino acids. It contains three [[disulfide bond]]s and a total of four possible [[glycosylation]] sites. α-antithrombin is the dominant form of antithrombin found in [[blood plasma]] and has an oligosaccharide occupying each of its four glycosylation sites. A single glycosylation site remains consistently un-occupied in the minor form of antithrombin, β-antithrombin.<ref>{{cite book |last = Bjork | first = I | coauthors = Olson, JE | title = Antithrombin, A bloody important serpin (in Chemistry and Biology of Serpins) | publisher = Plenum Press | date = 1997 | pages=17-33 | id=ISBN 0-306-45698-2}}</ref>
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| ==== Reference Range ====
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| {|
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| | '''Level''' || '''0.14-0.39 g/l'''
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| |-style="background:silver; color:black"
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| | '''Activity''' || '''70-120% of Normal Activity'''
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| == Nomenclature ==
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| Antithrombin is officially termed '''antithrombin III''' (AT III) and it is a member of a larger family of antithrombins, numbered antithrombin I (AT I) through to antithrombin VI (AT VI). All antithrombins are [[serine protease inhibitor|serpin]]s, however only AT III and possibly AT I are medically significant. AT III is generally referred to solely as ''antithrombin'' and it is antithrombin III that is discussed in this article.
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| ==Structure==
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| Antithrombin has a [[half life]] in [[blood plasma]] of around 3 days.<ref>{{cite journal | author = Collen DJ, Schetz F. ''et al''. | title = Metabolism of antithrombin III (heparin cofactor) in man: Effects of venous thrombosis of heparin administration | journal = Eur. J. Clin. Invest | year=1977 | volume=7 | pages=27-35 | id = PMID 65284 }}</ref>
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| The normal antithrombin concentration in human [[blood plasma]] is high at approximately 0.12 mg/ml, which is equivalent to a [[Concentration#Molarity|molar]] concentration of 2.3 μM.<ref>{{cite journal | author = Conrad J, Brosstad M. ''et al.'' | title = Molar antithrombin concentration in normal human plasma | journal = Haemostasis | year=1983 | volume=13 | pages=363-368 | id = PMID 6667903 }}</ref>
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| Antithrombin has been isolated from the plasma of a large number of species additional to humans.<ref>{{cite journal | author = Jordan RE. | title = Antithrombin in vertebrate species: Conservation of the heparin-dependent anticoagulant mechanism | journal = Arch. Biochem. Biophys | year=1983 | volume=227 | pages=587-595 | id = PMID 6607710 }}</ref>
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| As deduced from protein and [[cDNA]] sequencing, cow, sheep, rabbit and mouse antithrombins are all 433 amino acids in length, which is one amino acid longer than human antithrombin III. The extra amino acid is thought to occur at amino acid position 6. Cow, sheep, rabbit, mouse and human antithrombins share between 84 and 89% amino acid sequence identity.<ref name=olson>{{cite journal | author = Olson ST, Bjork I. | title = Regulation of thrombin activity by antithrombin and heparin | journal = Sem. Thromb. Hemost. | year=1994 | volume=20 | issue=4 | pages=373-409 | id = PMID 7899869 }}</ref>
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| They all have four potential [[N-glycosylation]] sites. These occur at [[asparagine]] (Asn) amino acid numbers 96, 135, 155 and 192 in humans and at similar amino acid numbers in other species. All these sites are occupied by covalently attached oligosaccharide side chains in the predominant form of human antithrombin, α-antithrombin. The potential glycosylation site at asparagine 135 is not occupied in a minor form of antithrombin, β-antithrombin.<ref>{{cite journal | author = Brennan SO, George PM, Jordan, RE. | title = Physiological variant of antithrombin-III lacks carbohydrate side chain at Asn 135 | journal = FEBS Lett | year=1987 | volume=219 | pages=431-436 | id = PMID 3609301 }}</ref>
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| Shown below are the location of the four potential glycosylation sites within the [[tertiary structure]] of an antithrombin [[monomer]], as taken from the [[protein data bank]] file [http://www.pdb.org/pdb/explore/explore.do?structureId=2ANT 2ANT]. In this structure only Asn 155 is glycosylated by the addition of a single [[N-Acetylglucosamine|''N''-acetylglucosamine]] residue.
