Journal articles: 'Antithrombin'

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Izaguirre, Gonzalo, Richard Swanson, Srikumar M. Raja, Alireza R. Rezaie, and Steven T. Olson. "Mechanism by Which Exosites Promote the Inhibition of Blood Coagulation Proteases by Heparin-activated Antithrombin." Journal of Biological Chemistry 282, no. 46 (September 17, 2007): 33609–22. http://dx.doi.org/10.1074/jbc.m702462200.

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Heparin activates the serpin, antithrombin, to inhibit its target blood-clotting proteases by generating new protease interaction exosites. To resolve the effects of these exosites on the initial Michaelis docking step and the subsequent acylation and conformational change steps of antithrombin-protease reactions, we compared the reactions of catalytically inactive S195A and active proteases with site-specific fluorophore-labeled antithrombins that allow monitoring of these reaction steps. Heparin bound to N,N′-dimethyl-N-(acetyl)-N′-(7-nitrobenz-3-oxa-1,3-diazol-4-yl)ethylenediamine (NBD)-fluorophore-labeled antithrombins and accelerated the reactions of the labeled inhibitor with thrombin and factor Xa similar to wild type. Equilibrium binding of NBD-labeled antithrombins to S195A proteases showed that exosites generated by conformationally activating antithrombin with a heparin pentasaccharide enhanced the affinity of the serpin for S195A factor Xa minimally 100-fold. Moreover, additional bridging exosites provided by a hexadecasaccharide heparin activator enhanced antithrombin affinity for both S195A factor Xa and thrombin at least 1000-fold. Rapid kinetic studies showed that these exosite-mediated enhancements in Michaelis complex affinity resulted from increases in kon and decreases in koff and caused antithrombin-protease reactions to become diffusion-controlled. Competitive binding and kinetic studies with exosite mutant antithrombins showed that Tyr-253 was a critical mediator of exosite interactions with S195A factor Xa; that Glu-255, Glu-237, and Arg-399 made more modest contributions to these interactions; and that exosite interactions reduced koff for the Michaelis complex interaction. Together these results show that exosites generated by heparin activation of antithrombin function both to promote the formation of an initial antithrombin-protease Michaelis complex and to favor the subsequent acylation of this complex.

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Zhou, Aiwu, James A. Huntington, and Robin W. Carrell. "Formation of the Antithrombin Heterodimer In Vivo and the Onset of Thrombosis." Blood 94, no. 10 (November 15, 1999): 3388–96. http://dx.doi.org/10.1182/blood.v94.10.3388.422k20_3388_3396.

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Antithrombin is shown to undergo a slow spontaneous conversion to its inactive latent conformation with readily discernible amounts present in plasma on incubation at 37°C for 72 hours. More rapid conversion occurs on incubation of isolated antithrombin at 41°C or 50°C, but the appearance on electrophoresis of free latent antithrombin is preceded by the formation, in reciprocal proportions, of a new slow band. This slow component is shown to be a heterodimer of active and latent antithrombin. It can be isolated as a single stable band either by incubation of antithrombin or by mixing equimolar proportions of active and latent antithrombin under the same conditions that give overnight crystallization of the active/latent antithrombin heterodimer. Similarly, equimolar addition of latent antithrombin to plasma results electrophoretically in a quantitative shift to the slower heterodimer mobility. Clinically, the presence of latent antithrombin is potentially deleterious, because its linkage to form the heterodimer results in inactivation of the otherwise normal molecule linked to the latent antithrombin. In the case of -antithrombin, because the dimer readily dissociates, there is only a 11% additive loss of activity, but with β-antithrombin the dimer appears more stable, with the additive loss of activity from the normal β component being 21%, increasing to 33% on stabilization of the dimer with heparin. This linked and selective loss of activity of β-antithrombin provides an explanation for the unexpected severity of thrombotic episodes in heterozygotes with conformationally unstable antithrombins.

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Chang, Wun-Shaing W., and Paul L. Harper. "Commercial Antithrombin Concentrate Contains Inactive L-forms of Antithrombin." Thrombosis and Haemostasis 77, no. 02 (1997): 323–28. http://dx.doi.org/10.1055/s-0038-1655962.

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SummaryThe preparation of antithrombin concentrate for clinical use requires a viral inactivation step. In most commercial preparations this is achieved by heat pasteurisation. This process would be expected to alter the conformation of antithrombin from the active native species to an inactive latent (L-form) state (1, 2). To determine if this occurs during commercial preparation and to identify the proportion of the product in the inactive state, we examined the various antithrombin conformations within a therapeutic concentrate. The antithrombin concentrate was separated into five fractions by heparin-Sepharose chromatography. The fraction with the highest heparin affinity retained full activity, whereas the four fractions with reduced heparin affinity (~40% of the total antithrombin) had lost their inhibitory function. These inactive antithrombins were intact, monomeric, thermostable and resistant to unfolding in 8 M urea. Moreover, the protein patterns on isoelectric focusing and non-denaturing-PAGE showed that there were at least two different L-forms with isoelectric points separate from the native active species. Our findings demonstrate that approximately 40% of the antithrombin preparation examined exists as inactive l-forms. The clinical significance of administering this altered material is uncertain.

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Zhang, Weiqing, Yung-Jen Chuang, Richard Swanson, Juan Li, Kyunga Seo, Lawrence Leung, Lester F. Lau, and Steven T. Olson. "Antiangiogenic antithrombin down-regulates the expression of the proangiogenic heparan sulfate proteoglycan, perlecan, in endothelial cells." Blood 103, no. 4 (February 15, 2004): 1185–91. http://dx.doi.org/10.1182/blood-2003-08-2920.

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Abstract Antithrombin, a key serpin family regulator of blood coagulation proteases, is transformed into a potent antiangiogenic factor by limited proteolysis or mild heating. Here, we show by cDNA microarray, semiquantitative reverse transcriptase–polymerase chain reaction (RT-PCR), Northern blotting, and immunoblotting analyses that the expression of the proangiogenic heparan sulfate proteoglycan (HSPG), perlecan, but not other HSPGs, is dramatically down-regulated in human umbilical vein endothelial cells (HUVECs) treated with antiangiogenic cleaved and latent forms of antithrombin but not with the native form. Down-regulation of perlecan expression by cleaved and latent antithrombins was observed in both basic fibroblast growth factor (bFGF)–stimulated and unstimulated cells, whereas the antiangiogenic antithrombins inhibited the proliferation of only bFGF-stimulated HUVECs by arresting cells at the G1 cell cycle phase. The importance of perlecan expression levels in mediating the antiproliferative effect of the antiangiogenic antithrombins was suggested by the finding that transforming growth factor-β1, a potent stimulator of perlecan expression in endothelial cells, blocked the down-regulation of perlecan expression and antiproliferative activity of cleaved antithrombin on endothelial cells. The previously established key role of perlecan in mediating bFGF stimulation of endothelial cell proliferation and angiogenesis suggests that a primary mechanism by which antiangiogenic antithrombins exert their effects is through the down-regulation of perlecan expression.

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Kaneider, Nicole C., Christina M. Reinisch, Stefan Dunzendorfer, Jürgen Römisch, and Christian J. Wiederman. "Syndecan-4 mediates antithrombin-induced chemotaxis of human peripheral blood lymphocytes and monocytes." Journal of Cell Science 115, no. 1 (January 1, 2002): 227–36. http://dx.doi.org/10.1242/jcs.115.1.227.

