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The Cochrane Database of Systematic... Oct 2006Acquired Antithrombin (AT) deficiency is a common and prognostically important finding in sick preterm infants with respiratory distress syndrome (RDS). It has been... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Acquired Antithrombin (AT) deficiency is a common and prognostically important finding in sick preterm infants with respiratory distress syndrome (RDS). It has been hypothesised that AT concentrate may improve clinical outcomes in preterm infants with RDS.
OBJECTIVES
To determine whether the administration of AT concentrate decreases mortality in preterm infants with RDS compared with placebo or no treatment.
SEARCH STRATEGY
An electronic literature search in the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE in August 2006 was performed. No language restriction was applied. References from identified studies were cross-checked for possible additional studies. Experts in the field and pharmaceutical companies were contacted for unpublished data. Abstracts of the American Society of Pediatric Research and European Society of Pediatric Research meetings (1983-2005) were searched and authors of relevant studies were contacted to obtain additional information.
SELECTION CRITERIA
Randomized controlled trials comparing any dose and duration of AT therapy with placebo or no treatment in preterm infants with RDS.
DATA COLLECTION AND ANALYSIS
Two reviewers independently extracted data from included studies regarding mortality, intraventricular hemorrhage, mechanical ventilation, and other reported events in the clinical course of the patients. Data for similar outcomes were combined where appropriate, using a fixed-effects model in MetaView 4.2 (Update Software).
MAIN RESULTS
Two trials consisting of 182 preterm infants, fulfilled the inclusion criteria. Mean gestational age of patients included was 28 weeks. In one trial, patients had to be intubated and ventilated for RDS to be eligible for the study. In the other trial, RDS was not mentioned as an inclusion criteria, however the vast majority of infants in the study received surfactant. No individual trial showed a significant difference in mortality. One of the trials was stopped early because of an increase in deaths in the AT group. The pooled analysis for mortality within the first week of life showed a typical relative risk of 2.67 (95% CI 0.72-9.83) in favour of the control group. Only the trial that was stopped early followed the infants long enough to report neonatal mortality. This trial reported 7 deaths (11.5%) in the AT group and two deaths (3.3%) in the placebo group within 28 days of life. Secondary outcomes included days of mechanical ventilation and supplemental oxygen which were only reported in 1 trial. Both outcomes were in favour of the control group and statistically significant (p < 0.05).
AUTHORS' CONCLUSIONS
Preterm infants with RDS are unlikely to benefit from AT treatment and may be harmed.
Topics: Anticoagulants; Antithrombin III; Antithrombins; Humans; Infant, Newborn; Infant, Premature; Pulmonary Surfactants; Randomized Controlled Trials as Topic; Respiratory Distress Syndrome, Newborn
PubMed: 17054254
DOI: 10.1002/14651858.CD005383.pub2 -
The Journal of Biological Chemistry Nov 2013Allosteric conformational changes in antithrombin induced by binding a specific heparin pentasaccharide result in very large increases in the rates of inhibition of...
The allosteric mechanism of activation of antithrombin as an inhibitor of factor IXa and factor Xa: heparin-independent full activation through mutations adjacent to helix D.
Allosteric conformational changes in antithrombin induced by binding a specific heparin pentasaccharide result in very large increases in the rates of inhibition of factors IXa and Xa but not of thrombin. These are accompanied by CD, fluorescence, and NMR spectroscopic changes. X-ray structures show that heparin binding results in extension of helix D in the region 131-136 with coincident, and possibly coupled, expulsion of the hinge of the reactive center loop. To examine the importance of helix D extension, we have introduced strong helix-promoting mutations in the 131-136 region of antithrombin (YRKAQK to LEEAAE). The resulting variant has endogenous fluorescence indistinguishable from WT antithrombin yet, in the absence of heparin, shows massive enhancements in rates of inhibition of factors IXa and Xa (114- and 110-fold, respectively), but not of thrombin, together with changes in near- and far-UV CD and (1)H NMR spectra. Heparin binding gives only ∼3-4-fold further rate enhancement but increases tryptophan fluorescence by ∼23% without major additional CD or NMR changes. Variants with subsets of these mutations show intermediate activation in the absence of heparin, again with basal fluorescence similar to WT and large increases upon heparin binding. These findings suggest that in WT antithrombin there are two major complementary sources of conformational activation of antithrombin, probably involving altered contacts of side chains of Tyr-131 and Ala-134 with core hydrophobic residues, whereas the reactive center loop hinge expulsion plays only a minor additional role.
