Find information on thousands of medical conditions and prescription drugs.

Antithrombin deficiency, congenital

Antithrombin is a small molecule that inactivates several enzymes of the coagulation system. It is a glycoprotein produced by the liver. more...

Aagenaes syndrome
Aarskog Ose Pande syndrome
Aarskog syndrome
Aase Smith syndrome
Aase syndrome
ABCD syndrome
Abdallat Davis Farrage...
Abdominal aortic aneurysm
Abdominal cystic...
Abdominal defects
Absence of Gluteal muscle
Accessory pancreas
Achard syndrome
Achard-Thiers syndrome
Achondrogenesis type 1A
Achondrogenesis type 1B
Achondroplastic dwarfism
Acid maltase deficiency
Ackerman syndrome
Acne rosacea
Acoustic neuroma
Acquired ichthyosis
Acquired syphilis
Acrofacial dysostosis,...
Activated protein C...
Acute febrile...
Acute intermittent porphyria
Acute lymphoblastic leukemia
Acute lymphocytic leukemia
Acute mountain sickness
Acute myelocytic leukemia
Acute myelogenous leukemia
Acute necrotizing...
Acute promyelocytic leukemia
Acute renal failure
Acute respiratory...
Acute tubular necrosis
Adams Nance syndrome
Adams-Oliver syndrome
Addison's disease
Adducted thumb syndrome...
Adenoid cystic carcinoma
Adenosine deaminase...
Adenosine monophosphate...
Adie syndrome
Adrenal incidentaloma
Adrenal insufficiency
Adrenocortical carcinoma
Adrenogenital syndrome
Aicardi syndrome
AIDS Dementia Complex
Albright's hereditary...
Alcohol fetopathy
Alcoholic hepatitis
Alcoholic liver cirrhosis
Alexander disease
Alien hand syndrome
Alopecia areata
Alopecia totalis
Alopecia universalis
Alpers disease
Alpha 1-antitrypsin...
Alport syndrome
Alternating hemiplegia
Alzheimer's disease
Ambras syndrome
Amelogenesis imperfecta
American trypanosomiasis
Amyotrophic lateral...
Androgen insensitivity...
Anemia, Diamond-Blackfan
Anemia, Pernicious
Anemia, Sideroblastic
Aneurysm of sinus of...
Angelman syndrome
Ankylosing spondylitis
Annular pancreas
Anorexia nervosa
Anthrax disease
Antiphospholipid syndrome
Antisocial personality...
Antithrombin deficiency,...
Anton's syndrome
Aortic aneurysm
Aortic coarctation
Aortic dissection
Aortic valve stenosis
Apert syndrome
Aphthous stomatitis
Aplastic anemia
Argininosuccinic aciduria
Arnold-Chiari malformation
Arrhythmogenic right...
Arteriovenous malformation
Arthritis, Juvenile
Arthrogryposis multiplex...
Aseptic meningitis
Asherman's syndrome
Asphyxia neonatorum
Ataxia telangiectasia
Atelosteogenesis, type II
Atopic Dermatitis
Atrial septal defect
Atrioventricular septal...
Attention Deficit...
Autoimmune hepatitis
Autonomic dysfunction
Familial Alzheimer disease


Antithrombin is a serpin (serine protease inhibitor) that inactivates a number of enzymes from the coagulation system, namely the activated forms of Factor X, Factor IX and Factor II (thrombin). Its affinity for these molecules (i.e. its effectivity) is enhanced by heparin.

Role in disease

Antithrombin deficiency is a rare hereditary disorder that generally comes to light when a patient suffers recurrent venous thrombosis and pulmonary embolism. This was first described by Egeberg in 1965. The patients are treated with anticoagulants or, more rarely, with antithrombin concentrate.

In renal failure, especially nephrotic syndrome, antithrombin is lost in the urine, leading to a higher activity of Factor II and Factor X and in increased tendency to thrombosis.