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Antithrombin inhibits chemokine-induced migration of neutrophils by activating heparan sulfate proteoglycan-dependent signaling. Whether antithrombin affects migration of other types of leukocytes is not known. We investigated the effects of antithrombin on spontaneous and chemokine-triggered migration of lymphocytes and monocytes from human peripheral blood in modified Boyden chamber micropore filter assays. Lymphocyte and monocyte populations from human peripheral blood were purified using magnetic antibody cell sorting. The signaling mechanisms required for antithrombin-dependent migration were studied using signaling enzyme blockers. Expression of heparan sulfate proteoglycan core protein was studied by RT-PCR and flow cytometry. The antithrombins used were Kybernin®P from human plasma and a monoclonal-antibody-purified preparation from this plasma. Pretreatment of lymphocytes and monocytes with antithrombin inhibited chemotaxis toward optimal concentrations of interleukin-8 or Rantes (regulated upon activation normal T-cell expressed and activated) at concentrations of antithrombin as low as 10 nU/ml. In the absence of the chemokines, direct exposure of cells to gradients of antithrombin stimulated migration. Effects of antithrombin were abolished by pretreating cells with heparinase-1, chondroitinase, sodium chlorate and anti-syndecan-4 antibodies. Expression of syndecan-4 mRNA and protein in monocytes and lymphocytes was demonstrated in RT-PCR and anti-syndecan-4 immunoreactivity assays, respectively. In the presence of pentasaccharide, antithrombin lost its effect on cells. Data indicate that antithrombin directly inhibits chemokine-stimulated migration of monocytes and lymphocytes via the effects of its heparin-binding site on cell surface syndecan-4 by activation of protein kinase C and Rho signaling.

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George, PM, P. Pemberton, IC Bathurst, RW Carrell, HL Gibson, S. Rosenberg, RA Hallewell, and PJ Barr. "Characterization of antithrombins produced by active site mutagenesis of human alpha 1-antitrypsin expressed in yeast." Blood 73, no. 2 (February 1, 1989): 490–96. http://dx.doi.org/10.1182/blood.v73.2.490.490.

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Abstract Both congenital and acquired antithrombin-III (AT-III) deficiencies are amenable to replacement therapy. We describe two antithrombins produced by recombinant DNA techniques from human alpha 1-antitrypsin (alpha 1AT) cDNA in yeast. Alteration of the alpha 1AT active site, replacing methionine 358 with arginine, results in a thrombin inhibition rate similar to that of heparin-activated AT-III. Alteration of two further residues, to give a five-residue sequence identical to AT-III, does not increase this rate further. Neither antithrombin is activated by heparin; both are unglycosylated and have shorter in vivo half-lives (t1/2) than human alpha 1AT. These antithrombins should be suitable for therapeutic replacement of AT-III in cases of congenital deficiency and in conditions associated with acquired AT-III deficiency, such as disseminated intravascular coagulation.

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George, PM, P. Pemberton, IC Bathurst, RW Carrell, HL Gibson, S. Rosenberg, RA Hallewell, and PJ Barr. "Characterization of antithrombins produced by active site mutagenesis of human alpha 1-antitrypsin expressed in yeast." Blood 73, no. 2 (February 1, 1989): 490–96. http://dx.doi.org/10.1182/blood.v73.2.490.bloodjournal732490.

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Both congenital and acquired antithrombin-III (AT-III) deficiencies are amenable to replacement therapy. We describe two antithrombins produced by recombinant DNA techniques from human alpha 1-antitrypsin (alpha 1AT) cDNA in yeast. Alteration of the alpha 1AT active site, replacing methionine 358 with arginine, results in a thrombin inhibition rate similar to that of heparin-activated AT-III. Alteration of two further residues, to give a five-residue sequence identical to AT-III, does not increase this rate further. Neither antithrombin is activated by heparin; both are unglycosylated and have shorter in vivo half-lives (t1/2) than human alpha 1AT. These antithrombins should be suitable for therapeutic replacement of AT-III in cases of congenital deficiency and in conditions associated with acquired AT-III deficiency, such as disseminated intravascular coagulation.

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8

Navarro-Fernández, José, María Morena-Barrio, José Padilla, Antonia Miñano, Nataliya Bohdan, Sonia Águila, Irene Martínez-Martínez, et al. "Antithrombin Dublin (p.Val30Glu): a relatively common variant with moderate thrombosis risk of causing transient antithrombin deficiency." Thrombosis and Haemostasis 116, no. 07 (January 2016): 146–54. http://dx.doi.org/10.1160/th15-11-0871.

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SummaryThe key haemostatic role of antithrombin and the risk of thrombosis associated with its deficiency support that the low incidence of antithrombin deficiency among patients with thrombosis might be explained by underestimation of this disorder. It was our aim to identify mutations in SERPINC1 causing transient antithrombin deficiency. SERPINC1 was sequenced in 214 cases with a positive test for antithrombin deficiency, including 67 with no deficiency in the sample delivered to our laboratory. The p.Val30Glu mutation (Antithrombin Dublin) was identified in five out of these 67 cases, as well as in three out of 127 cases with other SERPINC1 mutations. Genotyping in 1593 patients with venous thrombosis and 2592 controls from two populations, revealed a low prevalent polymorphism (0.3 %) that moderately increased the risk of venous thrombosis (OR: 2.9; 95 % CI: 1.07–8.09; p= 0.03) and identified one homozygous patient with an early thrombotic event. Carriers had normal anti-FXa activity, and plasma antithrombin was not sensitive to heat stress or proteolytic cleavage. Analysis of one sample with transient deficit revealed a type I deficiency, without aberrant or increased latent forms. The recombinant variant, which lacked the two amino-terminal residues, had reduced secretion from HEK-EBNA cells, formed hyperstable disulphidelinked polymers, and had negligible activity. In conclusion, p.Val30Glu by affecting the cleavage of antithrombin’s signal peptide, results in a mature protein lacking the N-terminal dipeptide with no functional consequences in normal conditions, but that increases the sensitivity to be folded intracellularly into polymers, facilitating transient antithrombin deficiency and the subsequent risk of thrombosis.

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9

KOIDE, Takehiko. "Antithrombin." Journal of Japan Atherosclerosis Society 23, no. 10 (1996): 573–79. http://dx.doi.org/10.5551/jat1973.23.10_573.

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10

Roemisch, J., E. Gray, J. N. Hoffmann, and C. J. Wiedermann. "Antithrombin." Blood Coagulation& Fibrinolysis 13, no. 8 (December 2002): 657–70. http://dx.doi.org/10.1097/00001721-200212000-00001.

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11

Sakuragawa, Nobuo, Shin-ichi Kondo, Masahiko Katoh, Kaoru Takahashi, and Takehiko Koide. "Antithrombin III microheterogeneity in antithrombin III deficiency and in the antithrombin III abnormality, “antithrombin III toyama”." Thrombosis Research 47, no. 2 (July 1987): 147–53. http://dx.doi.org/10.1016/0049-3848(87)90371-9.

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12

Owen, MC, JY Borg, C. Soria, J. Soria, J. Caen, and RW Carrell. "Heparin binding defect in a new antithrombin III variant: Rouen, 47 Arg to His." Blood 69, no. 5 (May 1, 1987): 1275–79. http://dx.doi.org/10.1182/blood.v69.5.1275.1275.

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Abstract Antithrombin III (AT-III) Rouen is a hereditary abnormal antithrombin with normal progressive inhibitory activity and reduced heparin cofactor activity. It was isolated from the plasma of a woman who suffered a sudden idiopathic sensorineural hearing loss and balance impairment. There was no familial history of thrombosis. By heparin- Sepharose chromatography, AT-III Rouen was separated from the normal antithrombin on elution with increasing concentrations of NaCl. AT-III Rouen eluted earlier than is normal at both pH 7.4 and pH 6.0. At the lower pH, the antithrombins bound more avidly to the column, with the abnormal AT-III eluting closer to the normal than at the higher pH. Two- dimensional peptide mapping of tryptic and Staphylococcus aureus V8 protease digests of carboxymethylated antithrombins was performed on thin-layer silica plates. The abnormal peptide was located by tryptophan staining, and amino acid analysis and sequence studies demonstrated a substitution of an arginine at residue 47 for a histidine. Results from this study suggest that replacement of arginine 47 by a partially positively charged histidine has less effect on the heparin binding affinity than dose replacing it with a neutral cysteine side chain as in AT-III Toyama, in which no heparin binding was observed. In addition, heparin binding per se is not a sufficient condition to activate AT-III.

