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Minerva Anestesiologica May 2002Antithrombin III plays many different roles during cardiac operations with cardiopulmonary bypass. Basically, it acts as the natural inhibitor of thrombin, which, in... (Review)
Review
Antithrombin III plays many different roles during cardiac operations with cardiopulmonary bypass. Basically, it acts as the natural inhibitor of thrombin, which, in presence of heparin, blocks the thrombin action and avoids gross thrombus formation inside the extracorporeal circulation circuit. By acting as a "suicide substrate", antithrombin III is consumed during cardiopulmonary bypass; at the same time, thrombin is extensively formed during and after cardiopulmonary bypass. As a result, at the end of the operation there is a potential imbalance in the antithrombin III-thrombin interaction, leading to a prothrombotic status. Moreover, patients pre-treated with heparin reach the operating theater with reduced levels of circulating antithrombin III; this may lead to the heparin resistance phenomenon and may further increase the risk for postoperative thrombotic complications. Finally, the anti-inflammatory properties of antithrombin III in the setting of the "whole body inflammatory reaction" induced by the cardiopulmonary bypass represents a new and unexplored field of research.
Topics: Anticoagulants; Antithrombin III; Cardiopulmonary Bypass; Extracorporeal Circulation; Heparin; Humans; Inflammation; Serine Proteinase Inhibitors; Thrombosis
PubMed: 12029263
DOI: No ID Found -
Minerva Anestesiologica May 2002Antithrombin III (ATIII) has been found to be a marker for DIC and to be of prognostic significance in septic patients. Several studies have shown that administration of... (Review)
Review
Antithrombin III (ATIII) has been found to be a marker for DIC and to be of prognostic significance in septic patients. Several studies have shown that administration of ATIII in patients with sepsis related DIC is effective in shortening the duration of DIC. Despite a meta-analysis of randomized controlled trials have shown a significant reduction in 28-day mortality, a prospective randomized double-blind placebo-controlled trial failed to show a significant improvement in overall survival. However the concomitant use of heparin, which does not seem to have an additional beneficial effect, may have obscured the efficacy of ATIII. More studies are needed to understand mechanism of action of ATIII and better define patient population that may benefit from ATIII.
Topics: Anticoagulants; Antithrombin III; Biomarkers; Disseminated Intravascular Coagulation; Humans; Sepsis; Serine Proteinase Inhibitors
PubMed: 12029261
DOI: No ID Found -
Clinical and Applied... Jan 2018Thrombate III is a human plasma-derived antithrombin III (AT-III) often utilized in patients on extracorporeal membrane oxygenation (ECMO) with suspected AT-III-mediated...
Thrombate III is a human plasma-derived antithrombin III (AT-III) often utilized in patients on extracorporeal membrane oxygenation (ECMO) with suspected AT-III-mediated heparin resistance. It is supplied as 500-U and 1000-U vials, costing US$4.66 per unit. Literature is limited in describing the clinical value of AT-III in relation to its high cost. The primary objective was to determine conditions of use and associated cost of potentially unnecessary utilization of AT-III at The Johns Hopkins Hospital. Secondary objectives included evaluating the effect of AT-III on anticoagulation parameters and the overall cost utilized and wasted on AT-III. A retrospective cohort study was performed. The primary end point was the total cost associated with potentially unnecessary utilization of AT-III. There were 326 doses of AT-III administered to 65 patients in 2014. There were 177 (54%) potentially unnecessary doses associated with a cost of US$541 634. Antithrombin III repletion significantly increased median AT-III levels in non-ECMO and ECMO patients compared to baseline (non-ECMO: 62% vs 81%, P < .01; ECMO: 63% vs 81%, P < .01); however, 37.3% of ECMO and 49% of non-ECMO patients had therapeutic anticoagulation monitoring parameters prior to administration. A total cost of US$688 478 was spent on administered AT-III and US$417 194 (38%) was wasted. Utilizing restriction criteria and a new dosing strategy potentially results in estimated annual savings of US$556 000. Utilizing restriction criteria and alternative dosing strategies to mitigate waste and unnecessary use has the potential to result in significant cost savings.
Topics: Adolescent; Adult; Antithrombin III; Child; Child, Preschool; Costs and Cost Analysis; Extracorporeal Membrane Oxygenation; Humans; Infant; Male; Middle Aged; Retrospective Studies
PubMed: 28301908
DOI: 10.1177/1076029617693941 -
Comparative Medicine Aug 2009The characterization of porcine antithrombin III (ATIII)-a highly powerful anticoagulant-is essential for using porcine liver in xenotransplantation applications. The...
