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Annual Review of Medicine 1978
Review
Topics: Antithrombin III; Antithrombins; Binding Sites; Blood Coagulation; Blood Coagulation Disorders; Blood Platelets; Chemical Phenomena; Chemistry; Heparin; Humans; Molecular Conformation; Structure-Activity Relationship; Thrombin; gamma-Globulins
PubMed: 77142
DOI: 10.1146/annurev.me.29.020178.002055 -
Transfusion 1992
Review
Topics: Antithrombin III; Antithrombin III Deficiency; Humans
PubMed: 1502714
DOI: 10.1046/j.1537-2995.1992.32692367206.x -
Seminars in Thrombosis and Hemostasis Sep 2023Thrombophilia is a complex disease process, clinically manifesting in various forms of venous thromboembolism. Although both genetic and acquired (or environmental)...
Thrombophilia is a complex disease process, clinically manifesting in various forms of venous thromboembolism. Although both genetic and acquired (or environmental) risks factors have been reported, the presence of a genetic defect (antithrombin [AT], protein C [PC], protein S [PS]) is considered three of the major contributing factors of thrombophilia. The presence of each of these risk factors can be established by clinical laboratory analysis; however, the clinical provider and laboratory personnel must understand the testing limitations and shortcomings associated with the assays for these factors to be able to ensure an accurate diagnosis. This article will describe the major pre-analytical, analytical, and post-analytical issues associated with the various types of assays and discuss evidence-based algorithms for analyzing AT, PC, and PS in plasma.
Topics: Humans; Antithrombins; Protein C; Anticoagulants; Thrombophilia; Antithrombin III; Protein S
PubMed: 36940716
DOI: 10.1055/s-0043-1764468 -
Thrombosis Research Oct 2023Hereditary antithrombin (AT) deficiency type I causes venous thrombosis due to decreased levels of AT antigen in the blood. We identified one novel and one known...
INTRODUCTION
Hereditary antithrombin (AT) deficiency type I causes venous thrombosis due to decreased levels of AT antigen in the blood. We identified one novel and one known abnormal variant in two unrelated Japanese families with venous thrombosis. In this study, we analyzed the mechanism by which these abnormal variants cause type I AT deficiency.
MATERIALS AND METHODS
Wild-type and variant AT expression vectors were constructed and transiently expressed in human embryonic kidney 293 cells, and AT antigen levels and N-glycosylation of cell lysates and culture medium were evaluated by western blot analysis. Subcellular co-localization of AT was also examined using confocal microscopy, and chase experiments with cycloheximide and MG132 were performed to investigate the degradation pathway of AT variants.
RESULTS
Genetic analysis identified a novel variant, c.613delC (p.Leu205Trpfs79), and the known variant c.283T>C (p.Tyr95His). These AT variants exhibited significantly reduced extracellular secretion compared with the wild-type; N-glycosylation of the AT protein was normal. Co-localization analysis suggested that the transport of these abnormal AT proteins to the Golgi apparatus was impaired. The c.613delC variant was degraded early by the proteasome, suggesting that the c.283T>C variant is stored in the endoplasmic reticulum (ER).
CONCLUSIONS
The AT variants identified here synthesize abnormal AT proteins that exhibit suppressed secretion and impaired transport from the ER to the Golgi apparatus. These results provide clues that could help elucidate the mechanism of type I AT deficiency and facilitate therapy development.
Topics: Humans; Antithrombins; Antithrombin Proteins; Antithrombin III; Antithrombin III Deficiency; Venous Thrombosis
PubMed: 37607435
DOI: 10.1016/j.thromres.2023.08.010 -
Critical Care (London, England) Feb 2006In disseminated intravascular coagulation (DIC) there is extensive crosstalk between activation of inflammation and coagulation. Endogenous anticoagulatory pathways are... (Review)
Review
In disseminated intravascular coagulation (DIC) there is extensive crosstalk between activation of inflammation and coagulation. Endogenous anticoagulatory pathways are downregulated by inflammation, thus decreasing the natural anti-inflammatory mechanisms that these pathways possess. Supportive strategies aimed at inhibiting activation of coagulation and inflammation may theoretically be justified and have been found to be beneficial in experimental and initial clinical studies. This review assembles the available experimental and clinical data on biological mechanisms of antithrombin in inflammatory coagulation activation. Preclinical research has demonstrated partial interference of heparin--administered even at low doses--with the therapeutic effects of antithrombin, and has confirmed--at the level of cellular mechanisms--a regulatory role for antithrombin in DIC. Against this biological background, re-analyses of data from randomized controlled trials of antithrombin in sepsis suggest that antithrombin has the potential to be developed further as a therapeutic agent in the treatment of DIC. Even though there is a lack of studies employing satisfactory methodology, the results of investigations conducted thus far into the mechanisms of action of antithrombin allow one to infer that there is biological plausibility in the value of this agent. Final assessment of the drug's effectiveness, however, must await the availability of positive, prospective, randomized and placebo-controlled studies.
