Inherited Antithrombin Deficiency Causing Thrombophilia

Egeberg, O.

doi:10.1055/s-0038-1656297

Cited by 810 publications

(410 citation statements)

References 26 publications

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“…3 This initial observation has since been confirmed by other groups from different parts of the world.4-6 The pattern of inheritance of Our understanding of the molecular basis of the inherited disorders of antithrombin has been greatly facilitated by the cloning and characterization of the antithrombin gene. 1O -12 It is now recognized that the antithrombin molecule has two important functional domains, namely a thrombin binding domain and a heparin binding domain."…”

Section: Prevalencementioning

confidence: 90%

“…The association between familial antithrombin deficiency and venous thromboembolism was first recognized in a Norwegian family by Egeberg in 1965. 3 This initial observation has since been confirmed by other groups from different parts of the world.4-6 The pattern of inheritance of Our understanding of the molecular basis of the inherited disorders of antithrombin has been greatly facilitated by the cloning and characterization of the antithrombin gene.…”

Section: Prevalencementioning

confidence: 99%

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The Diagnosis and Clinical Management of Thrombophilia

Greaves

Preston

1993

Vascular Medicine Review

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Section: Prevalencementioning

confidence: 90%

Section: Prevalencementioning

confidence: 99%

The Diagnosis and Clinical Management of Thrombophilia

Greaves

Preston

1993

Vascular Medicine Review

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“…Similarly, when plasma kallikrein (final concentration, 32 ,ug/ml) was incubated with either a2PI (70,ug/ml), Clinh Previous studies from many laboratories have shown that the specificities of these inhibitors are broad and to some extent overlapping. For example, Clinh inhibits not only the action of CYbut also the actions of plasmin (26), plasma kallikrein (26), HFf (25), and act.…”

Section: Methodsmentioning

confidence: 99%

“…For example, Clinh deficiency is associated with hereditary angioneurotic edema (30), a1-anti-trypsin deficiency with pulmonary emphysema and hepatic disease (31), and antithrombin III deficiency with thrombosis (32). Thus, the physiologic role of each inhibitor appears to be quite specific, whereas each inhibitor demonstrates a broad in vitro specificity.…”

Section: Methodsmentioning

confidence: 99%

Inhibitory spectrum of alpha 2-plasmin inhibitor.

Saito¹,

Goldsmith²,

Moroi³

et al. 1979

Proc. Natl. Acad. Sci. U.S.A.

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ABSTRACTarPlasmin inhibitor (a2PI) has been recently characterized as a fast-reacting inhibitor of plasmin in human plasma and appears to play an important role in the regulation of fibrinolysis in vivo. We have studied the effect of purified a2PI upon various proteases participating in human blood coagulation and kinin generation. At physiological concentration (50 ;sg/ml), a2PI inhibited the clot-promoting and prekallikrein-activating activity of Hageman factor fragments, the amidolytic, kininogenase, and clot-promoting activities of plasma kallikrein, and the clot-promoting properties of activated plasma thromboplastin antecedent (PTA, Factor XIa) and thrombin. a2PI had minimal inhibitory effect on surface-bound activated PTA and activated Stuart factor (Factor Xa). a2PI did not inhibit the activity of activated Christmas factor (Factor IXa) or urinary kallikrein. Heparin (1.5-2.0 units/ml) did not enhance the inhibitory function of a2PI. These results suggest that, like other plasma protease inhibitors, a2PI possesses a broad in vitro spectrum of inhibitory properties.a2-Plasmin inhibitor (a2PI) has been recently identified as a fast-reacting inhibitor of plasmin in human plasma (1-3). a2PI has strong inhibitory activity against plasmin and is the first inhibitor that reacts with plasmin, whether plasminogen activation occurs in vitro or in vivo (4-6).Although the action of a2PI on plasmin is well characterized, relatively little information is available about the effect of this newly isolated inhibitor upon other plasma proteases (7,8). This paper reports the effect of physiologic concentrations of a2PI upon various proteases participating in blood coagulation and kinin generation and defines the in vitro spectrum of this inhibitor. We also compare the action of a2PI with that of some other plasma protease inhibitors in these systems. MATERIALS AND METHODSInhibitors. Human a2PI was prepared as described (1) and was judged greater than 95% homogeneous on disc gel electrophoresis, sodium dodecyl sulfate gel electrophoresis, and immunoelectrophoresis. The concentration of purified a2PI was determined by using 7.03 as extinction coefficient El% at 280 um. a2-Macroglobulin (a2M), isolated from human plasma (9), gave a single band by sodium dodecyl sulfate gel electrophoresis after reduction with 2-mercaptoethanol (Mr, approximately 180,000). The concentration of a2M was determined by single radial immunodiffusion on Immuno-plates (Hyland, Costa Mesa, CA). Normal serum contains approximately 2 mg of a2M per ml. a2M at 2 mg/ml was essentially free of a2PI (<0.2 ,g/ml) when tested by a sensitive radioitnmunoassay for a2PI (unpublished data). a2M (8 mg/ml) contained no detectable C1 esterase inhibitor (Clinh), a1-antitrypsin, or antithrombin III as assayed by immunodiffusion using monospecific antiserum. Purified Clinh and monospecific antiserum against Clinh were generous gifts of J. Pensky

