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Antithrombin Activity and Association with Risk of Thrombosis and Mortality in Patients with Cancer.International Journal of Molecular... Dec 2022Venous and arterial thromboembolism (VTE/ATE) are common complications in cancer patients. Antithrombin deficiency is a risk factor for thrombosis in the general... (Observational Study)
Observational Study
Venous and arterial thromboembolism (VTE/ATE) are common complications in cancer patients. Antithrombin deficiency is a risk factor for thrombosis in the general population, but its connection to risk of cancer-associated thrombosis is unclear. We investigated the association of antithrombin activity levels with risk of cancer-associated VTE/ATE and all-cause mortality in an observational cohort study including patients with cancer, the Vienna Cancer and Thrombosis Study. In total, 1127 patients were included (45% female, median age: 62 years). Amongst these subjects, 110 (9.7%) patients were diagnosed with VTE, 32 (2.8%) with ATE, and 563 (49.9%) died. Antithrombin was not associated with a risk of VTE (subdistribution hazard ratio (SHR): 1.00 per 1% increase in antithrombin level; 95% CI: 0.99-1.01) or ATE (SHR: 1.00; 95% CI: 0.98-1.03). However, antithrombin showed a u-shaped association with the risk of all-cause death, i.e., patients with very low but also very high levels had poorer overall survival. In the subgroup of patients with brain tumors, higher antithrombin levels were associated with ATE risk (SHR: 1.02 per 1% increase; 95% CI: 1.00-1.04) and mortality (HR: 1.01 per 1% increase; 95% CI: 1.00-1.02). Both high and low antithrombin activity was associated with the risk of death. However, no association with cancer-associated VTE and ATE across all cancer types was found, with the exception of in brain tumors.
Topics: Humans; Female; Middle Aged; Male; Antithrombins; Venous Thromboembolism; Antithrombin III; Thrombosis; Risk Factors; Brain Neoplasms
PubMed: 36555414
DOI: 10.3390/ijms232415770 -
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 -
Paediatric Anaesthesia May 2023
Topics: Humans; Child; Antithrombins; Antithrombin III; Cardiac Surgical Procedures; Anticoagulants; Heart
PubMed: 36651693
DOI: 10.1111/pan.14633 -
Hematology/oncology Clinics of North... Oct 1992The general characteristics of antithrombin III (AT III) concentrates available in the United States are described in this article. The effectiveness of AT III... (Review)
Review
The general characteristics of antithrombin III (AT III) concentrates available in the United States are described in this article. The effectiveness of AT III concentrates in the prevention and treatment of thrombotic episodes in patients with hereditary AT III deficiency are summarized, and the use of this product in various conditions with acquired AT III deficiency are reported.
Topics: Antithrombin III; Antithrombin III Deficiency; Chromatography, Affinity; Humans; Thrombosis; Virus Diseases
PubMed: 1400075
DOI: No ID Found -
Acta Medica Austriaca 2002Leukocyte-endothelial cell interaction and microvascular perfusion failure are characteristic deteriorations of the microcirculation in endotoxaemia and are known to... (Review)
Review
Leukocyte-endothelial cell interaction and microvascular perfusion failure are characteristic deteriorations of the microcirculation in endotoxaemia and are known to play a crucial role in the development of septic multiple organ dysfunction. Recent studies have indicated that antithrombin III treatment is capable of significantly ameliorating these microcirculatory disorders. Endothelial cells have important anticoagulant systems, including the heparan sulfate-antithrombin system. Antithrombin III stimulates prostacyclin generation in endothelial cells by interacting with heparan sulfate of endothelial cells and inhibits cytokine and tissue factor production in endothelial cells and monocytes. Similar mechanisms may be involved in cellular actions of antithrombin III causing desensitization of chemoattractant receptors of leukocytes by activating the heparan sulfate proteoglycan, syndecan-4. Thus, antithrombin III might be among the useful agents for treating coagulation abnormalities associated with sepsis or other inflammation because it inhibits not only coagulation but also downregulation of anticoagulant activities of endothelial cells and affects leukocyte activation.
Topics: Anti-Inflammatory Agents; Antithrombin III; Antithrombins; Blood Coagulation; Endothelium, Vascular; Humans; Leukocytes; Sepsis
PubMed: 12168569
DOI: 10.1046/j.1563-2571.2002.02012.x -
Anesthesia and Analgesia Jun 2023Various cohort studies, both retrospective and prospective, showed that low antithrombin levels after cardiac surgery (at the arrival in the intensive care unit and...