Topics: Animals; Antithrombin III; Antithrombins; Blood Coagulation; Humans; Sepsis
PubMed: 16542481
DOI: 10.1186/cc4822 -
Clinical Journal of the American... Feb 2023Nephrotic syndrome is associated with an acquired hypercoagulopathy that is thought to drive its predisposition for venous thromboembolism. Previous studies have... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Nephrotic syndrome is associated with an acquired hypercoagulopathy that is thought to drive its predisposition for venous thromboembolism. Previous studies have suggested that urinary antithrombin (AT) loss leading to acquired AT deficiency is the primary mechanism underlying this hypercoagulopathy, but this hypothesis has not been directly tested. The objectives of this study were to test the influence of AT levels on hypercoagulopathy in nephrotic syndrome patient samples and perform meta-analyses to evaluate the likelihood of AT deficiency in patients with nephrotic syndrome.
METHODS
Samples from three independent nephrotic syndrome cohorts were analyzed. AT antigen and activity assays were performed using ELISA and amidolytic assays, respectively. Plasma thrombin generation, albumin, and urine protein-to-creatinine ratios were determined using established methods. Meta-analyses were performed by combining these new data with previously published data.
RESULTS
AT levels were not consistently related to either plasma albumin or proteinuria. AT was quantitatively related to hypercoagulopathy in adult nephrotic syndrome, whereas AT activity was inconsistently associated with hypercoagulopathy in childhood nephrotic syndrome. Notably, hypercoagulopathy did not differ between patients with normal AT levels and those with levels below the threshold used to define clinical AT deficiency (<70%). Moreover, ex vivo AT supplementation did not significantly alter hypercoagulopathy in AT-deficient plasma samples. The meta-analyses demonstrated that AT deficiency was not a uniform feature of nephrotic syndrome and was more common in children than adults.
CONCLUSIONS
These data suggest that AT deficiency plays only a limited role in the mechanisms underlying the acquired hypercoagulopathy of nephrotic syndrome. Moreover, AT deficiency was not present in all patients with nephrotic syndrome and was more likely in children than adults despite the higher risk for venous thromboembolism in adults than children.
Topics: Adult; Child; Humans; Nephrotic Syndrome; Antithrombins; Venous Thromboembolism; Cohort Studies; Antithrombin III
PubMed: 36754010
DOI: 10.2215/CJN.0000000000000047 -
International Journal of Laboratory... Jun 2011Antithrombin (AT) deficiency is associated with an increased risk of deep vein thrombosis and pulmonary embolism which are major causes of morbidity and death. The... (Review)
Review
INTRODUCTION
Antithrombin (AT) deficiency is associated with an increased risk of deep vein thrombosis and pulmonary embolism which are major causes of morbidity and death. The incidence of deficiency in healthy populations has been reported to vary from 1/600 to 1/5000, with the variation being due to the different populations studied and detection methods used. When reduced activity levels are identified it is important to measure the AT antigen levels to differentiate type I from type II disorders, as type II defects have varying thrombotic risk.
METHODS
Functional AT assays detect the ability of AT to inactivate thrombin or factor Xa, and AT antigen assays detect the quantity of AT in plasma. In functional assays, reducing the incubation time of sample with enzyme/heparin reagent may increase sensitivity to type II defects. An excess of antigen over activity level suggests the presence of functionally defective AT, which can be characterized further by assaying AT in the absence of heparin, electrophoresis to investigate the ability of heparin to bind to AT, and gene sequencing.
RESULTS
Many patients with AT deficiency have a type II defect and these defects may not be detected by all routine diagnostic assays. Assays using human thrombin may lack specificity and assays that use factor Xa may fail to detect the common variant, AT Cambridge II, which can be detected by assays using bovine thrombin, especially if activity is compared to antigen by ratio. Factor Xa based assays may be particularly sensitive to certain heparin binding defects, and sensitivity of assays to both heparin binding and reactive site defects can be improved by shortening the incubation time with enzyme.
CONCLUSION
uAT activity assays are essential for the detection of AT deficiency because type II defects are relatively common in patients with heritable deficiency. No one functional assay can be assumed to detect all forms of AT deficiency, and assays can sometimes be improved by reducing reaction time of AT with thrombin or factor Xa.
Topics: Antithrombin III; Antithrombin III Deficiency; Antithrombins; Biological Assay; Humans; Phenotype
PubMed: 21401902
DOI: 10.1111/j.1751-553X.2011.01307.x -
Scientific Reports Dec 2023Disseminated intravascular coagulation (DIC) is a frequent complication in patients with sepsis and is associated with increased mortality. Anticoagulant therapy may be...
Risk stratification utilizing sequential organ failure assessment (SOFA) score, antithrombin activity, and demographic data in sepsis-associated disseminated intravascular coagulation (DIC).