The gene for antithrombin is located on the first chromosome, locus 1q23-q25.1.


Antithrombin is officially called antithrombin III and is a member of a larger family of antithrombins (numbered I, II etc. to VI). All are serpins. Only AT III (and possibly AT I) is medically significant, with AT III generally referred to as antithrombin.


  • Egeberg O. Inherited antithrombin deficiency causing thrombophilia. Thromb Diath Haemorrh 1965;13:516–520. PMID 14347873.


[List your site here Free!]

Hydration effects of heparin on antithrombin probed by osmotic stress
From Biophysical Journal, 2/1/02 by McGee, Maria P

ABSTRACT Antithrombin is a key inhibitor of blood coagulation proteases and a prototype metastable protein. Heparin binding to antithrombin induces conformational transitions distal to the binding site. We applied osmotic stress techniques and rate measurements in the stopped flow fluorometer to investigate the possibility that hydration changes are associated with these transitions. Water transfer was identified from changes in the free energy of activation, (Delta)G^^, with osmotic pressure r. The (Delta)G^^ was determined from the rate of fluorescence enhancement/decrease associated with heparin binding/release. The volume of water transferred, (Delta)V, was determined from the relationship, (Delta)G/pi = AV. With an osmotic probe of 4 Angstrom radius, the volumes transferred correspond to 158 +/- 11 water molecules from reactants to bulk during association and 162 +/- 22 from bulk to reactants during dissociation. Analytical characterization of water-permeable volumes in x-ray-derived bound and free antithrombin structures were correlated with the volumes measured in solution. Volume changes in water permeable pockets were identified at the loop-insertion and heparin-binding regions. Analyses of the pockets' atomic composition indicate that residues Ser-79, Ala-86, Val-214, Leu-215, Asn-217, Ile-219, and Thr-218 contribute atoms to both the heparin-binding pockets and to the loop-insertion region. These results demonstrate that the increases and decreases in the intrinsic fluorescence of antithrombin during heparin binding and release are linked to dehydration and hydration reactions, respectively. Together with the structural analyses, results also suggest a direct mechanism linking heparin binding/release to loop expulsion/insertion.


Antithrombin is a circulating serine proteinase inhibitor essential for the control of blood coagulation reactions (Jordan et al., 1980; Olson et al., 1993). Congenital or acquired antithrombin deficiencies are associated with thrombosis (Lane et al., 1992; Beauchamp et al., 1998). Antithrombin's inhibitory activity is potentiated by the sulfated glycosaminoglycan heparin, which induces conformational changes that increase antithrombin's binding affinity for its target proteinases by several orders of magnitude. These conformational changes are associated with spectral changes including an enhancement of -40% in intrinsic protein fluorescence (Olson and Shore, 1981; Huntington et al., 1996). Subsequent interaction of the heparin/antithrombin complex with the proteinase is linked to both reversal of the fluorescence enhancement and release of the heparin (Craig et al., 1989).