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| [[Image:antithrombin 1.jpeg|500px]]
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| == Function ==
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| Antithrombin is a [[serine protease inhibitor|serpin]] (serine protease inhibitor). The physiological target [[protease]]s of antithrombin are those of the [[Coagulation#Contact activation pathway|''contact activation pathway'']] (formerly known as the intrinsic pathway), namely the activated forms of [[Factor X]] (Xa), [[Factor IX]] (IXa), [[Factor XI]] (XIa), [[Factor XII]] (XIIa) and [[Factor II]] (thrombin) (IIa) and also the activated form of [[Factor VII]] (VIIa) from the [[Coagulation#Tissue factor pathway|''tissue factor pathway'']] (formerly known as the extrinsic pathway).<ref>{{cite journal | author = Persson E, Bak H and Olsen OH. | title = Substitution of valine for leucine 305 in factor VIIa increases the intrinsic enzymatic activity | journal = J. Biol. Chem. | year=2001 | volume=276 | issue=31 | pages=29195-29199 | id = PMID 11389142}}</ref> Protease inactivation results as a consequence of the trapping the protease in an equimolar complex with antithrombin in which the active site of the protease enzyme is inaccessible to its usual [[substrate]].<ref name=olson/> The formation of an antithrombin-protease complex involves an interaction between the protease and a specific reactive [[peptide bond]] within antithrombin. In human antithrombin this bond is between [[arginine]] (arg) 393 and [[serine]] (ser) 394.<ref name=olson/> As shown below the reactive arg 393 - ser 394 bond is located on an exposed loop at the surface of the molecule. This loop is termed the reactive site loop.
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| [[Image:antithrombin 2.jpeg|300px]]
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| It is thought the trapping of protease enzymes in inactive antithrombin-protease complexes results as a consequence of their attack of the reactive bond. Where the attack of a similar bond within their normal substrate results in its rapid [[proteolytic]] cleavage, on initiating an attack on the antithrombin reactive bond the antithrombin inhibitor is activated to trap the enzyme at an intermediate stage during the proteolytic process. Given time thrombin is able to cleave the reactive bond within antithrombin and an inactive thrombin-antithrombin complex will dissociate, however the time it takes for this to occur may be greater than 3 days.<ref>{{cite journal | author = Danielsson A and Bjork, I | title = Slow, spontaneous dissociation of the antithrombin-thrombin complex produces a proteolytically modified form of the inhibitor | journal = FEBS Lett | year=1980 | volume=119 | pages=241-244 | id = PMID 7428936}}</ref>
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| The rate of antithrombin's inhibition of protease activity is greatly enhanced by its additional binding to [[heparin]].
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| ==Antithrombin and heparin==
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| AT-III binds to a specific pentasaccharide sulfation sequence contained within the heparin polymer
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| GlcNAc/NS(6S)-GlcA-GlcNS(3S,6S)-IdoA(2S)-GlcNS(6S)
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| Upon binding to this pentasaccharide sequence, inhibition of protease activity is increased by heparin as a result of two distinct mechanisms.<ref>{{cite journal | author = Johnson DJ, Langdown J, ''et al''. | title = Crystal structure of monomeric native antithrombin reveals a novel reactive center loop conformation | journal = J. Biol. Chem. | year=2006 | volume=281 | issue=46 | pages=35478-35486 | id = PMID 16973611}}</ref> In one mechanism heparin stimulation of Factor IXa and Xa inhibition depends on a conformational change within antithrombin involving the reactive site loop and is thus [[allosteric]]. This conformational change results in an approximate 300 fold increase in Factor IXa and Xa inhibitory activity.<ref name=Langdown>{{cite journal | author = Langdown J, Johnson DJ. ''et al''. | title = Allosteric activation of antithrombin critically depends upon hinge region extension | journal = J. Biol. Chem. | year=2004 | volume=279 | issue=45 | pages=47288-47297 | id = PMID 15326167}}</ref> In another mechanism stimulation of thrombin inhibition depends on the formation of a [[ternary complex]] between AT-III, thrombin, and heparin. Formation of this complex results in an approximate 4 fold increase in antithrombin inhibitory activity.<ref name=Langdown/>
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| ===Allosteric activation===
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| Increased Factor IXa and Xa inhibition requires the minimal heparin pentasaccharide sequence. The conformational changes that occur within antithrombin in response to pentasaccharide binding are well documented.<ref>{{cite journal | author = Schreuder HA, de Boer B. ''et al''. | title = The intact and cleaved human antithrombin III complex as a model for serpin-proteinase interactions | journal = Nat. Struct. Biol. | year=1994 | volume=1 | issue=1 | pages=48-54 | id = PMID 7656006}}</ref><ref>{{cite journal | author = Carrell RW, Stein PE.''et al''. | title = Biological implications of a 3 A structure of dimeric antithrombin | journal = Structure | year=1994 | volume=2 | issue=4 | pages=257-270 | id = PMID 8087553}}</ref><ref>{{cite journal | author = Whisstock JC, Pike RN. ''et al''. | title = Conformational changes in serpins: II. The mechanism of activation of antithrombin by heparindagger | journal = J. Mol. Biol. | year=2000 | volume=301 | issue=5 | pages=1287-1305 | id = PMID 10966821}}</ref> Shown below are two [[X-ray crystallography|crystal structure]]s for antithrombin. Model '''A''' is taken from the [[Protein Data Bank|pdb]] file [http://www.pdb.org/pdb/explore/explore.do?structureId=2ANT 2ANT] and model '''B''' from pdb file [http://www.pdb.org/pdb/explore/explore.do?structureId=1AZX 1AZX]. Model '''B''' is complexed with a pentasaccharide while model '''A''' is uncomplexed.