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13

Owen, MC, JY Borg, C. Soria, J. Soria, J. Caen, and RW Carrell. "Heparin binding defect in a new antithrombin III variant: Rouen, 47 Arg to His." Blood 69, no. 5 (May 1, 1987): 1275–79. http://dx.doi.org/10.1182/blood.v69.5.1275.bloodjournal6951275.

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Antithrombin III (AT-III) Rouen is a hereditary abnormal antithrombin with normal progressive inhibitory activity and reduced heparin cofactor activity. It was isolated from the plasma of a woman who suffered a sudden idiopathic sensorineural hearing loss and balance impairment. There was no familial history of thrombosis. By heparin- Sepharose chromatography, AT-III Rouen was separated from the normal antithrombin on elution with increasing concentrations of NaCl. AT-III Rouen eluted earlier than is normal at both pH 7.4 and pH 6.0. At the lower pH, the antithrombins bound more avidly to the column, with the abnormal AT-III eluting closer to the normal than at the higher pH. Two- dimensional peptide mapping of tryptic and Staphylococcus aureus V8 protease digests of carboxymethylated antithrombins was performed on thin-layer silica plates. The abnormal peptide was located by tryptophan staining, and amino acid analysis and sequence studies demonstrated a substitution of an arginine at residue 47 for a histidine. Results from this study suggest that replacement of arginine 47 by a partially positively charged histidine has less effect on the heparin binding affinity than dose replacing it with a neutral cysteine side chain as in AT-III Toyama, in which no heparin binding was observed. In addition, heparin binding per se is not a sufficient condition to activate AT-III.

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14

Bararu-Bojan, Iris, Maria Cristina Vladeanu (Apavaloaie), Andrei Bojan, Paul-Dan Sirbu, Manuela Ciocoiu, and Oana Badulescu. "The Role of Antithrombin III in the Pathogenesis of the Thrombotic Status in Type 2 Diabetes Mellitus." Revista de Chimie 70, no. 3 (April 15, 2019): 1047–52. http://dx.doi.org/10.37358/rc.19.3.7061.

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Diabetes mellitus is one of the costliest chronic pathology worldwide with a continuous rising incidence. Diabetes mellitus is linked to frequent cardiovascular events. It is associated with vascular events, especially when the glycated hemoglobin has elevated values. Diabetic patients seem to develop abnormalities of the haemostatic process, such as alterations of the thrombocytic function, modifications of the coagulation and of the fibrinolysis that lead to a thrombophillic status. The acquired thrombophilia present in diabetic patients may be due to the non-enzymatic glycosilation of clotting inhibitors such as antithrombine. Antithrombin III has both an anticoagulant and an antiinflammatory effect. The anticoagulant effect appears after acting upon endothelial heparan sulfate or on the molecule of heparine, thus leading to an inhibition of thrombin. A decrease in antithrombin III levels may lead to a diminished neutralisation of thrombin and a lower activity of proteins C and S, thus inducing procoagulant consequences and increasing the susceptibility for thrombotic events. Our research tried to establish whether the levels of antithrombin III in type 2 diabetic patiens are modified, thus creating a predisposition for thrombotic events. Therefore we conducted an observational study on a sample composed of 60 patients having a diagnostic of type 2 diabetes associated with coronary artery disease, controlled with diet or with oral antidiabetics and we evaluated the levels of antithrombin III in function of the metabolic, inflammatory and coronarographic parameters. Our research showed that even though all patients were characterized by the diabetic dyslipidemia, there was no statistic relationship between antithrombin III and the lipidic fractions. As a result we cannot say that the adverse cardiac events seen in type 2 diabetic patients are influenced by the levels of antithrombin III, as a marker of an increased clotting activity.

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Kottke-Marchant, Kandice, and Alexander Duncan. "Antithrombin Deficiency." Archives of Pathology & Laboratory Medicine 126, no. 11 (November 1, 2002): 1326–36. http://dx.doi.org/10.5858/2002-126-1326-ad.

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Abstract Objective.—To review the current understanding of the pathophysiology of antithrombin deficiency and its role in congenital thrombophilia. Recommendations for diagnostic testing of antithrombin function and concentration, derived from the medical literature and consensus opinions of recognized experts in the field, are included. These recommendations specify whom, how, and when to test. Data Sources.—Review of the published medical literature. Data Extraction and Synthesis.—A summary of the medical literature and proposed testing recommendations were prepared and presented at the College of American Pathologists Conference XXXVI: Diagnostic Issues in Thrombophilia. After discussion at the conference, consensus recommendations presented in this article were accepted after a two-thirds majority vote by the participants. Conclusions.—Antithrombin deficiency is an infrequent genetic abnormality that may be a significant contributing cause of thrombophilia. Antithrombin deficiency also may be observed in conjunction with other genetic or acquired risk factors. Assay of antithrombin plasma levels is appropriate in the laboratory evaluation of individuals with thrombophilia, preferably using a functional, amidolytic antithrombin assay. The diagnosis of antithrombin deficiency should be established only after other acquired causes of antithrombin deficiency, such as liver disease, consumptive coagulopathy, or heparin therapy, are excluded. A low antithrombin level should be confirmed with a subsequent assay on a fresh specimen, and family studies may be helpful to establish the diagnosis. Antigenic antithrombin assays may be of benefit in subclassification of the type of antithrombin deficiency and to confirm the decreased antithrombin level in patients with type I deficiency.

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Cada, Dennis J., Terri L. Levien, and Danial E. Baker. "Antithrombin (Recombinant)." Hospital Pharmacy 44, no. 9 (September 2009): 785–93. http://dx.doi.org/10.1310/hpj4409-785.

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Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing inservices. A comprehensive target drug utilization evaluation (DUE) is also provided each month. With a subscription, the monographs are sent in print and are also available online. Monographs can be customized to meet the needs of a facility. Subscribers to The Formulary Monograph Service also receive access to a pharmacy bulletin board, The Formulary Information Exchange (The F.I.X.). All topics pertinent to clinical and hospital pharmacy are discussed on The F.I.X. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service or The F.I.X., call The Formulary at 800-322-4349. The September 2009 monograph topics are dronedarone, prasugrel, ferumoxytol injection, canakinumab injection, and ibuprofen injection. The DUE is on dronedarone.

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O'Reilly, Michael. "Antiangiogenic Antithrombin." Seminars in Thrombosis and Hemostasis 33, no. 7 (October 2007): 660–66. http://dx.doi.org/10.1055/s-2007-991533.

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Cieśla, Marek, Ewa Wypasek, Javier Corral, Martine Alhenc-Gelas, and Anetta Undas. "Antithrombin Katowice." Blood Coagulation & Fibrinolysis 26, no. 1 (January 2015): 95–97. http://dx.doi.org/10.1097/mbc.0000000000000182.

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Szymańska, Magdalena, Martine Alhenc-Gelas, and Anetta Undas. "Antithrombin Rybnik." Blood Coagulation & Fibrinolysis 24, no. 5 (July 2013): 579–80. http://dx.doi.org/10.1097/mbc.0b013e32835ef7b3.

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Beresford, Charles H., and Maurice C. Owen. "Antithrombin III." International Journal of Biochemistry 22, no. 2 (January 1990): 121–28. http://dx.doi.org/10.1016/0020-711x(90)90172-y.