The activating conformational changes propagate throughout the antithrombin structure in ways that are not completely understood but that appear to involve allosteric mechanisms (Lawrence, 1997; Wilczynska et al., 1997; Gils and Declerk, 1998). The transition from the circulating native conformation to the activated, heparin-bound, antithrombin conformation includes the release of the reactive center loop from an inserted position between two strands of a beta-sheet structure in the protein's core. In x-ray-derived models of unbound native antithrombin, the reactive center loop is partially inserted into the P-sheet (Schereuder et al., 1994; Skinner et al., 1997; Carrell et al., 1991). In the only one available x-ray-derived model of bound, activated antithrombin, the reactive loop is free and completely exposed to solvent. In this structure, the heparin-binding groove (Ersdal-Badju et al., 1998) is partially occupied by an oversulfated heparin analog, pentasaccharide (Jin et al., 1997). It has been proposed that antithrombin circulates in a metastable state that is destabilized by heparin during initial binding. The alteration in the rate and/or sequence of conformational changes at the loop insertion-region observed in certain antithrombin mutants is considered a prototype mechanism of "conformational disease" (Beauchamp et al., 1998; Zou et al., 1999). Kinetically, considerable evidence indicates that the heparin-antithrombin interaction is a twostep reaction with a strong electrostatic component. An initial, low-affinity step equilibrates very rapidly and induces conformational transitions leading to high-affinity interactions (Olson et al., 1993; Desai et al., 1998). The subsequent inhibition of the proteinase is also a two-step process with initial fast equilibration and readily reversible formation of a ternary complex). Interactions in the ternary complex lead via an acyl-enzyme intermediate to heparin release and formation of an irreversible antithrombin-proteinase complex (Kvassman et al., 1998). Recent structure/ function analyses also indicate that proteinase inhibition and heparin release are linked to reinsertion of the reactive loop into the beta-sheet and translocation of the proteinase from its initial low-affinity interaction site in the exposed reactive loop to the other end of the antithrombin molecule (Stratikos and Gettins, 1999).

This work was supported by NSF grant MCB-9601411 and National Institutes of Health-HL 57936. The computational geometry component was supported in part by NSF grant DBI-0078270 to J. Liang.


Arakawa, T., and S. N. Timasheff. 1985. Mechanisms of poly(ethylene glycol) interaction with proteins. Biochemistry. 24:6756-6762.

Atha, D. H., and K. C. Ingham. 1981. Mechanism of precipitation of proteins by polyethylene glycols: analysis in term of excluded volume. J. Biol. Chem. 256:12108-12117.

Beauchamp, N. J., R. N. Pike, M. Daly, L. Butler, M. Makris, T. R. Dafforn, A. Zhou, H. L. Fitton, F. E. Preston, I. R. Peake, and R. W. Carrell. 1998. Antithrombins Wibble and Wobble (T85M/K): archetypal conformational diseases with in vivo latent-transition, thrombosis, and heparin activation. Blood. 92:2696-2706.

Bryant, R. G. 1996. The dynamics of water-protein interactions. Annu. Rev. Biophys. Biomol. Struct. 25:29-53.

Carrell, R. W., D. L. Evans, and P. E. Stein. 1991. Mobile reactive centre of serpins and the control of thrombosis. Nature. 353:576-579. Colombo, M. F., D. C. Rau, and V. A. Parsegian. 1992. Protein solvation

in allosteric regulation: a water effect on hemoglobin. Science. 256: 655-659.

Connolly, M. L. 1983. Analytical molecular surface calculations. J. AppL Cryst. 16:548-558.

Craig, P. A., S. T. Olson, and J. D. Shore. 1989. Transient kinetics of heparin-catalyzed protease inactivation by antithrombin In: characterization of assembly, product formation, and heparin dissociation steps in the factor Xa reaction. J. Biol. Chem. 264:5452-5461.

Desai, U. R., M. Petitou, I. Bjork, and S. T. Olson. 1998. Mechanism of heparin activation of antithrombin: evidence for an induced-fit model of allosteric activation involving two interaction subsites. Biochemistry. 37:13033-13041.

Douzou, P. 1994. Osmotic regulation of gene action. Proc. Natl. Acad. Sci. U.S.A. 91:1657-1661.

Ersdal-Badju, E., A. Lu, Y. Zuo, V. Picard, and S. C. Bock. 1997. Identification of the antithrombin III heparin binding site. J. Biol. Chem. 272:19393-19400.

Futamura, A., and P. G. Gettins. 2000. Serine 380 (P14) - glutamate mutation activates antithrombin as an inhibitor of factor Xa. J. Biol. Chem. 275:4092-4098.

Glasstone, S., K. Laidler, and H. Eyrin. 1941. The Theory of Rate Processes. McGraw-Hill, New York. 1-27.