Topics: Allosteric Regulation; Antithrombin III; Circular Dichroism; Factor IXa; Factor Xa; Humans; Mutation; Nuclear Magnetic Resonance, Biomolecular; Protein Structure, Secondary
PubMed: 24068708
DOI: 10.1074/jbc.M113.510727 -
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 -
International Journal of Molecular... Jan 2021N-linked glycosylation is a crucial post-translational modification involved in protein folding, function, and clearance. N-linked glycosylation is also used...
N-linked glycosylation is a crucial post-translational modification involved in protein folding, function, and clearance. N-linked glycosylation is also used therapeutically to enhance the half-lives of many proteins. Antithrombin, a serpin with four potential N-glycosylation sites, plays a pivotal role in hemostasis, wherein its deficiency significantly increases thrombotic risk. In this study, we used the introduction of N-glycosylation sites as a tool to explore what effect this glycosylation has on the protein folding, secretion, and function of this key anticoagulant. To accomplish this task, we introduced an additional N-glycosylation sequence in each strand. Interestingly, all regions that likely fold rapidly or were surrounded by lysines were not glycosylated even though an N-glycosylation sequon was present. The new sequon in the strands of the A- and B-sheets reduced secretion, and the B-sheet was more sensitive to these changes. However, the mutations in the strands of the C-sheet allowed correct folding and secretion, which resulted in functional variants. Therefore, our study revealed crucial regions for antithrombin secretion and could potentially apply to all serpins. These results could also help us understand the functional effects of natural variants causing type-I deficiencies.
Topics: Antithrombin III; Antithrombin Proteins; Circular Dichroism; Glycosylation; Humans; Models, Molecular; Mutant Proteins; Mutation; Protein Conformation; Protein Processing, Post-Translational; Thrombosis
PubMed: 33419227
DOI: 10.3390/ijms22020516 -
EBioMedicine Mar 2017We previously reported that insufficiency of antithrombin III (ATIII), the major anti-coagulation molecule in vivo, exacerbated renal ischemia-reperfusion injury in...
We previously reported that insufficiency of antithrombin III (ATIII), the major anti-coagulation molecule in vivo, exacerbated renal ischemia-reperfusion injury in animal models and possibly humans. In the present study, we investigated the relationship between ATIII level and contrast induced nephropathy (CIN) in patients and examined therapeutic effect of ATIII on CIN in Sprague-Dawley rats. Patients with low ATIII activity presented a higher incidence of acute kidney injury (AKI) following coronary angiography. ATIII (500μg/kg) was intravenously injected before or after the induction of AKI in rats. Our data demonstrated ATIII significantly attenuated the elevation of serum creatinine, blood urea nitrogen, and renal histological injury. The beneficial effects of ATIII were accompanied by diminished renal inflammatory response, oxidative stress, cell apoptosis and improved renal blood flow in rats. In conclusion, ATIII appears to attenuate CIN through inhibiting inflammation, oxidative stress, apoptosis and improving renal blood flow. ATIII administration may represent a promising strategy for the prevention and treatment of contrast-induced AKI.
Topics: Acute Kidney Injury; Aged; Aged, 80 and over; Animals; Antithrombin III; Contrast Media; Coronary Angiography; Female; Humans; Injections, Intravenous; Iodine; Male; Middle Aged; Rats; Rats, Sprague-Dawley
PubMed: 28219627
DOI: 10.1016/j.ebiom.2017.02.009 -
Electrophoresis Nov 2019Preterm birth (PTB) related health problems take over one million lives each year, and currently, no clinical analysis is available to determine if a fetus is at risk...
Preterm birth (PTB) related health problems take over one million lives each year, and currently, no clinical analysis is available to determine if a fetus is at risk for PTB. Here, we describe the preparation of a key PTB risk biomarker, thrombin-antithrombin (TAT), and characterize it using dot blots, MS, and microchip electrophoresis (µCE). The pH for fluorescently labeling TAT was also optimized using spectrofluorometry and spectrophotometry. The LOD of TAT was measured in µCE. Lastly, TAT was combined with six other PTB risk biomarkers and separated in µCE. The ability to make and characterize TAT is an important step toward the development of an integrated microfluidic diagnostic for PTB risk.
Topics: Antithrombin III; Biomarkers; Electrophoresis, Microchip; Humans; Limit of Detection; Mass Spectrometry; Peptide Hydrolases; Point-of-Care Systems
PubMed: 31373007
DOI: 10.1002/elps.201900235 -
Journal of Thrombosis and Haemostasis :... May 2023The natural history and genotype-phenotype correlation of congenital antithrombin (AT) deficiency in children are unknown.