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Morrisette, Matthew J., Amanda Zomp-Wiebe, Katherine L. Bidwell, Steven P. Dunn, Michael G. Gelvin, Dustin T. Money, and Surabhi Palkimas. "Antithrombin supplementation in adult patients receiving extracorporeal membrane oxygenation." Perfusion 35, no. 1 (June 19, 2019): 66–72. http://dx.doi.org/10.1177/0267659119856229.

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Introduction: Extracorporeal membrane oxygenation is associated with an increased risk of thrombosis and hemorrhage. Acquired antithrombin deficiency often occurs in patients receiving extracorporeal membrane oxygenation, necessitating supplementation to restore adequate anticoagulation. Criteria for antithrombin supplementation in adult extracorporeal membrane oxygenation patients are not well defined. Methods: In this retrospective observational study, adult patients receiving antithrombin supplementation while supported on extracorporeal membrane oxygenation were evaluated. Antithrombin was supplemented when anti-Xa levels were subtherapeutic with unfractionated heparin infusion rates of 15-20 units/kg/h and measured antithrombin activity <50%. Patients were evaluated for changes in degree of anticoagulation and signs of bleeding 24 hours pre- and post-antithrombin supplementation. Results: A total of 14 patients received antithrombin supplementation while on extracorporeal membrane oxygenation. The median percentage of time therapeutic anti-Xa levels were maintained was 0% (0-43%) and 40% (9-84%) in the pre-antithrombin and post-antithrombin groups, respectively (p = 0.13). No difference was observed in the number of patients attaining a single therapeutic anti-Xa level (pre-antithrombin = 6, post-antithrombin = 13; p = 0.37) or unfractionated heparin infusion rate (pre-antithrombin = 7.35 (1.95-10.71) units/kg/h, post-antithrombin = 6.81 (3.45-12.58) units/kg/h; p = 0.33). Thirteen patients (92%) achieved an antithrombin activity at goal following supplementation. Antithrombin activity was maintained within goal range 52% of the time during the replacement period. Four bleeding events occurred pre-antithrombin and 10 events post-antithrombin administration (p = 0.26) with significantly more platelets administered post-antithrombin (pre-antithrombin = 0.5 units, post-antithrombin = 4.5 units; p = 0.01). Conclusion: Therapeutic anticoagulation occurred more frequently following antithrombin supplementation; however, this difference was not statistically significant. More bleeding events occurred following antithrombin supplementation while observing an increase in platelet transfusions.

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Bruzzese, Antonella, Cristina Santoro, Erminia Baldacci, Antonietta Ferretti, Simone Pieroni, Alessandra Serrao, Robin Foà, and Antonio Chistolini. "Antithrombin concentrate during pregnancy in congenital antithrombin deficiency." Blood Coagulation & Fibrinolysis 30, no. 6 (September 2019): 304–7. http://dx.doi.org/10.1097/mbc.0000000000000835.

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de Morais, Karen Batista, Carolina Okamoto Vieira, Isaura Yoshico Hirata, and Anita Mitico Tanaka-Azevedo. "Bothrops jararaca antithrombin: Isolation, characterization and comparison with other animal antithrombins." Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology 152, no. 2 (February 2009): 171–76. http://dx.doi.org/10.1016/j.cbpb.2008.11.002.

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Broman, Lars Mikael. "When antithrombin substitution strikes back." Perfusion 35, no. 1_suppl (May 2020): 34–37. http://dx.doi.org/10.1177/0267659120906770.

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Commercially available products used for antithrombin supplementation, for example, in extracorporeal life support, may contain latent antithrombin, a hyper-stable strongly procoagulative and anti-angiogenic residue. Latent antithrombin is associated with severe thrombosis in the critically ill. In the manufacturing process of fractionated antithrombin from plasma, heat treatment, citrate, and freeze drying speed up the transformation of native antithrombin to latent antithrombin. Manufacturers are not required to assess and report the latent antithrombin content of their products. When reported, the latent antithrombin fractions in their product range from <1% to 40% of total antithrombin compared with <3% in the healthy adult and less in children. The aims of this work were (1) to convey increased awareness to clinicians who may experience defaulted, expected effect after antithrombin supplementation in, for example, heparin anticoagulation during extracorporeal life support and (2) to urge manufacturers to assess and disclose latent antithrombin content in their products.

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Larsson, Helena, Peter Åkerud, Kerstin Nordling, Elke Raub-Segall, Lena Claesson-Welsh, and Ingemar Björk. "A Novel Anti-angiogenic Form of Antithrombin with Retained Proteinase Binding Ability and Heparin Affinity." Journal of Biological Chemistry 276, no. 15 (January 12, 2001): 11996–2002. http://dx.doi.org/10.1074/jbc.m010170200.

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Latent antithrombin, an inactive antithrombin form with low heparin affinity, has previously been shown to efficiently inhibit angiogenesis and tumor growth. We now show that heat treatment similar to that used for preparation of latent antithrombin also transforms antithrombin to another form, which we denote prelatent, with potent anti-angiogenic and anti-tumor activity but with retained proteinase- and heparin-binding properties. The ability of prelatent antithrombin to inhibit angiogenesis is presumably due to a limited conformational change, which may partially resemble that in latent antithrombin. Such a change is evidenced by a different cleavage pattern of prelatent than of native antithrombin by nontarget proteinases. Prelatent antithrombin exerts its anti-angiogenic effect by a similar mechanism as latent antithrombin,i.e.by inhibiting focal adhesion formation and focal adhesion kinase activity, thereby leading to decreased proliferation of endothelial cells. The proteinase inhibitory fractions in commercial antithrombin preparations, which have been heat treated during production, also have anti-angiogenic activity, comparable with that of the prelatent antithrombin form.

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Sanfelippo, Michael J., Jessica M. Engel, and Adedayo A. Onitilo. "Antithrombin Levels Are Unaffected by Warfarin Use." Archives of Pathology & Laboratory Medicine 138, no. 7 (July 1, 2014): 967–68. http://dx.doi.org/10.5858/arpa.2013-0065-oa.

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Context.—The results of studies among patients with antithrombin deficiency have suggested that the use of warfarin will increase the level of antithrombin. Objective.—To reevaluate the effect of warfarin on antithrombin levels using an automated amidolytic method in current use. Design.—Antithrombin levels were measured in patients who were receiving warfarin for atrial fibrillation and were compared with antithrombin levels in preoperative patients who had not received warfarin. Results.—Patients receiving warfarin had a mean antithrombin level of 100.40% (range, 81%–153%). Patients not receiving warfarin had a mean antithrombin level of 99.97% (range, 79%–120%). The Student t test was not significant for a difference between the mean antithrombin levels of the 2 populations. Conclusions.—The use of warfarin does not increase the level of antithrombin in patients receiving the drug.

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Hatton, MW, SL Moar, and M. Richardson. "On the interaction of rabbit antithrombin III with the luminal surface of the normal and deendothelialized rabbit thoracic aorta in vitro." Blood 67, no. 4 (April 1, 1986): 878–86. http://dx.doi.org/10.1182/blood.v67.4.878.878.

