-
Thrombosis Research Sep 2018Antithrombin is a key endogenous anticoagulant whose deficiency constitutes a strong risk factor for thrombosis. The study of antithrombin deficiency has generated... (Review)
Review
Antithrombin is a key endogenous anticoagulant whose deficiency constitutes a strong risk factor for thrombosis. The study of antithrombin deficiency has generated excellent, and in some cases, surprising results that may be extrapolated to other thrombophilia and genetic disorders. Routine diagnosis of antithrombin deficiency is based on functional assays. Few specialized laboratories also perform genetic analysis, even though nowadays it is a simple, fast and cheap process that generates relevant information with clinical usefulness. Molecular analysis of SERPINC1, the gene encoding antithrombin, has been restricted so far to cases with confirmed or familial antithrombin deficiency. However, some pathogenic mutations are not detected by current functional methods and other gene defects may have functional consequences only observed under specific conditions. Thus, molecular analysis may be the best method to identify antithrombin deficiency. Up to 80% of patients with antithrombin deficiency have SERPINC1 gene defects, mostly (90% of the 315 gene defects described so far) point mutations or small deletions or insertions affecting the 7 exons or flanking regions. The description of new SERPINC1 gene defects may reveal new residues with functional or structural relevance and new mechanisms causing deficiency of this endogenous anticoagulant. Moreover, other genes and mechanisms may also be involved in antithrombin deficiency. Thus, disorders of N-glycosylation explain up to 5% of cases with antithrombin deficiency. However, there are still up to 10-15% of cases with antithrombin deficiency of unknown cause, whose study may reveal new genes and mechanisms involved in thrombosis.
Topics: Animals; Antithrombin III; Antithrombin III Deficiency; Genetic Predisposition to Disease; Humans; Models, Molecular; Mutation; Protein Conformation
PubMed: 30005274
DOI: 10.1016/j.thromres.2018.07.008 -
Clinical Science (London, England :... May 2017The gene encodes a serine protease inhibitor named antithrombin III (ATIII). This protease demonstrates both anticoagulant and anti-inflammatory action. ATIII is the... (Review)
Review
The gene encodes a serine protease inhibitor named antithrombin III (ATIII). This protease demonstrates both anticoagulant and anti-inflammatory action. ATIII is the most important coagulation factor inhibitor, and even minor changes in ATIII can significantly alter the risk of thromboembolism. ATIII can also suppress inflammation via a coagulation-dependent or -independent effect. Moreover, apart from ATIII deficiency, ATIII and its gene may also be related to many diseases (e.g. hypertension, kidney diseases). The present review summarizes how ATIII affects the progress of kidney disease and its mechanism. Further studies are required to investigate how ATIII affects renal function and the treatment.
Topics: Antithrombin III; Antithrombin III Deficiency; Blood Coagulation; Humans; Inflammation; Kidney Diseases; Models, Biological; Risk Factors; Signal Transduction; Thromboembolism
PubMed: 28424376
DOI: 10.1042/CS20160669 -
Clinical and Applied... 2023Antithrombin (AT) is a natural anticoagulant pivotal in inactivating serine protease enzymes in the coagulation cascade, making it a potent inhibitor of blood clot...
Antithrombin (AT) is a natural anticoagulant pivotal in inactivating serine protease enzymes in the coagulation cascade, making it a potent inhibitor of blood clot formation. AT also possesses anti-inflammatory properties by influencing anticoagulation and directly interacting with endothelial cells. Hereditary AT deficiency is one of the most severe inherited thrombophilias, with up to 85% lifetime risk of venous thromboembolism. Acquired AT deficiency arises during heparin therapy or states of hypercoagulability like sepsis and premature infancy. Optimization of AT levels in individuals with AT deficiency is an important treatment consideration, particularly during high-risk situations such as surgery, trauma, pregnancy, and postpartum. Here, we integrate the existing evidence surrounding the approved uses of AT therapy, as well as potential additional patient populations where AT therapy has been considered by the medical community, including any available consensus statements and guidelines. We also describe current knowledge regarding cost-effectiveness of AT concentrate in different contexts. Future work should seek to identify specific patient populations for whom targeted AT therapy is likely to provide the strongest clinical benefit.