Disseminated intravascular coagulation (DIC) is a frequent complication in patients with sepsis and is associated with increased mortality. Anticoagulant therapy may be appropriate for certain patients with DIC, particularly those with increased disease severity and deficiency in the physiologic anticoagulant antithrombin. We retrospectively analyzed post-marketing survey data from 1562 patients with sepsis-associated DIC and antithrombin activity of 70% or less. All the patients were treated with antithrombin concentrates. Baseline sequential organ failure assessment (SOFA) score, DIC score, and antithrombin activity were assessed. Cox multivariate regression analysis, Kaplan-Meier curve analysis, and receiver operating characteristic (ROC) curve analysis were performed to evaluate the performance of variables used to assess mortality. Furthermore, a decision tree was constructed to classify the risk of 28-day mortality. COX multivariate regression analysis demonstrated a significant association of age, sex, baseline SOFA score, baseline antithrombin activity, and the presence of pneumonia or skin/soft tissue infection with increased mortality. The area under the curve of SOFA score or antithrombin activity for mortality was 0.700 and 0.614, respectively. Kaplan-Meier analysis demonstrated that mortality was significantly higher in patients with SOFA score ≥ 12 and antithrombin activity < 47%. The decision tree analysis accurately classified the risk of death into high (> 40%), medium (40%-20%), and low (< 20%) categories in 86.1% of the cohort. Twenty eight-day mortality can be strongly predicted using baseline SOFA score, antithrombin activity, infection site, age, and sex as variables in the clinical decision tree for patients with sepsis-associated disseminated intravascular coagulation (DIC).
Topics: Humans; Antithrombins; Organ Dysfunction Scores; Disseminated Intravascular Coagulation; Retrospective Studies; Anticoagulants; Antithrombin III; Sepsis; Risk Assessment; Demography
PubMed: 38110515
DOI: 10.1038/s41598-023-49855-y -
Acta Haematologica 2023Severe COVID-19 illness can lead to thrombotic complications, organ failure, and death. Antithrombin (AT) regulates thromboinflammation and is a key component of... (Observational Study)
Observational Study
INTRODUCTION
Severe COVID-19 illness can lead to thrombotic complications, organ failure, and death. Antithrombin (AT) regulates thromboinflammation and is a key component of chemical thromboprophylaxis. Our goal was to examine the link between AT activity and responsiveness to thromboprophylaxis, markers of hypercoagulability, and inflammation among severe COVID-19 patients.
METHODS
This was a single-center, prospective observational study enrolling SARS-CoV-2-positive patients admitted to the intensive care unit on prophylactic enoxaparin. Blood was collected daily for 7 days to assess AT activity and anti-factor Xa levels. Patient demographics, outcomes, and hospital laboratory results were collected. Continuous variables were compared using Mann-Whitney tests, and categorical variables were compared using χ2 tests. Multivariable logistic regression was used to determine the association between AT activity and mortality.
RESULTS
In 36 patients, 3 thromboembolic events occurred, and 18 (50%) patients died. Patients who died had higher fibrinogen, D-dimer, and C-reactive protein (CRP) levels and lower AT activity. Reduced AT activity was independently associated with mortality and correlated with both markers of hypercoagulability (D-dimer) and inflammation (CRP).
CONCLUSION
Low AT activity is associated with mortality and persistent hypercoagulable and proinflammatory states in severe COVID-19 patients. The anti-thromboinflammatory properties of AT make it an appealing therapeutic target for future studies.
Topics: Humans; COVID-19; Anticoagulants; Inflammation; SARS-CoV-2; Antithrombins; Thromboinflammation; Thrombosis; Venous Thromboembolism; Thrombophilia; Antithrombin III
PubMed: 36538905
DOI: 10.1159/000528584 -
Blood Coagulation & Fibrinolysis : An... Apr 1998During severe sepsis, the sustained consumption and/or inhibition of antithrombin leads to a prolonged procoagulant state, which indicates that the administration of... (Review)
Review
During severe sepsis, the sustained consumption and/or inhibition of antithrombin leads to a prolonged procoagulant state, which indicates that the administration of antithrombin may be useful in this condition. Animal studies have shown that high doses of antithrombin concentrates can prevent disseminated intravascular coagulation and death. In humans, high doses of antithrombin are required to maintain supranormal antithrombin levels and overcome the magnitude of antithrombin consumption. Three placebo-controlled, double-blind studies of antithrombin concentrates have been performed in France, Germany and northwestern Europe. A meta-analysis of these three studies showed a nonsignificant 22% reduction in 30-day, all-cause mortality. A multicenter phase III trial is needed to demonstrate that antithrombin administration can reduce mortality in septic patients.
Topics: Animals; Antithrombin III; Dose-Response Relationship, Drug; Humans; Inflammation; Leukocyte Elastase
PubMed: 9662468
DOI: No ID Found