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Abstract Pure rabbit antithrombin III was isotope labeled (with 125I or 3H) by two different methods; neither procedure caused a loss of antithrombin activity although both methods affected the affinity of the protein for Sepharose-heparin. From segments from freshly excised rabbit aorta, the uptake of isotope-labeled antithrombin III by the endothelium was rapid and saturable, although relatively small compared to the uptake of thrombin; binding of 3H-antithrombin III to the endothelium resembled that of 125I-antithrombin III. Transendothelial passage of antithrombin III into the subendothelial layers (intima-media) was slow and progressive. Endothelium binding was not affected by pretreating the vessel with either heparin, thrombin, or glycosaminoglycan-specific enzymes. Endothelium-bound antithrombin III was not selectively displaced by either heparin or thrombin. In contrast, endothelium-bound thrombin was rapidly dislodged by antithrombin III as a thrombin- antithrombin III complex. The surface of the deendothelialized aorta (ie, subjected to a balloon catheter) bound antithrombin III avidly. Pretreatment of the deendothelialized vessel with glycosaminoglycan- specific enzymes, particularly heparitinase, decreased intima-media binding by up to 80%. 125I-antithrombin III, when bound to the deendothelialized vessel surface, was actively displaced by either heparin, thrombin, or by unlabeled antithrombin III. The relatively poor binding of antithrombin III compared with that of thrombin by the endothelium in vitro supports an earlier proposal (Lollar P, Owen WG: J Clin Invest 66:1222–1230, 1980) that thrombin bound to high-affinity sites, possibly pericellular proteoglycan, of the endothelium is inactivated by plasma antithrombin III in vivo. Such a situation probably holds for large arteries at least.

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Hatton, MW, SL Moar, and M. Richardson. "On the interaction of rabbit antithrombin III with the luminal surface of the normal and deendothelialized rabbit thoracic aorta in vitro." Blood 67, no. 4 (April 1, 1986): 878–86. http://dx.doi.org/10.1182/blood.v67.4.878.bloodjournal674878.

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Pure rabbit antithrombin III was isotope labeled (with 125I or 3H) by two different methods; neither procedure caused a loss of antithrombin activity although both methods affected the affinity of the protein for Sepharose-heparin. From segments from freshly excised rabbit aorta, the uptake of isotope-labeled antithrombin III by the endothelium was rapid and saturable, although relatively small compared to the uptake of thrombin; binding of 3H-antithrombin III to the endothelium resembled that of 125I-antithrombin III. Transendothelial passage of antithrombin III into the subendothelial layers (intima-media) was slow and progressive. Endothelium binding was not affected by pretreating the vessel with either heparin, thrombin, or glycosaminoglycan-specific enzymes. Endothelium-bound antithrombin III was not selectively displaced by either heparin or thrombin. In contrast, endothelium-bound thrombin was rapidly dislodged by antithrombin III as a thrombin- antithrombin III complex. The surface of the deendothelialized aorta (ie, subjected to a balloon catheter) bound antithrombin III avidly. Pretreatment of the deendothelialized vessel with glycosaminoglycan- specific enzymes, particularly heparitinase, decreased intima-media binding by up to 80%. 125I-antithrombin III, when bound to the deendothelialized vessel surface, was actively displaced by either heparin, thrombin, or by unlabeled antithrombin III. The relatively poor binding of antithrombin III compared with that of thrombin by the endothelium in vitro supports an earlier proposal (Lollar P, Owen WG: J Clin Invest 66:1222–1230, 1980) that thrombin bound to high-affinity sites, possibly pericellular proteoglycan, of the endothelium is inactivated by plasma antithrombin III in vivo. Such a situation probably holds for large arteries at least.

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Logston, Brittany B., Emily A. Rodman, Kimberly L. Dinh, Jennifer L. Placencia, Brady S. Moffett, and Danielle R. Rios. "Effect of Exogenous Antithrombin Administration on Anti-Xa Levels in Infants Treated With Enoxaparin." Journal of Pediatric Pharmacology and Therapeutics 23, no. 4 (July 1, 2018): 315–19. http://dx.doi.org/10.5863/1551-6776-23.4.315.

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OBJECTIVES Determine the effect of exogenous antithrombin III administration on low molecular weight heparin anti-Xa levels in the context of enoxaparin dosing in infants. METHODS A retrospective chart review of infants receiving concomitant antithrombin III and enoxaparin. The primary objective of this study was to determine the median change in anti-Xa level with antithrombin III supplementation. Secondary objectives were to analyze the median change in antithrombin III levels after administration of exogenous antithrombin III, the dosing of antithrombin III, and the dose of enoxaparin throughout therapy. For a safety analysis, any bleeding events were recorded. RESULTS The study included 17 patients who received a total of 33 doses of antithrombin III. The median change in anti-Xa levels in infants receiving exogenous antithrombin III was 0.2 units/mL (p < 0.001). The median dose of antithrombin III was 50 units/kg and was administered when patients were receiving a median enoxaparin dose of 1.71 mg/kg. The median increase in antithrombin III levels was 16.5% (p < 0.001). CONCLUSIONS These results demonstrated that administration of exogenous antithrombin III to infants who were being treated with enoxaparin results in a significant increase in anti-Xa levels. At this time, there is insufficient evidence to recommend routine administration of antithrombin III to infants on enoxaparin. However, antithrombin III supplementation could be considered a potential option for patients who are unable to adequately achieve therapeutic anti-Xa levels with enoxaparin alone.

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Iba, Toshiaki, Tetsuya Sasaki, Kazutoshi Ohshima, Koichi Sato, Isao Nagaoka, and Jecko Thachil. "The Comparison of the Protective Effects of α- and β-Antithrombin against Vascular Endothelial Cell Damage Induced by Histone in Vitro." TH Open 01, no. 01 (June 2017): e3-e10. http://dx.doi.org/10.1055/s-0037-1603926.

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AbstractAntithrombin is a promising option for the treatment of sepsis, and vascular endothelium is an important target for this fatal condition. Here, we aimed to evaluate the protective effects of different glycoforms of antithrombin on histone-induced endothelial cell damage and explore the responsible mechanisms in an experimental model in vitro. Endothelial cells were treated in vitro using histone H4 to induce cellular damage. Various doses of either α- or β-antithrombin were used as treatment interventions, and both cell viability and the levels of lactate dehydrogenase (LDH) in the medium were assessed. Endothelial cell damage was also assessed using microscopic examination and immunofluorescent staining with anti-syndecan-4 and anti-antithrombin antibodies. As a result, both glycoforms of antithrombin significantly improved cell viability when administered at a physiological dose (150 μg/mL). Cellular injury as evaluated using the LDH level was significantly suppressed by β-antithrombin at a supranormal dose (600 μg/mL). Microscopic observation suggested that β-antithrombin suppressed the endothelial cell damage more efficiently than α-antithrombin. β-Antithrombin suppressed the intensity of syndecan-4 staining which became evident after treatment with histone H4, more prominently than α-antithrombin. The distribution of antithrombin was identical to that of syndecan-4. In conclusion, both α- and β-antithrombin can protect vascular endothelial cells from histone H4-induced damage, although the effect was stronger for β-antithrombin. The responsible mechanisms might involve the binding of antithrombin to the glycocalyx on the endothelial surface. These results provide a theoretical basis for the application of antithrombin to the prevention and treatment of sepsis-related endothelial damage.

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Erdjument, H., D. A. Lane, H. Ireland, M. Panico, V. Di Marzo, I. Blench, and H. R. Morris. "Formation of a covalent disulfide-linked antithrombin-albumin complex by an antithrombin variant, antithrombin “Northwick Park”." Journal of Biological Chemistry 262, no. 28 (October 1987): 13381–84. http://dx.doi.org/10.1016/s0021-9258(19)76436-9.

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Weiler, J. M., and R. J. Linhardt. "Antithrombin III regulates complement activity in vitro." Journal of Immunology 146, no. 11 (June 1, 1991): 3889–94. http://dx.doi.org/10.4049/jimmunol.146.11.3889.