Topics: Pregnancy; Female; Humans; Antithrombins; Endothelial Cells; Anticoagulants; Antithrombin III; Blood Coagulation; Antithrombin III Deficiency
PubMed: 37822179
DOI: 10.1177/10760296231205279 -
Blood Apr 2023
Topics: Antithrombins; Factor IXa; Antithrombin III; Anticoagulants
PubMed: 37079331
DOI: 10.1182/blood.2023019793 -
Arteriosclerosis, Thrombosis, and... Jul 2023Antithrombin, PC (protein C), and PS (protein S) are circulating natural anticoagulant proteins that regulate hemostasis and of which partial deficiencies are causes of...
BACKGROUND
Antithrombin, PC (protein C), and PS (protein S) are circulating natural anticoagulant proteins that regulate hemostasis and of which partial deficiencies are causes of venous thromboembolism. Previous genetic association studies involving antithrombin, PC, and PS were limited by modest sample sizes or by being restricted to candidate genes. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, we meta-analyzed across ancestries the results from 10 genome-wide association studies of plasma levels of antithrombin, PC, PS free, and PS total.
METHODS
Study participants were of European and African ancestries, and genotype data were imputed to TOPMed, a dense multiancestry reference panel. Each of the 10 studies conducted a genome-wide association studies for each phenotype and summary results were meta-analyzed, stratified by ancestry. Analysis of antithrombin included 25 243 European ancestry and 2688 African ancestry participants, PC analysis included 16 597 European ancestry and 2688 African ancestry participants, PSF and PST analysis included 4113 and 6409 European ancestry participants. We also conducted transcriptome-wide association analyses and multiphenotype analysis to discover additional associations. Novel genome-wide association studies and transcriptome-wide association analyses findings were validated by in vitro functional experiments. Mendelian randomization was performed to assess the causal relationship between these proteins and cardiovascular outcomes.
RESULTS
Genome-wide association studies meta-analyses identified 4 newly associated loci: 3 with antithrombin levels (, , and ) and 1 with PS levels (-). transcriptome-wide association analyses identified 3 newly associated genes: 1 with antithrombin level (), 1 with PC (), and 1 with PS (). In addition, we replicated 7 independent loci reported in previous studies. Functional experiments provided evidence for the involvement of , , and genes in antithrombin regulation.
CONCLUSIONS
The use of larger sample sizes, diverse populations, and a denser imputation reference panel allowed the detection of 7 novel genomic loci associated with plasma antithrombin, PC, and PS levels.
Topics: Protein C; Protein S; Genome-Wide Association Study; Antithrombins; Transcriptome; Anticoagulants; Antithrombin III; Polymorphism, Single Nucleotide
PubMed: 37128921
DOI: 10.1161/ATVBAHA.122.318213 -
Thrombosis Research Sep 2018
Topics: ABO Blood-Group System; Antithrombin III; Antithrombin III Deficiency; Genetic Predisposition to Disease; Genetic Variation; Humans; INDEL Mutation; Intracranial Thrombosis; Venous Thrombosis
PubMed: 30170635
DOI: 10.1016/j.thromres.2018.08.009 -
Artificial Organs Dec 2023Bleeding and thrombosis are common extracorporeal membrane oxygenation (ECMO) complications associated with increased mortality. Heparin is the most commonly used ECMO...
BACKGROUND
Bleeding and thrombosis are common extracorporeal membrane oxygenation (ECMO) complications associated with increased mortality. Heparin is the most commonly used ECMO anticoagulant, employed in 94% of cases. Reduced antithrombin III (AT3) levels could decrease heparin effectiveness. Neonates have inherently lower levels of AT3 than adults, and pediatric patients on ECMO can develop AT3 deficiency. One potential approach for patients on ECMO with AT3 deficiency is exogenous AT3 supplementation. However, there is conflicting data concerning the use of AT3 for pediatric and neonatal patients on ECMO.
METHODS
We analyzed the Bleeding and Thrombosis during ECMO database of 514 neonatal and pediatric patients on ECMO. We constructed daily regression models to determine the association between AT3 supplementation and rates of bleeding and thrombosis. Given the physiological differences between pediatric patients and neonates, we constructed separate models for each.
RESULTS
AT3 administration was associated with increased rates of daily bleeding among pediatric (adjusted odds ratio [aOR] 1.59, p < 0.01) and neonatal (aOR 1.37, p = 0.04) patients. AT3 supplementation did not reduce the rate of thrombosis for either pediatric or neonatal patients.
CONCLUSION
AT3 administration was associated with increased rates of daily bleeding, a hypothesized potential complication of AT3 supplementation. In addition, AT3 supplementation did not result in lower rates of thrombosis. We recommend clinicians utilize caution when considering supplementing patients on ECMO with exogenous AT3.