The characterization of porcine antithrombin III (ATIII)-a highly powerful anticoagulant-is essential for using porcine liver in xenotransplantation applications. The objective of this study was to clarify the functions of porcine ATIII through comparison with human ATIII. We cloned porcine ATIII and compared its important functional sites with those of human ATIII. The full-length cDNA of porcine ATIII was cloned by screening a porcine liver cDNA library, and the ATIII activities of 23 pigs were determined. The full-length cDNA of porcine ATIII spanned 1498 bp and encoded 463 amino acids. Porcine ATIII shared 87.67% nucleotide identity and 89.06% amino acid identity with human ATIII. Complete identity was found at active center Arg393-Ser394, and remarkably high similarities were found at 2 critical heparin-binding sites (residues 41 through 49 and 114 through 156) and in some key residues involved in heparin binding. An ATIII assay found no significant difference between porcine and human plasma. The high level of similarity between porcine ATIII and human ATIII suggests that porcine ATIII will function in a manner similar to human ATIII in xenotransplantation.
Topics: Amino Acid Sequence; Animals; Antithrombin III; Base Sequence; Cloning, Molecular; DNA, Complementary; Humans; Male; Molecular Sequence Data; Sequence Homology, Amino Acid; Swine
PubMed: 19712578
DOI: No ID Found -
Haematologica Oct 2023
Topics: Humans; Antithrombins; Founder Effect; Poland; Antithrombin III; Mutation; Anticoagulants
PubMed: 37021543
DOI: 10.3324/haematol.2022.282459 -
Blood Advances Feb 2022Plasmodium falciparum-derived histidine-rich protein II (HRPII) has been shown to inhibit heparin-dependent anticoagulant activity of antithrombin (AT) and induce...
Plasmodium falciparum-derived histidine-rich protein II (HRPII) has been shown to inhibit heparin-dependent anticoagulant activity of antithrombin (AT) and induce inflammation in vitro and in vivo. In a recent study, we showed that HRPII interacts with the AT-binding vascular glycosaminoglycans (GAGs) not only to disrupt the barrier-permeability function of endothelial cells but also to inhibit the antiinflammatory signaling function of AT. Here we investigated the mechanisms of the proinflammatory function of HRPII and the protective activity of AT in cellular and animal models. We found that AT competitively inhibits the GAG-dependent HRPII-mediated activation of NF-κB and expression of intercellular cell adhesion molecule 1 (ICAM1) in endothelial cells. Furthermore, AT inhibits HRPII-mediated histone H3 citrullination and neutrophil extracellular trap (NET) formation in HL60 cells and freshly isolated human neutrophils. In vivo, HRPII induced Mac1 expression on blood neutrophils, MPO release in plasma, neutrophil infiltration, and histone H3 citrullination in the lung tissues. HRPII also induced endothelial cell activation as measured by increased ICAM1 expression and elevated vascular permeability in the lungs. AT effectively inhibited HRPII-mediated neutrophil infiltration, NET formation, and endothelial cell activation in vivo. AT also inhibited HRPII-meditated deposition of platelets and fibrin(ogen) in the lungs and circulating level of von Willebrand factor in the plasma. We conclude that AT exerts protective effects against pathogenic effects of P falciparum-derived HRPII in both cellular and animal models.
Topics: Animals; Anticoagulants; Antigens, Protozoan; Antithrombin III; Antithrombins; Endothelial Cells; Histidine; Histones; Inflammation; Plasmodium falciparum; Protozoan Proteins
PubMed: 34768285
DOI: 10.1182/bloodadvances.2021005836 -
Blood May 1992A cDNA containing the complete open-reading frame encoding rabbit antithrombin III (AT-III) was isolated from a rabbit liver cDNA expression library, using a specific...