Hermans, J. 1982. Excluded-volume theory of polymer-protein interactions based on polymer chain statistics. J. Chem. Phys. 77:2193-2203. Hochachka, P. W., and G. N. Somero. 1973. Strategies of Biochemical

Adaptation. W. B. Saunder Co., Philadelphia. 358.

Huntington, J. A., S. T. Olson, B. Fan, and P. G. Gettins. 1996. Mechanism of heparin activation of antithrombin: evidence for reactive loop prein

sertion with expulsion upon heparin binding. Biochemistry. 35: 8495-8503.

Jin, L., J. P. Abrahams, R. Skinner, M. Petitou, R. N. Pike, and R. W. Carrell. 1997. The anticoagulant activation of antithrombin by heparin. Proc. Natl. Acad. Sci. U.S.A. 94:14683-14688.

Johnson, F. H., and H. Eyrin. 1970. High Pressure Effects on Cellular Processes. A. H. Zimmerman, editor. Academic Press, New York. 1-44. Jordan, R. E., G. M. Oosta, W. T. Gardner, and R. D. Rosenberg. 1980. The

kinetics of hemostatic enzyme-antithrombin interactions in the presence of low molecular weight heparin. J. Biol. Chem. 255:10081-10900. Knoll, D., and J. Hermans. 1983. Polymer-protein interactions: comparison

of experiment and excluded volume theory. J. Biol. Chem. 258: 5710-5715.

Kuga, S. 206. 1981. Pore size distribution analysis of gel substances by size exclusion chromatography. J. Chromat. 206:449-461.

Kvassman, J. O., I. Verhamme, and J. D. Shore. 1998. Inhibitory mechanisms of serpins: loop insertion forces acylation of plasminogen activator by plasminogen activator inhibitor 1. Biochemistry. 37: 15491-15502.

Lane, D. A., R. R. Olds, and S. L. Thein. 1992. Antithrombin and its deficiency states. Blood Coagul. Fibrinolysis. 3:315-341.

Lawrence, D. A. 1997. The serpin-proteinase complex revealed. Nat. Struct. Biol. 4:339-341.

Lee, K. N., H. Im, S. W. Kang, and M.-H. Yu. 1998. Characterization of a human a 1-antitrypsin variant that is as stable as ovalbumin. J Biol. Chem. 273:2509-2516.

Liang, J., H. Edelsbrunner, P. Fu, P. V. Sudhakar, and S. Subramanian. 1998. Analytical shape computation of macromolecules: I. Molecular area and volume through alpha shape. Proteins. 33:1-17.

Liang, J., H. Edelsbrunner, and C. Woodward. 1998. Anatomy of protein pockets and cavities: measurement of binding site geometry and implications for ligand design. Protein Sci. 7:1884-1897.

Liang, J., and M. P. McGee. 1998. Hydration structure of antithrombin conformers and water transfer during reactive loop insertion. Biophys. J. 75:573-582.

Low, P. S., and. G. N. Somero. 1975. Protein hydration changes during catalysis: a new mechanism of enzymic rate-enhancement and ion activation/inhibition of catalysis. Proc. Natl. Acad. Sci. U.S.A. 72: 3305-3309.

Meagher, J. L., J. M. Beechem, S. T. Olson, and P. G. Gettins. 1998. Deconvolution of the fluorescence emission spectrum of human antithrombin and identification of the tryptophan residues that are responsive to heparin binding. J. Biol. Chem. 273:23283-23289.

Olson, S. T., I. Bjork, and J. D. Shore. 1993. Kinetic characterization of heparin-catalyzed and uncatalyzed inhibition of blood coagulation proteinases by antithrombin. Methods Enzymol. 222:525-559.

Olson S. T., and J. D. Shore. 1981. Binding of high affinity heparin to antithrombin III. Characterization of the protein fluorescence enhancement. J. Biol. Chem. 256:11065-11072.