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| [[Image:Antithrom+heparin.jpeg|center|300px]]
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| The conformational change most relevant for Factor IXa and Xa inhibition occurs within the [[N-terminus|N-terminal]] portion of the reactive site loop and is circled in model '''B''' above. This region has been termed the hinge region and it has been shown that by preventing the normal extension of this region in response to heparin binding, increased Factor IXa and Xa inhibition does not occur.<ref name=Langdown/> It is thought that the increased flexibility given to the reactive site loop as a result of the hinge region conformational change is a key factor in influencing increased Factor IXa and Xa inhibition.
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| ===Non-allosteric activation=== | | ==Category== |
| Increased thrombin inhibition requires the minimal heparin pentasaccharide plus at least an additional 13 monomeric units.<ref>{{cite journal | author = Petitou M, Herault JP, Bernat A, Driguez PA, ''et al''. | title= Synthesis of Thrombin inhibiting Heparin mimetics without side effects | journal= Nature | year=1999 | volume=398 | pages=417-422 | id= PMID 10201371}}</ref> This is thought to be due to a requirement that antithrombin and thrombin must bind to the same heparin chain adjacent to each other. This can be seen in the series of models below taken from the pdb file [http://www.pdb.org/pdb/explore/explore.do?structureId=1TB6 1TB6]
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| [[Image:Throm+anti+hep_complex.jpeg|center|400px]]
| | ==US Brand Names== |
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| == Role in disease == | | ==FDA Package Insert== |
| {{details|Antithrombin III deficiency}}
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| Evidence for the important role antithrombin plays in regulating normal blood coagulation is demonstrated by the correlation between [[inherited disorder|inherited]] or [[acquired disorder|acquired]] antithrombin deficiencies and an increased risk of any affected individual developing thrombotic disease.<ref>{{cite journal | author = van Boven HH and Lane DA.| title = Antithrombin and its inherited deficiency states | journal = Semin. Hematol. | year=1997 | volume=34 | issue=3 | pages=188-204 | id = PMID 9241705}}</ref> [[Antithrombin deficiency]] generally comes to light when a patient suffers recurrent venous [[thrombosis]] and [[pulmonary embolism]]. Variability across patients in the levels of antithrombin III account for some of the variability in patients' response to [[heparin]].
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| ===Acquired antithrombin deficiency===
| | '''| [[Antithrombin III indications and usage|Indications and Usage]]''' |
| Acquired antithrombin deficiency may result from a range of disorders such as [[Acute liver failure#Coagulopathy |liver dysfunction (coagulopathy)]], [[sepsis]], or [[premature birth]] or as a result of interventions such as [[surgery|major surgery]] or [[cardiopulmonary bypass]].<ref>{{cite journal | author = Maclean PS and Tait RC. | title = Hereditary and acquired antithrombin deficiency: epidemiology, pathogenesis and treatment options | journal = Drugs | year=2007 | volume=67 | issue=10 | pages=1429-1440 | id = PMID 17600391}}</ref> Smoking and oral contraceptives reduce antithrombin III levels.