Various cohort studies, both retrospective and prospective, showed that low antithrombin levels after cardiac surgery (at the arrival in the intensive care unit and during the next days) were associated with a number of adverse outcomes, including surgical reexploration and thromboembolic events, eventually leading to prolonged stay in the intensive care. Values lower than 58% to 64% of antithrombin activity were indicative of this higher morbidity with good sensitivity and specificity. The scenario generated the hypothesis that low antithrombin levels needed to be corrected by supplementation to improve postoperative outcome. However, randomized controlled studies run to test this idea failed to demonstrate any benefit of antithrombin supplementation, showing no effects on outcome, neither as preemptive preoperative strategy nor for treating postoperative low antithrombin values. In addition, randomized trials highlighted that those patients who received antithrombin experienced significantly higher incidence of acute kidney injury with a pooled odds ratio of 4.41 (95% CI, 1.90-10.23; P = .001). A strongly decreased thrombin activity after antithrombin correction may eventually affect the efficiency of the glomerular filtration and cause the deterioration of kidney function, but underlying biological mechanisms remain unclear. In conclusion, low levels of antithrombin activity after cardiac surgery should be considered as a marker of greater severity of the patient's conditions and/or of the complexity of the surgical procedure. There are no indications for antithrombin supplementation in cardiac surgery unless for correcting heparin resistance.
Topics: Humans; Anticoagulants; Antithrombin III; Antithrombins; Cardiac Surgical Procedures; Prospective Studies; Retrospective Studies
PubMed: 36853953
DOI: 10.1213/ANE.0000000000006314 -
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 -
Critical Care Medicine Apr 2021
Topics: Anticoagulants; Antithrombin III; Antithrombins; Extracorporeal Membrane Oxygenation; Humans
PubMed: 33731637
DOI: 10.1097/CCM.0000000000004812 -
Advances in Experimental Medicine and... 1975By devising and applying quantitative methods for the assay of thrombin and autoprothrombin C and by developing techniques for their purification, it was possible to... (Review)
Review
By devising and applying quantitative methods for the assay of thrombin and autoprothrombin C and by developing techniques for their purification, it was possible to obtain information about the function and properties of antithrombin. The inhibitor is a protein for which the initial purification steps consist of removing fibrinogen from plasma by heating to 56 degrees for 3 min, removing prothrombin complex by absorption on barium carbonate, absorbing the antithrombin on aluminum hydroxide, and eluting with phosphate buffer. Antithrombin is limited in its capacity to neutralize thrombin activity, and, under some conditions, the rate of inhibition was accelerated, but equivocal results were involved. Heparin cofactor was found to be essential for retarding the formation of thrombin, and, by inference, it is essential for retarding the formation of autoprothrombin C. Heparin cofactor and antithrombin III are the same. Thrombin absorbs on fibrin, and this has been referred to as the "antithrombin I effect." Interference with the thrombin-fibrinogen reaction by mixtures of antithrombin III and heparin is called the "antithrombin II henomenon." The acceleration of thrombin inactivation at the time thrombin forms is called the "antithrombin IV effect." It was discovered that antithrombin III neutralizes thrombin, as well as autoprothrombin C. The inhibitor and the enzyme form a mutual depletion system. To assay for antithrombin III, a standard quantity of thrombin (about 1,100U/ml) was reacted with antithrombin III for 2 hr. The percent thrombin inactivated was then measured. In random samples of human blood, a wide range of antithrombin III concentration was found. The inhibitor is relatively stable in plasma and serum. It is not changed in concentration when Dicumarol therapy is instituted. Ether extraction of plasma reduces antithrombin III activity. Seitz filtration of plasma did not remove activity. Under special conditions, antithrombin III enhances esterase activity of thrombin. Under special conditions, thrombin regenerates from the thrombin-antithrombin III complex. Antithrombin III neutralizes the activity of prethrombin-E and thrombin-E; consequently, an active histidine center found in the B1 chain of thrombin is not essential for the binding of antithrombin. Autoprothrombin II-A activity was neutralized by antithrombin III. Autoprothrombin C was found to be neutralized by antithrombin III; the amounts required varied with the molecular forms of autoprothrombin C. Thrombin and autoprothrombin C apparently occupy the same binding sites on antithrombin III. An equation was developed to account for all the known characteristics of antithrombin III functions. The kinetic aspects of thrombin neutralization were found to correspond exactly with those of autoprothrombin C. Antithrombin III is a high-capacity inhibitor of the two most powerful enzymes in blood coagulation.
Topics: Antithrombin III; Antithrombins; Binding Sites; Blood Coagulation; Blood Coagulation Factors; Calcium; Dicumarol; Enzyme Precursors; Esterases; Factor X; Fibrin; Fibrinogen; Heparin; Kinetics; Peptide Fragments; Protein Conformation; Prothrombin; Thrombin
PubMed: 47704
DOI: No ID Found -
Methods in Enzymology 1976
Topics: Alpha-Globulins; Animals; Antithrombin III; Antithrombins; Blood Coagulation Tests; Blood Protein Electrophoresis; Chromatography, Affinity; Enzyme Activation; Humans; Macromolecular Substances; Methods; Molecular Weight; Species Specificity; Thrombin
PubMed: 64915
DOI: 10.1016/s0076-6879(76)45056-5