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Abstract Heparin, a polyion, exerts its main activity to inhibit coagulation through a serine protease inhibitor, antithrombin III. Previous studies have clearly shown that heparin in the absence of antithrombin III also has the capacity to regulate C activity. The present studies examined the ability of purified human antithrombin III to regulate classical and alternative pathways of C, alone and in the presence of heparin. Antithrombin III alone inhibited generation of both pathways in a dose-related manner; antithrombin III at 8 micrograms/10(7) cellular intermediates inhibited generation of the classical and alternative pathway convertases by 60 and 42%, respectively. Antithrombin III and heparin augmented each other's capacity to inhibit generation of both convertases in a dose-related manner. Antithrombin III did not appear to inhibit on the basis of charge because it is only slightly anionic (isoelectric pH value, 5.0); instead, antithrombin III may have acted as a serine protease inhibitor of the proteolytic enzymes of the C cascades. Antithrombin III acted only to inhibit formation of the alternative pathway convertase but had no activity on terminal lysis by this pathway; similarly, antithrombin III inhibited preformed EAC1,4b,2a,3b but had no activity on classical pathway cellular intermediates containing additional components. Finally, antithrombin III inhibited consumption of factor B hemolytic activity in a reaction mixture that also contained factor D and C3b, suggesting that factor D activity was also inhibited. These studies demonstrate the capacity of antithrombin III to regulate C and suggest that, in concert with heparin, antithrombin III may play an important role in the regulation of C in vivo.

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Hayakawa, Mineji, Kazuma Yamakawa, Daisuke Kudo, and Kota Ono. "Optimal Antithrombin Activity Threshold for Initiating Antithrombin Supplementation in Patients With Sepsis-Induced Disseminated Intravascular Coagulation: A Multicenter Retrospective Observational Study." Clinical and Applied Thrombosis/Hemostasis 24, no. 6 (March 8, 2018): 874–83. http://dx.doi.org/10.1177/1076029618757346.

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Low-dose antithrombin supplementation therapy (1500 IU/d for 3 days) improves outcomes in patients with sepsis-induced disseminated intravascular coagulation (DIC). This retrospective study evaluated the optimal antithrombin activity threshold to initiate supplementation, and the effects of supplementation therapy in 1033 patients with sepsis-induced DIC whose antithrombin activity levels were measured upon admission to 42 intensive care units across Japan. Of the 509 patients who had received antithrombin supplementation therapy, in-hospital mortality was significantly reduced only in patients with very low antithrombin activity (≤43%; bottom quartile; adjusted hazard ratio: 0.603; 95% confidence interval: 0.368-0.988; P = .045). Similar associations were not observed in patients with low, moderate, or normal antithrombin activity levels. Supplementation therapy did not correlate with the incidence of bleeding requiring transfusion. The adjusted hazard ratios for in-hospital mortality increased gradually with antithrombin activity only when initial activity levels were very low to normal but plateaued thereafter. We conclude that antithrombin supplementation therapy in patients with sepsis-induced DIC and very low antithrombin activity may improve survival without increasing the risk of bleeding.

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Hoffmann, Johannes, Christian Wiedermann, Mathias Juers, Helmut Ostermann, Joachim Kienast, Josef Briegel, Richard Strauss, Brian Warren, and Steven Opal. "Benefit/risk profile of high-dose antithrombin in patients with severe sepsis treated with and without concomitant heparin." Thrombosis and Haemostasis 95, no. 05 (2006): 850–56. http://dx.doi.org/10.1160/th05-07-0530.

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SummaryA randomised, prospective, placebo-controlled phase III multicentre clinical trial (KyberSept) has been performed to test the efficacy of high-dose antithrombin therapy in patients with severe sepsis. Concomitant low-dose heparin has been routinely given in two thirds of patients for deep vein thrombosis prophylaxis.This study analyses heparin – antithrombin interactions in terms of long-term mortality, adverse events, and thromboembolic events. From a total of 2,314 patients with severe sepsis (placebo: n=1,157; antithrombin: n=1,157) 1,616 patients (placebo: 811, antithrombin: 805) received heparin concomitantly with study drug (antithrombin 30,000 IU) over four days, whereas 698 patients (346 and 352, respectively) did not. In patients with no concomitant heparin, 28-day mortality was lower with antithrombin than with placebo (37.8% vs. 43.6%; absolute reduction: 5.8%; risk ratio: 0.860 [0.725–1.019]), which increased until day-90 (44.9% vs. 52.5%; absolute reduction: 7.6%; risk ratio: 0.851 [0.735–0.987]). In patients with concomitant heparin, no effect of antithrombin on mortality was seen (28-day mortality: 39.4% vs. 36.6%; absolute increase: 2.8%; risk ratio: 1.08 [0.96–1.22]). Frequency of use of concomitant heparin increased during conduct of the study. Increased bleeding incidences were reported with antithrombin plus concomitant heparin as compared to antithrombin alone. Rates of thromboembolic events were similar when antithrombin was given with or without concomitant heparin. In the treatment of severe sepsis, high-dose antithrombin may sufficiently protect against development of venous thromboembolism when no concomitant heparin is given. Combined administration of the two increases bleeding risk and probably abolishes efficacy of antithrombin.

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Devraj-Kizuk, R., DH Chui, EV Prochownik, CJ Carter, FA Ofosu, and MA Blajchman. "Antithrombin-III-Hamilton: a gene with a point mutation (guanine to adenine) in codon 382 causing impaired serine protease reactivity." Blood 72, no. 5 (November 1, 1988): 1518–23. http://dx.doi.org/10.1182/blood.v72.5.1518.1518.

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Abstract Antithrombin-III-Hamilton is a structural mutant of antithrombin III with defective serine protease reactivity, demonstrable in three members of a French Canadian family. The propositus, a 54-year-old man with a history of recurrent thromboembolic events, and his two asymptomatic grown children are heterozygous for the mutant antithrombin III gene. In all three individuals, the immunoreactive antithrombin III level is normal, while the antithrombin and antifactor Xa activity is approximately 50% of the control value. Two dimensional immunoelectrophoresis of antithrombin-III-Hamilton in the presence of heparin is normal. Purified antithrombin-III-Hamilton did not form thrombin-antithrombin III complex when incubated with thrombin for up to 30 minutes. The normal and mutant antithrombin III alleles of the propositus could be distinguished by linkage to Pstl restriction fragment length polymorphisms (RFLP). Genomic DNA from the propositus was cloned into EMBL 3 phage vectors and two clones containing nearly complete copies of the antithrombin-III-Hamilton allele were identified. Exon 6 of both clones was subcloned into M13 phage vector and sequenced, revealing a G----A point mutation in the first base of codon 382. Codon 382 codes for alanine in the normal allele and for threonine in the antithrombin-III-Hamilton allele. Alanine-382, 12 residues from the reactive center, is a highly conserved amino acid in the family of serine protease inhibitors known as the serpins. We postulate that, as a result of the substitution of threonine for alanine in antithrombin-III-Hamilton, either the tertiary structure or the hydrophobicity of the thrombin-binding region is altered, causing aberrant conformation of the Arg-393-Ser-394 bond at the reactive center impairing the interaction between antithrombin-III-Hamilton and the activated serine proteases.

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Devraj-Kizuk, R., DH Chui, EV Prochownik, CJ Carter, FA Ofosu, and MA Blajchman. "Antithrombin-III-Hamilton: a gene with a point mutation (guanine to adenine) in codon 382 causing impaired serine protease reactivity." Blood 72, no. 5 (November 1, 1988): 1518–23. http://dx.doi.org/10.1182/blood.v72.5.1518.bloodjournal7251518.