Impact of SERPINC1 mutation on thrombotic phenotype in children with congenital antithrombin deficiency-first analysis of the International Society on Thrombosis and Haemostasis pediatric antithrombin deficiency database and biorepository.
BACKGROUND
The natural history and genotype-phenotype correlation of congenital antithrombin (AT) deficiency in children are unknown.
OBJECTIVES
To describe the clinical presentation of congenital AT deficiency in children and evaluate its correlation to specific mutations in SERPINC1.
METHODS
In 2017, a prospective pediatric database and DNA biorepository for congenital AT deficiency was established. During the pilot phase, the database was opened at 4 tertiary care centers in Canada and US. Approval from research ethics board was obtained at each participating center. Written consent/assent was obtained from guardians/subjects who met eligibility. Demographic/clinical data were uploaded into a database. DNA extraction and SERPINC1 sequencing were centralized for US centers. Standard statistical methods were used to summarize parameters. Probability of VTE-free survival was assessed using the Kaplan-Meier method.
RESULTS
Overall, 43 participants (25 females) from 31 unique kindreds were enrolled. Median age (range) at enrollment was 14.8 years (1-21 years). Median AT activity was 52% (24%-87%), and median AT antigen (n = 20) was 55% (38%-110%). Nineteen (44%) participants had a history of venous thromboembolism (VTE). Median age at VTE diagnosis was 12.8 years (0.1-19.2 years). SERPINC1 sequencing was completed for 31 participants and 21 unique mutations were identified, including 5 novel variants. Probability of 5-year VTE-free survival (95% CI) for carriers of missense mutations (92.0% [95% CI: 71.6%-97.9%]) was significantly higher compared with carriers of null mutations (66.7% [95% CI: 19.5%-90.4%]); p = .0012.
CONCLUSION
To our knowledge, this is the first pediatric study to document a severe thrombotic phenotype in carriers of null mutations in SERPINC1, when compared with carriers of missense mutations; underscoring the importance of genetic testing.
Topics: Female; Humans; Antithrombin III; Antithrombin III Deficiency; Antithrombins; Hemostasis; Mutation; Phenotype; Prospective Studies; Thrombosis; Databases, Factual
PubMed: 36764659
DOI: 10.1016/j.jtha.2023.01.037 -
Nefrologia 2022
Topics: Humans; Nephrotic Syndrome; Thrombosis; Antithrombin III; Antithrombins
PubMed: 36870820
DOI: 10.1016/j.nefroe.2023.02.003 -
Polish Archives of Internal Medicine Jan 2022
Topics: Antithrombin III; Antithrombin III Deficiency; Fibrin; Humans; Mutation
PubMed: 34851072
DOI: 10.20452/pamw.16158 -
International Journal of Molecular... Dec 2020(1) Background: The endothelial glycocalyx is a primary target during the early phase of sepsis. We previously reported a newly developed recombinant non-fucosylated...
(1) Background: The endothelial glycocalyx is a primary target during the early phase of sepsis. We previously reported a newly developed recombinant non-fucosylated antithrombin has protective effects in vitro. We further evaluated the effects of this recombinant antithrombin on the glycocalyx damage in an animal model of sepsis. (2) Methods: Following endotoxin injection, in Wistar rats, circulating levels of hyaluronan, syndecan-1 and other biomarkers were evaluated in low-dose or high-dose recombinant antithrombin-treated animals and a control group ( = 7 per group). Leukocyte adhesion and blood flow were evaluated with intravital microscopy. The glycocalyx was also examined using side-stream dark-field imaging. (3) Results: The activation of coagulation was inhibited by recombinant antithrombin, leukocyte adhesion was significantly decreased, and flow was better maintained in the high-dose group (both < 0.05). Circulating levels of syndecan-1 ( < 0.01, high-dose group) and hyaluronan ( < 0.05, low-dose group; < 0.01, high-dose group) were significantly reduced by recombinant antithrombin treatment. Increases in lactate and decreases in albumin levels were significantly attenuated in the high-dose group ( < 0.05, respectively). The glycocalyx thickness was reduced over time in control animals, but the derangement was attenuated and microvascular perfusion was better maintained in the high-dose group recombinant antithrombin group ( < 0.05). (4) Conclusions: Recombinant antithrombin maintained vascular integrity and the microcirculation by preserving the glycocalyx in this sepsis model, effects that were more prominent with high-dose therapy.
Topics: Animals; Antithrombin III; Antithrombins; Endothelium, Vascular; Endotoxins; Glycocalyx; Protective Agents; Rats; Rats, Wistar; Recombinant Proteins; Sepsis
PubMed: 33375342
DOI: 10.3390/ijms22010176