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Serpin peptidase inhibitor, clade C (antithrombin), member 1
Antithrombin dimer drawn from PDB 1E03.
Available structures: 1ant, 1ath, 1azx, 1br8, 1dzg, 1dzh, 1e03, 1e04, 1e05, 1jvq, 1lk6, 1nq9, 1oyh, 1r1l, 1sr5, 1t1f, 1tb6, 2ant, 2b4x, 2b5t, 2beh, 2gd4
Symbol(s) SERPINC1; AT3; ATIII; MGC22579
External IDs OMIM: 107300 MGI: 88095 Homologene: 20139
RNA expression pattern

More reference expression data

Human Mouse
Entrez 462 11905
Ensembl ENSG00000117601 ENSMUSG00000026715
Uniprot P01008 Q543J5
Refseq NM_000488 (mRNA)
NP_000479 (protein)
NM_080844 (mRNA)
NP_543120 (protein)
Location Chr 1: 172.14 - 172.15 Mb Chr 1: 162.82 - 162.84 Mb
Pubmed search [1] [2]

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 bonds 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.[1]



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 serpins, however only AT III and possibly AT I are medically significant. AT III is generally referred to soley as antithrombin and it is antithrombin III that is discussed in this article.


Antithrombin has a half life in blood plasma of around 3 days.[2] The normal antithrombin concentration in human blood plasma is approximately 0.12 mg/ml, which is equivalent to a molar concentration of 2.3 μM.[3] Antithrombin has been isolated from the plasma of a large number of species additional to humans.[4] 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.[5] 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.[6] 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 2ANT. In this structure only Asn 155 is glycosylated by the addition of a single N-acetylglucosamine residue.


Antithrombin is a serpin (serine protease inhibitor). The physiological target proteases of antithrombin are those of the intrinsic coagulation system, namely the activated forms of Factor X (Xa), Factor IX (IXa), Factor VII (VIIa), Factor XI (XIa), Factor XII (XIIa) and Factor II (thrombin) (IIa). 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.[5] 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.[5] 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.

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.[7]

The rate of antithrombin's inhibition of protease activity is greatly enhanced by its additional binding to heparin.

Role in disease

For more details on this topic, see Antithrombin III deficiency.

Evidence for the important role antithrombin plays in regulating normal blood coagulation is demonstrated by the correlation between inherited or acquired antithrombin deficiencies and an increased risk of any affected individual developing thrombotic disease.[8] Antithrombin deficiency generally comes to light when a patient suffers recurrent venous thrombosis and pulmonary embolism.

Acquired antithrombin deficiency

Acquired antithrombin deficiency may result from a range of disorders such as liver dysfunction (coagulopathy), sepsis, or premature birth or as a result of interventions such as major surgery or cardiopulmonary bypass.[9]

Inherited antithrombin deficiency

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.[10] This type of deficiency is classified as type I antithrombin deficiency.

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.[10] This type of deficiency is classified as type II antithrombin deficiency.

Both type I and type II antithrombin deficiency have been shown to be the result of any one of a number of frameshift mutations, missense mutations or nonsense mutations in the gene that encodes antithrombin.[10][11][12]

Renal losses of antithrombin account for an increased risk of thrombosis in patients with nephrotic syndrome.


  1. ^ Bjork, I; Olson, JE (1997). Antithrombin, A bloody important serpin (in Chemistry and Biology of Serpins). Plenum Press, 17-33. ISBN 0-306-45698-2. 
  2. ^ Collen DJ, Schetz F. et al. (1977). "Metabolism of antithrombin III (heparin cofactor) in man: Effects of venous thrombosis of heparin administration". Eur. J. Clin. Invest 7: 27-35. PMID 65284.
  3. ^ Conrad J, Brosstad M. et al. (1983). "Molar antithrombin concentration in normal human plasma". Haemostasis 13: 363-368. PMID 6667903.
  4. ^ Jordan RE. (1983). "Antithrombin in vertebrate species: Conservation of the heparin-dependent anticoagulant mechanism". Arch. Biochem. Biophys 227: 587-595. PMID 6607710.
  5. ^ a b c Olson ST, Bjork I. (1994). "Regulation of thrombin activity by antithrombin and heparin". Sem. Thromb. Hemost. 20 (4): 373-409. PMID 7899869.
  6. ^ Brennan SO, George PM, Jordan, RE. (1987). "Physiological variant of antithrombin-III lacks carbohydrate side chain at Asn 135". FEBS Lett 219: 431-436. PMID 3609301.
  7. ^ Danielsson A and Bjork, I (1980). "Slow, spontaneous dissociation of the antithrombin-thrombin complex produces a proteolytically modified form of the inhibitor". FEBS Lett 119: 241-244. PMID 7428936.
  8. ^ van Boven HH and Lane DA. (1997). "Antithrombin and its inherited deficiency states". Semin. Hematol. 34 (3): 188-204. PMID 9241705.
  9. ^ Maclean PS and Tait RC. (2007). "Hereditary and acquired antithrombin deficiency: epidemiology, pathogenesis and treatment options". Drugs 67 (10): 1429-1440. PMID 17600391.
  10. ^ a b c Lane DA, Olds RJ and Thein SL. (1994). "Antithrombin III: summary of first database update". Nucleic Acids Res. 1994 Sep;22(17):3556-9. 22 (17): 3556-3559. PMID 7937056.
  11. ^ Lane DA, Ireland H. et al. (1991). "Antithrombin III: a database of mutations". Thromb. Haemost. 66 (6): 657-661. PMID 1796410.
  12. ^ Picard V, Nowak-Göttl U. et al (2006). "Molecular bases of antithrombin deficiency: twenty-two novel mutations in the antithrombin gene". Hum. Mutat. 27 (6): 600. PMID 16705712.
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Antithrombin". A list of authors is available in Wikipedia.
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