Topics: Infant, Newborn; Adult; Humans; Child; Antithrombin III; Extracorporeal Membrane Oxygenation; Retrospective Studies; Anticoagulants; Heparin; Thrombosis; Hemorrhage; Dietary Supplements
PubMed: 37658611
DOI: 10.1111/aor.14639 -
Clinical Laboratory Oct 2021Myocardial infarction (MI) or acute myocardial infarction (AMI), commonly referred to as a heart attack, happens when the blood flow to part of the heart stops, causing...
BACKGROUND
Myocardial infarction (MI) or acute myocardial infarction (AMI), commonly referred to as a heart attack, happens when the blood flow to part of the heart stops, causing damage to the heart muscle. Chest pain or discomfort that may flow into the shoulder, arm, back, neck, or jaw is the most common symptom. Most MIs occur due to coronary artery disease. High blood pressure, smoking, diabetes, lack of exercise, obesity, high blood pressure, poor diet, excessive alcohol use, etc. are risk factors. Antithrombin III (AT III) is a glycoprotein produced by the liver and consists of 432 amino acids. Protein C, also referred to as autoprothrombin IIA and factor XIV of blood coagulation, is a zymogen. In regulating anticoagulation, inflammation, cell death, and maintaining the permeability of blood vessel walls in humans and other animals, the activated form of protein C plays an important role.
METHODS
A case control study was conducted in Saudi Arabia to determine the levels of AT III and protein C in Saudi MI patients. Samples (n = 150) from MI patients as well as healthy controls (n = 50) were collected (2.5 mL of venous blood for sandwich ELISA).
RESULTS
This study showed that the mean AT III and protein C levels were within normal levels in patients (86 ± 19.63 and 76.20 ± 30.64, respectively). A comparison of mean AT III and protein C levels in patient and control groups showed no significant difference (p-value = 0.26, 0.2, and 0.19, respectively). The results also showed that some of the samples had low levels of AT III (8.7%) and protein C (11.3%).
CONCLUSIONS
A deficiency of AT III and protein C were not strong significant risk factors for myocardial infarction.
Topics: Anticoagulants; Antithrombin III; Case-Control Studies; Humans; Myocardial Infarction; Protein C; Saudi Arabia
PubMed: 34655191
DOI: 10.7754/Clin.Lab.2021.201206 -
Journal of Orthopaedic Surgery (Hong... Jan 2017Patients with fractures of the pelvis and/or lower extremities are at a high risk of developing postoperative venous thromboembolism (VTE). The purpose of this study was...
PURPOSE
Patients with fractures of the pelvis and/or lower extremities are at a high risk of developing postoperative venous thromboembolism (VTE). The purpose of this study was to determine whether the thrombin-antithrombin III complex (TAT) tests could be used for postoperative screening of VTE in patients with lower limb or pelvic fractures.
METHODS
We enrolled 133 patients who underwent surgical treatment for fracture of the pelvis or lower extremities. TAT and D-dimer levels were compared in patients with and without VTE. Receiver operating characteristic (ROC) curve analysis was done and the appropriate TAT and D-dimer cutoff levels were determined for VTE screening.
RESULTS
VTE was diagnosed in 41 patients (30.8%). Patients with VTE had significantly higher levels of TAT and D-dimer on postoperative days 1, 3, and 7 than those without VTE, respectively. ROC curve analysis suggested that TAT test at postoperative day 7 had the highest accuracy for predicting postoperative VTE. With the optimal cutoff TAT level of 3.0 ng/mL, sensitivity and specificity were 93.3% and 70.1%, respectively. With the optimal cutoff D-dimer level of 7.4 µg/mL, sensitivity and specificity were 93.3% and 57.0%, respectively.
CONCLUSION
TAT levels measured at postoperative day 7 could be the most useful parameter for screening postoperative VTE. TAT can be used as a screening tool for screening postoperative VTE in patients with lower limb and pelvic fractures.
Topics: Adult; Aged; Antithrombin III; Bones of Lower Extremity; Case-Control Studies; Female; Fibrin Fibrinogen Degradation Products; Fracture Fixation, Internal; Fractures, Bone; Humans; Male; Middle Aged; Peptide Hydrolases; Postoperative Complications; Sensitivity and Specificity; Venous Thromboembolism
PubMed: 28418276
DOI: 10.1177/0170840616684501 -
Blood Jul 2022
Topics: Antithrombin III; Antithrombin III Deficiency; Antithrombins; Glycosylation; Humans; Sugars; Thrombophilia
PubMed: 35834281
DOI: 10.1182/blood.2022016677