A cDNA containing the complete open-reading frame encoding rabbit antithrombin III (AT-III) was isolated from a rabbit liver cDNA expression library, using a specific antibody as a probe. Sequence analysis showed 84% identity between the deduced amino acid sequences of the rabbit and human proteins. A previously described cell-free expression system was used to verify the identity of the clone. The full-length cDNA was inserted into an expression vector, and messenger RNA (mRNA) transcripts generated. In vitro translation of these transcripts, in the presence of [35S]methionine, in an mRNA-dependent rabbit reticulocyte lysate system resulted in the synthesis of a 51-Kd polypeptide, as shown by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). This nonglycosylated protein was capable of forming SDS-stable complexes with human alpha-thrombin. Complex formation was significantly enhanced following the deletion of nucleotides encoding the signal peptide, and the resultant generation of a 47-Kd nonglycosylated mature protein product. When the template DNA giving rise to this product was internally truncated, two rabbit AT-III deletion mutants were generated that lacked the ability to interact with thrombin, but retained the ability to bind heparin. Cell-free expression plasmids encoding the human and rabbit AT-III mature molecules were manipulated to produce two interspecies fusion proteins. For the first, human codons were used to replace rabbit codons from residue 369-433, while in the second human codons replaced rabbit codons from residue 217-433. Both fusion proteins exhibited less efficient thrombin-complexing ability than the original cell-free-derived mature rabbit AT-III. Thus, portions of AT-III molecules from the two species, despite their high degree of homology, are not interchangeable. Knowledge of the structure of rabbit AT-III, combined with the availability of the rabbit cDNA, will permit defined experimentation aimed at understanding antithrombin III structure relative to its function in vivo.
Topics: Amino Acid Sequence; Animals; Antithrombin III; Base Sequence; Blotting, Northern; Cell-Free System; Cloning, Molecular; Heparin; Humans; Molecular Sequence Data; Rabbits; Thrombin
PubMed: 1571546
DOI: No ID Found -
Journal of the American College of... Dec 1986Thromboembolic obstruction to three major components of the circulation--arterial, venous and intravascular foreign surfaces--contributes to premature death and... (Review)
Review
Thromboembolic obstruction to three major components of the circulation--arterial, venous and intravascular foreign surfaces--contributes to premature death and disability in Western society. In many, but not all, of these conditions associated with thromboembolism, heparin and warfarin are the drugs of choice. It is the purpose of this presentation to provide some common ground in the area of anticoagulant prophylaxis that will be of intrinsic value for decision making in cardiac, cerebral and peripheral vascular disease. Only those aspects of the hemostatic mechanism most relevant to the antithrombotic action of heparin and warfarin are discussed. Assays for both drugs as well as some practical guidelines for their use in low, medium and high dose regimens are outlined. Techniques for improving the benefit/risk ratio for each drug are specifically detailed.
Topics: Antithrombin III; Blood Coagulation; Drug Therapy, Combination; Heparin; Humans; Thromboembolism; Warfarin
PubMed: 3537062
DOI: 10.1016/s0735-1097(86)80003-1 -
BMJ (Clinical Research Ed.) Dec 2007Evidence shows that it does not improve outcomes and increases the risk of bleeding
Evidence shows that it does not improve outcomes and increases the risk of bleeding
Topics: Antithrombin III; Critical Illness; Hemorrhage; Humans; Risk Factors; Treatment Outcome
PubMed: 18037614
DOI: 10.1136/bmj.39399.552245.80 -
British Journal of Clinical Pharmacology May 2020Antithrombin III (AT-III) concentrates have been used to prevent critical thrombosis in the immediate post-liver transplantation period without clear evidence regarding...
AIMS
Antithrombin III (AT-III) concentrates have been used to prevent critical thrombosis in the immediate post-liver transplantation period without clear evidence regarding the optimal dose or administration scheme. The relationship between the AT-III dosage and the plasma activity levels during the period was evaluated in this study.
METHODS
The plasma AT-III activity levels and clinical data obtained from patients who received liver transplantation from January 2017 to September 2018 were retrospectively analysed. A population pharmacokinetic (PK) model was developed using nonlinear mixed-effects method and externally validated thereafter. Several dosing scenarios were simulated to maintain the plasma AT-III activity level within the normal range using the developed PK model to search for an optimal AT-III dosing regimen.
RESULTS
The plasma AT-III activity levels were best described by a single compartment model with first order elimination kinetics. The recovery of endogenous AT-III level during the postoperative days was modelled using an E model. The typical values (95% confidence interval) of volume of distribution and clearance were 3.86 (3.40-4.32) L, and 0.129 (0.111-0.147) L h , respectively. Serum albumin and body weight had significant effect on clearance and were included in the model. External validation of the proposed model demonstrated adequate prediction performance. Furthermore, simulation of previously suggested or modified dosing scenarios showed successful maintenance of AT-III activity level within the normal range.
CONCLUSION
A population PK model of AT-III concentrate was developed using data from liver recipients. Dosing scenarios simulated in our study may help establish a practical guide for AT-III concentrate titration after liver transplantation.
Topics: Antithrombin III; Female; Humans; Liver Transplantation; Male; Models, Biological; Postoperative Period; Retrospective Studies; Treatment Outcome
PubMed: 31840271
DOI: 10.1111/bcp.14200