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Antithrombin-III-Hamilton is a structural mutant of antithrombin III with defective serine protease reactivity, demonstrable in three members of a French Canadian family. The propositus, a 54-year-old man with a history of recurrent thromboembolic events, and his two asymptomatic grown children are heterozygous for the mutant antithrombin III gene. In all three individuals, the immunoreactive antithrombin III level is normal, while the antithrombin and antifactor Xa activity is approximately 50% of the control value. Two dimensional immunoelectrophoresis of antithrombin-III-Hamilton in the presence of heparin is normal. Purified antithrombin-III-Hamilton did not form thrombin-antithrombin III complex when incubated with thrombin for up to 30 minutes. The normal and mutant antithrombin III alleles of the propositus could be distinguished by linkage to Pstl restriction fragment length polymorphisms (RFLP). Genomic DNA from the propositus was cloned into EMBL 3 phage vectors and two clones containing nearly complete copies of the antithrombin-III-Hamilton allele were identified. Exon 6 of both clones was subcloned into M13 phage vector and sequenced, revealing a G----A point mutation in the first base of codon 382. Codon 382 codes for alanine in the normal allele and for threonine in the antithrombin-III-Hamilton allele. Alanine-382, 12 residues from the reactive center, is a highly conserved amino acid in the family of serine protease inhibitors known as the serpins. We postulate that, as a result of the substitution of threonine for alanine in antithrombin-III-Hamilton, either the tertiary structure or the hydrophobicity of the thrombin-binding region is altered, causing aberrant conformation of the Arg-393-Ser-394 bond at the reactive center impairing the interaction between antithrombin-III-Hamilton and the activated serine proteases.

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Sorial, Mark N., Rebecca A. Greene, Andrew R. Zullo, Christine Berard-Collins, and Steve Willis. "Exogenous supplementation of antithrombin III in adult and pediatric patients receiving extracorporeal membrane oxygenation." International Journal of Artificial Organs 43, no. 5 (November 21, 2019): 315–22. http://dx.doi.org/10.1177/0391398819888932.

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Background: Antithrombin III deficiency can occur with heparin anticoagulation during extracorporeal membrane oxygenation leading to heparin resistance. Antithrombin III supplementation has been shown to improve anticoagulation; however, there is no consensus on appropriate administration. We described the effect of antithrombin III supplementation on coagulation parameters in adult and pediatric extracorporeal membrane oxygenation patients. Methods: We conducted a retrospective cohort study using electronic medical records of patients who received ⩾1 dose of antithrombin III during extracorporeal membrane oxygenation while on continuous heparin. Endpoints included the change in anti-Xa levels and antithrombin III activity at −6 versus 6 h relative to antithrombin III supplementation, and heparin infusion rates at 6 versus 12 h after antithrombin III supplementation. Results: Eighteen patients receiving 36 antithrombin III administrations were analyzed. Mean (standard deviation) anti-Xa values at −6 versus 6 h were 0.15 (0.07) versus 0.24 (0.15) IU/mL ( p-value: 0.250) for pediatrics and 0.19 (0.22) versus 0.31 (0.27) IU/mL ( p-value: 0.052) for adults. Mean (standard deviation) plasma antithrombin III activity at the same intervals were 32% (14.2%) versus 66.8% (25.1%; p-value: 0.062) for pediatrics and 30.3% (14%) versus 52.8% (8.1%; p-value: 0.094) for adults. Mean (standard deviation) heparin rates at 6 versus 12 h after antithrombin III for pediatrics were 23.6 (6) versus 23.5 (6.5) units/kg/h ( p-value: 0.728), and 15.3 (6.6) versus 13.5 (8) units/kg/h ( p-value: 0.188) for adults. Conclusion: Administration of antithrombin III improved anti-Xa levels in both populations, however, did not significantly reduce heparin rates. Our findings suggest that the use of antithrombin III restores heparin responsiveness in patients with low antithrombin III activity and low anti-Xa activity.

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Sharpe, Christopher J., Mark A. Crowther, and Kathryn E. Webert. "Cerebral Venous Thrombosis During Pregnancy in the Setting of Type I Antithrombin Deficiency: Case Report and Literature Review." Blood 114, no. 22 (November 20, 2009): 4447. http://dx.doi.org/10.1182/blood.v114.22.4447.4447.

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Abstract Abstract 4447 Antithrombin is a serine protease inhibitor that primarily inactivates thrombin and factor Xa as well as multiple other coagulation factors. Hereditary deficiency of antithrombin is associated with a 50%-lifetime risk of venous thrombosis. For women who are antithrombin deficient, each single pregnancy and puerperium also carries a 50% risk of a venous thrombotic complication, with the majority of episodes occurring post-partum. Lower extremity thrombosis is most common but unusual sites such as the central nervous system may also be involved. Although there have been previous reports of successful pregnancy outcomes in antithrombin-deficient women without the use of prophylactic anticoagulation in the form of unfractionated heparin or low molecular weight heparin, current treatment guidelines state that asymptomatic women with hereditary antithrombin deficiency should receive thromboprophylaxis during pregnancy. However, the indications for the use of antithrombin concentrate are less defined and current guidelines do not mandate their use during pregnancy in the absence of an episode of venous thromboembolism. Some authors have advocated that antithrombin should be maintained at adequate levels in women with documented antithrombin deficiency throughout the course of pregnancy and the puerperium, while others have recommended normalization of antithrombin levels during the time of delivery only. The use of plasma-derived antithrombin concentrate is controversial considering its expense as well as issues with the frequency and route of administration (daily intravenous injection) and serial monitoring of antithrombin levels. We present a case of a female with a family history of antithrombin deficiency in multiple first-degree relatives and a documented personal history of Type I antithrombin deficiency who presented with a central nervous system transverse sinus thrombosis in the third trimester of pregnancy despite the use of prophylactic therapeutic doses of low molecular weight heparin since conception. Once the cerebral venous thrombosis was diagnosed, a successful pregnancy outcome was achieved with the combined use of therapeutic anticoagulation and antithrombin concentrate to normalize antithrombin levels. This case further illustrates the highly thrombophilic state that exists in the setting of pregnancy and concomitant antithrombin deficiency and lends further debate to the issue of whether antithrombin concentrate, in addition to anticoagulation, should be routinely administered for venous thromboembolic prophylaxis during pregnancy and puerperium to women with documented antithrombin deficiency. This point may become more relevant as further experience is gained with the use of recombinant human antithrombin. Disclosures: Crowther: BI: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Research Funding; Leo Pharma: Consultancy, Honoraria, Research Funding; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Artisan Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Webert:Baxter: Research Funding.

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Jena, Sushanta Kumar, Minakshi Mohanty, Umesh Chandra Patra, and Sanatan Behera. "A study on demographic and clinical profile of children with extra hepatic portal venous obstruction and with special reference to thrombophilic factors." International Journal Of Community Medicine And Public Health 4, no. 3 (February 22, 2017): 640. http://dx.doi.org/10.18203/2394-6040.ijcmph20170468.

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Background: Extra-hepatic portal vein obstruction (EHPVO) due to portal vein thrombosis is an important cause of portal hypertension in several region including India. The cause of thrombosis in these patients remains unclear. Objective of the study was to study the demographic features, etiology, clinical, laboratory findings with special reference to thrombophilic factors like protein C, protein S and antithrombin III deficiency in children with EHPVO.Methods: The prospective analysis of 62 patients of EHPVO (<14 years of age) was done in the Department of Hepatology, SCB medical College, Cuttack. After detailed history, clinical examination, Ultrasound abdomen /color Doppler and Upper GI endoscopy, the subjects were analyzed for any deficiency of thrombophilic factors like protein C, protein S and antithrombin III.Results: A total of 62 patients (37 Male, 25 Female) with mean age of 8.3+3.1 years were studied. Growth retardation was present in the form of wasting (alone) 20.9%, stunting (alone) 25.8% and both wasting and stunting was found in 9.8% cases. History of neonatal, umbilical sepsis and umbilical vein catheterization was found in 15.9% and 10.2% of cases respectively. Haemorrhage from oesophageal varices was prevalent symptoms in 85.9% patients. Splenomegaly was found in 91.9% patients and ascites in 9.4% patients. 47 patients studied for protein C, S and antithromibin III. 14 patients were found to have thrombophilia: protein C deficiency in 9, protein S deficiency in 8, Antithrombin III deficiency in 6.Conclusions: The etiology of EHPVO in the majority of patients remain still unclear. It is commonly associated impaired somatic growth. The risk of EHPVO increases in the presence of thrombophilia, resulting from deficiency of naturally occurring anticoagulant proteins like Protein C, Protein S and Antithrombin III.