Parsegian, V. A., R. P. Rand, N. L. Fuller, and D. C. Rau. 1986. Osmotic stress for the direct measurement of intermolecular forces. Methods EnzymoL 227:400-416.

Parsegian, V. A., R. P. Rand, and D. C. Rau. 2000. Osmotic stress, crowding, preferential hydration, and binding: a comparison of perspectives. Proc. Natl. Acad. Sci. U. S. A. 97:3987-3992.

Parthasarathy, N., I. J. Goldberg, P. Silvaram, B. Mulloy, D. M. Frory, and W. D. Wagner. 1994. Oligosaccharide sequences of endothelial cell surface heparan sulfate proteoglycan with affinity for lipoprotein lipase J. BioL Chem. 269:22391-22396.

Rand, R. P. 1992. Raising water to new heights. Science. 256:618. Sakabe, N., K. Sakabe, and K. Sasaki. 1981. Structural Studies of Molecules of Biological Interest. G. Dodson, J. P. Glusker, and D. Sayre, editors. Clarendon, Oxford. 509-526.

Schechter, I., and A. Berger. 1967. On the size of active sites in proteases. I. Papain. Biochem. Biophys. Res. Commun. 27:157-162.

Skinner, R., J. P. Abrahams, J. C. Whisstock, A. M. Lesk, R. W. Carrell, and M. R. Wardell. 1997. The 2.6 A structure of antithrombin indicates a conformational change at the heparin binding site. J. Mol. Biol. 266:601-609.

Skinner, R., W. S. Chang, L. Jin, X. Pei, J. A. Huntington, J. P. Abrahams, R. W. Carrell, and D. A. Lomas. 1998. Implications for function and therapy of a 2.9 A structure of binary-complexed antithrombin. J. Mol. BioL 283:9-14.

Schreuder, H. A., B. deBoer, R. Dijkema, J. Mulder, H. J. Theunissen, P. D., Grootenhuis, and W. G. Hol. 1994. The intact and cleaved human antithrombin Ill complex as a model for serpin-proteinase interaction. Nat. Struct. Biol. 1:48-54.

Stratikos, E., and P. G. Gettins. 1999. Formation of the covalent serpinproteinase complex involves translocation of the proteinase by more than 70 A and full insertion of the reactive center loop into '3-sheet A. Proc. Natl. Acad. Sci. U.S.A. 96:4808-4813.

Tsiang, M. Jain, A. K., and C. S. Gibbs. 1997. Functional requirements for inhibition of thrombin by antithrombin III in the presence and absence of heparin. J. Biol. Chem. 272:12024-12029.

Wilczynska, M., M. Fa, J. Karolin, P. 1. Ohlsson, L. B. Johansson, and T. Ny. 1997. Structural insights into serpin-protease complexes reveal the inhibitory mechanisms of serpins. Nat. Struct. Biol. 4:354-357.

Zhou, A., J. A. Huntington, and R. W. Carrell. 1999. Formation of antithrombin heterodimer in vivo and the onset of thrombosis. Blood. 94:3388-3396.

Maria P. McGee,* Jie Liang,t and James Luba*

*Wake Forest University Medical School, Medicine and Biochemistry Departments, Medical Center Boulevard, Winston-Salem, North Carolina 27157 USA; and tUniversity of Illinois at Chicago, Bioengineering Department, Chicago, Illinois 60607 USA

Submitted May 10, 2001, and accepted for publication November 15, 2001.

Address reprint requests to: Maria P. McGee, Wake Forest University Medical School, Medicine and Biochemistry Departments, Medical Center Boulevard, Winston-Salem, NC 27157. Tel.: 336-716-6716; Fax: 336-7169821; E-mail:

Copyright Biophysical Society Feb 2002
Provided by ProQuest Information and Learning Company. All rights Reserved

Return to Antithrombin deficiency, congenital
Home Contact Resources Exchange Links ebay