| | '''| [[Antithrombin III dosage and administration|Dosage and Administration]]''' |
| | '''| [[Antithrombin III dosage forms and strengths|Dosage Forms and Strengths]]''' |
| | '''| [[Antithrombin III contraindications|Contraindications]]''' |
| | '''| [[Antithrombin III warnings|Warnings and Precautions]]''' |
| | '''| [[Antithrombin III adverse reactions|Adverse Reactions]]''' |
| | '''| [[Antithrombin III drug interactions|Drug Interactions]]''' |
| | '''| [[Antithrombin III use in specific populations|Use in Specific Populations]]''' |
| | '''| [[Antithrombin III overdosage|Overdosage]]''' |
| | '''| [[Antithrombin III description|Description]]''' |
| | '''| [[Antithrombin III clinical pharmacology|Clinical Pharmacology]]''' |
| | '''| [[Antithrombin III nonclinical toxicology|Nonclinical Toxicology]]''' |
| | '''| [[Antithrombin III clinical studies|Clinical Studies]]''' |
| | '''| [[Antithrombin III how supplied storage and handling|How Supplied/Storage and Handling]]''' |
| | '''| [[Antithrombin III patient counseling information|Patient Counseling Information]]''' |
| | '''| [[Antithrombin III labels and packages|Labels and Packages]]''' |
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| ===Inherited antithrombin deficiency=== | | ==Mechanism of Action== |
| Inherited deficiencies in blood antithrombin activity may be due to a low circulating level of structurally and functionally normal antithrombin. In this case typically antithrombin levels and therefore activity may be reduced by 50% compared to normal antithrombin levels.<ref name=Lane>{{cite journal | author = Lane DA, Olds RJ and Thein SL. | title = Antithrombin III: summary of first database update | journal = Nucleic Acids Res. | year=1994 | volume=22 | issue=17 | pages=3556-3559 | id = PMID 7937056}}</ref> This type of deficiency is classified as '''type I antithrombin deficiency'''.
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| Inherited deficiencies may also be the result of a structurally and functionally abnormal antithrombin protein circulating in the blood. In this case levels of antithrombin may be normal but the activity produced by this protein again may be reduced by 50% when compared to normal antithrombin activity levels.<ref name=Lane/> This type of deficiency is classified as '''type II antithrombin deficiency'''.
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| Both type I and type II antithrombin deficiency have been shown to be the result of any one of a number of [[frameshift mutation]]s, [[missense mutation]]s or [[nonsense mutation]]s in the gene that encodes antithrombin.<ref name=Lane/><ref>{{cite journal | author = Lane DA, Ireland H. ''et al''. | title = Antithrombin III: a database of mutations | journal = Thromb. Haemost. | year=1991 | volume=66 | issue=6 | pages=657-661 | id = PMID 1796410}}</ref><ref>{{cite journal | author = Picard V, Nowak-Göttl U. ''et al''| title = Molecular bases of antithrombin deficiency: twenty-two novel mutations in the antithrombin gene | journal = Hum. Mutat. | year=2006 | volume=27 | issue=6 | pages=600 | id = PMID 16705712}}</ref>
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| Renal losses of antithrombin account for an increased risk of [[thrombosis]] in patients with [[nephrotic syndrome]].
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| == Complete Differential Diagnosis of Disorders of Antithrombin III==
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| === Increased Antithrombin III ===
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| * [[Cholestasis]]
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| * [[Warfarin]] therapy
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| === Decreased Antithrombin III ===
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| * [[Coronary artery bypass grafting]]
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| * [[Cirrhosis]]
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| * Congenital heterozygous familial AT III deficiency
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| * [[Disseminated intravascular coagulation]] ([[DIC]])
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| * [[Heparin]] therapy
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| * Major surgery
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| * [[Nephrotic syndrome]]
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| * [[Oral contraceptive]]s
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| * [[Premature birth]]
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| * [[Protein-Losing Enteropathy]] or exudative enteropathy
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| * [[Sepsis]]
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| * Surgery involving large wound surfaces
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| * [[Thrombolysis]]
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| * [[Hepatic failure]]
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| * [[Trauma]]
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| ==References== | | ==References== |
| {{reflist|2}}
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| ==External links==
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| * {{MeshName|Antithrombin+III}}
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| == Acknowledgements ==
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| The content on this page was first contributed by {{CMG}}
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| {{Coagulation}}
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| {{Serpins}}
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| | {{Reflist|2}} |
| [[es:Antitrombina]]
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| [[it:Antitrombina]]
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| [[pl:Antytrombina]]
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| [[pt:Antitrombina]]
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