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KATO, Io, and Tetsuhito KOJIMA. "Antithrombin in clinic." Japanese Journal of Thrombosis and Hemostasis 25, no. 1 (2014): 33–39. http://dx.doi.org/10.2491/jjsth.25.33.

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Menache, Doris. "Antithrombin III Concentrates." Hematology/Oncology Clinics of North America 6, no. 5 (October 1992): 1115–20. http://dx.doi.org/10.1016/s0889-8588(18)30298-3.

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Carrell, Robin, Richard Skinner, Mark Wardell, and James Whisstock. "Antithrombin and heparin." Molecular Medicine Today 1, no. 5 (August 1995): 226–31. http://dx.doi.org/10.1016/s1357-4310(95)91494-3.

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Stringer, Kathleen A., and Joann Lindenfeld. "Hirudins: Antithrombin Anticoagulants." Annals of Pharmacotherapy 26, no. 12 (December 1992): 1535–40. http://dx.doi.org/10.1177/106002809202601211.

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OBJECTIVE: To review the chemistry, pharmacology, available clinical data, and adverse effects of the hirudin anticoagulants. DATA SOURCES: A MEDLINE search and a review of recent scientific abstracts was conducted to identify pertinent literature. STUDY SELECTION: Focus was placed on studies conducted in humans. Because hirudin is still an investigational agent, however, relevant animal data, particularly pharmacokinetic studies and studies of preclinical efficacy, were also selected. DATA EXTRACTION: Data from both human and animal studies were evaluated; emphasis was placed on human trials. DATA SYNTHESIS: Hirudin has demonstrated potent anticoagulant effects. Although hirudin could have a significant impact on the therapeutic management of patients requiring anticoagulant therapy, only a limited number of human studies have been published to date. Trials comparing hirudin and heparin in specific patient populations are still ongoing. CONCLUSIONS: Although still in clinical trials, hirudin is a unique agent that may represent a breakthrough in anticoagulant therapy. The specific role that this agent will play in the management of patients has yet to be determined.

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Beresford, C. H. "Antithrombin III deficiency." Blood Reviews 2, no. 4 (December 1988): 239–50. http://dx.doi.org/10.1016/0268-960x(88)90013-6.

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Uszynski, Mieczyslaw, Andrzej Kielkowski, Waldemar Uszynski, and Ewa Zekanowska. "Thrombin-Antithrombin III Complexes and Antithrombin III in Amniotic Fluid." Gynecologic and Obstetric Investigation 43, no. 1 (1997): 29–33. http://dx.doi.org/10.1159/000291813.

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Shiozaki, Arihiro, Takashi Arai, Rikuichi Izumi, Kenji Niiya, and Nobuo Sakuragawa. "Congenital antithrombin III deficient neonate treated with antithrombin III concentrates." Thrombosis Research 70, no. 3 (May 1993): 211–16. http://dx.doi.org/10.1016/0049-3848(93)90127-a.

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Rodgers, George. "Role of antithrombin concentrate in treatment of hereditary antithrombin deficiency." Thrombosis and Haemostasis 101, no. 05 (2009): 806–12. http://dx.doi.org/10.1160/th08-10-0672.

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SummaryAntithrombin (AT) functions as a potent natural anticoagulant and serine protease inhibitor that inactivates many enzymes in the coagulation cascade. Antithrombin also possesses anti-inflammatory properties, many of which are mediated by its actions as an anticoagulant. Hereditary AT deficiency is a rare, underrecognised medical condition that is associated with inadequate endogenous anticoagulation thought to result from impaired inhibition of serine protease coagulation factors. Inherited as an autosomal dominant trait, congenital AT deficiency typically reduces functional AT levels to 40–60% of normal. As a result, individuals with hereditary AT deficiency have a ≥50% lifetime risk of venous thromboembolism (VTE). Specifically, AT deficiency is associated with a three- to seven-fold higher risk of VTE compared with other thrombophilias. Thus, maintaining adequate levels of AT during high-risk periods is an important treatment goal. Long-term anticoagulant thromboprophylaxis is not recommended in asymptomatic patients with AT deficiency because of the increased risk of haemorrhage. However, treatment guidelines recommend short-term thromboprophylaxis in high-risk clinical settings, including surgery, trauma, and management of pregnancy, labour, and delivery. The goal of treatment for patients with hereditary AT deficiency is an initial increase in AT activity to ≥120% of normal levels followed by maintenance of AT activity at ≥80% of normal levels. Plasma-derived AT, heparin, fresh frozen plasma, and human recombinant AT are treatment options for individuals with hereditary AT deficiency. The objective of this review is to discuss hereditary AT deficiency and the role of AT replacement therapy in the treatment of patients with this congenital disorder.

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Águila, Sonia, Irene Martínez-Martínez, Miriam Collado, Pilar Llamas, Ana Antón, Consuelo Martínez-Redondo, José Padilla, et al. "Compound heterozygosity involving Antithrombin Cambridge II (p.Ala416Ser) in antithrombin deficiency." Thrombosis and Haemostasis 109, no. 03 (2013): 556–58. http://dx.doi.org/10.1160/th12-09-0707.

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Chan, Anthony K. C., Leslie R. Berry, Nethnapha Paredes, and Nagina Parmar. "Isoform composition of antithrombin in a covalent antithrombin–heparin complex." Biochemical and Biophysical Research Communications 309, no. 4 (October 2003): 986–91. http://dx.doi.org/10.1016/j.bbrc.2003.08.109.

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Beauchamp, N. J., R. N. Pike, M. Daly, L. Butler, M. Makris, T. R. Dafforn, A. Zhou, et al. "Antithrombins Wibble and Wobble (T85M/K): Archetypal Conformational Diseases With In Vivo Latent-Transition, Thrombosis, and Heparin Activation." Blood 92, no. 8 (October 15, 1998): 2696–706. http://dx.doi.org/10.1182/blood.v92.8.2696.

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Abstract The inherent variability of conformational diseases is demonstrated by two families with different mutations of the same conserved aminoacid in antithrombin. Threonine 85 underlies the opening of the main β-sheet of the molecule and its replacement, by the polar lysine, in antithrombin Wobble, resulted in a plasma deficiency of antithrombin with an uncharacteristically severe onset of thrombosis at 10 years of age, whereas the replacement of the same residue by a nonpolar methionine, antithrombin Wibble, gave near-normal levels of plasma antithrombin and more typical adult thromboembolic disease. Isolated antithrombin Wibble had a decreased thermal stability (Tm 56.2, normal 57.6°C) but was fully stabilized by the heparin pentasaccharide (Tm 71.8, normal 71.0°C), indicating that the prime abnormality is a laxity in the transition of the main sheet of the molecule from the 5- to 6-stranded form, as was confirmed by the ready conversion of antithrombin Wibble to the 6-stranded latent form on incubation. That this transition can occur in vivo was shown by the finding of nearly 10% of the proband’s plasma antithrombin in the latent form and also, surprisingly, of small but definitive amounts of latent antithrombin in normal plasma. The latent transition will be predictably accelerated not only by gross mutations, as with antithrombin Wobble, to give severe episodic thrombosis, but also by milder mutations, as with antithrombin Wibble, to trigger thrombosis in the presence of other predisposing factors, including the conformational stress imposed by the raised body temperatures of fevers. Both antithrombin variants had an exceptional (25-fold) increase in heparin affinity and this, together with an increased inhibitory activity against factor Xa, provides evidence of the direct linkage of A-sheet opening to the conformational basis of heparin binding and activation. © 1998 by The American Society of Hematology.

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Journal articles on the topic 'Antithrombin'

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