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“…1 The inhibitory effect of AT, due to the almost irreversible trapping of target proteases, is strongly enhanced by natural glycosaminoglycans such as heparin.…”

Section: Three Novel Mutations Of Antithrombin Inducing High-moleculamentioning

confidence: 99%

Three novel mutations of antithrombin inducing high-molecular-mass compounds.

Emmerich

Vidaud

Alhenc‐Gelas

et al. 1994

Arterioscler Thromb

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We have identified three novel mutations of the antithrombin (AT) gene in patients with thrombotic complications: a Cys 128 -» Tyr mutation, a G -» A mutation in the intervening sequence 4 (FVS4) 14 nucleotide 5' to exon 5, and a 9 bp deletion in the 3' end of exon 6 resulting in a short aberrant sequence after Arg 425. The latter mutation was associated with an Arg 47 -• His mutation in two compound heterozygous brothers. These three mutations led to the expression in the circulation of small amounts of inactive molecules with a high molecular mass in immunoblot analysis. In reducing conditions, these variant molecules had a normal molecular mass, which led us to postulate that these mutations prevent the formation of one intramolecular disulfidc bond and allow the formation of intermolecular disulfide bonds. Plasma from a heterozygous patient bearing the Cys 128 -• A ntithrombin (AT) is the main natural inhibitor of /\ thrombin and other coagulation proteases, and X A. its physiological importance was first shown in 1965 by the description of a hereditary AT deficiency in a family with unexplained thrombosis.1 The inhibitory effect of AT, due to the almost irreversible trapping of target proteases, is strongly enhanced by natural glycosaminoglycans such as heparin.The AT gene, the nucleotide sequence of which has recently been elucidated, 2 maps more than 13 480 bp, comprises 7 exons (1, 2, 3a, 3b, 4, 5, and 6), and encodes a polypeptide of 464 amino acids. Several intracellular modifications occur before the secretion of the folded protein, such as the formation of three intramolecular disulfide bonds in positions 8-128, 21-95, and 247-430 of the amino-acid sequence, glycosylation at four sites, and cleavage of a 32-amino-acid signal peptide (for a review see Reference 3). The structure of the mature protein presents large homologies with other serine protease inhibitors, forming a superfamily called serpins. Crystallographic study of cleaved a-1-antitrypsin provided a working model of three-dimensional serpin structure, 4 the validity of which was recently confirmed by crystal

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Inherited Antithrombin Deficiency Causing Thrombophilia

Cited by 810 publications

References 26 publications

The Diagnosis and Clinical Management of Thrombophilia

The Diagnosis and Clinical Management of Thrombophilia

Inhibitory spectrum of alpha 2-plasmin inhibitor.

Three novel mutations of antithrombin inducing high-molecular-mass compounds.

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