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The New England Journal of Medicine Aug 2021
Review
Topics: Anticoagulants; Antithrombin III Deficiency; Antithrombins; Blood Coagulation; Blood Coagulation Tests; Blood Platelets; COVID-19; Drug Resistance; Heparin; Humans
PubMed: 34437785
DOI: 10.1056/NEJMra2104091 -
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 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 -
Journal of Thrombosis and Thrombolysis Jul 2023Oral factor Xa (FXa) inhibitors significantly reduce incidence of stroke and thromboembolic events in patients with atrial fibrillation or venous thromboembolism. Due to...
Real-world clinical outcomes among US Veterans with oral factor xa inhibitor-related major bleeding treated with andexanet alfa or 4-factor prothrombin complex concentrate.
Oral factor Xa (FXa) inhibitors significantly reduce incidence of stroke and thromboembolic events in patients with atrial fibrillation or venous thromboembolism. Due to various factors and the lack of a randomized controlled trial comparing andexanet alfa to usual care, non-specific replacement agents including 4 F-PCC are still used off-label for FXa inhibitor bleed management. Clinical and mortality data were extracted from the inpatient medical data and Veteran Affairs (VA) vital status files over the time of March 2014 through December 2020. Propensity score-weighted models were used for this retrospective cohort study using data from the Veterans Affairs Informatics and Computing Infrastructure (VINCI). The study included 255 patients (85-andexanet alfa and 170-4 F-PCC) exposed to an oral factor Xa inhibitor and hospitalized with an acute major, gastrointestinal (GI), intracranial (ICH) or other bleed. In-hospital mortality was significantly lower in the andexanet alfa cohort compared to the 4 F-PCC cohort (10.6% vs. 25.3%, p = 0.01). Propensity score-weighted Cox models reveal a 69% lower hazard of in-hospital mortality for those treated with andexanet alfa (HR 0.31, 95% CI 0.14-0.71) compared to those treated with 4 F-PCC. Additionally, those treated with andexanet alfa had a lower 30-day mortality rate and lower 30-day hazard of mortality in the weighted Cox model (20.0% vs. 32.4%, p = 0.039; HR 0.54, 95% CI 0.30-0.98) compared to those treated with 4 F-PCC. Among 255 US veterans with major bleeding in the presence of an oral factor Xa inhibitor, treatment with andexanet alfa was associated with lower in-hospital and 30-day mortality than treatment with 4 F-PCC.
Topics: Humans; Factor Xa; Factor Xa Inhibitors; Veterans; Retrospective Studies; Blood Coagulation Factors; Hemorrhage; Antithrombin III; Factor IX; Recombinant Proteins; Anticoagulants
PubMed: 37219827
DOI: 10.1007/s11239-023-02820-y -
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 -
Blood Jul 2022
Topics: Antithrombin III; Antithrombin III Deficiency; Antithrombins; Glycosylation; Humans; Sugars; Thrombophilia
PubMed: 35834281
DOI: 10.1182/blood.2022016677 -
Perfusion May 2020Commercially available products used for antithrombin supplementation, for example, in extracorporeal life support, may contain latent antithrombin, a hyper-stable...
Commercially available products used for antithrombin supplementation, for example, in extracorporeal life support, may contain latent antithrombin, a hyper-stable strongly procoagulative and anti-angiogenic residue. Latent antithrombin is associated with severe thrombosis in the critically ill. In the manufacturing process of fractionated antithrombin from plasma, heat treatment, citrate, and freeze drying speed up the transformation of native antithrombin to latent antithrombin. Manufacturers are not required to assess and report the latent antithrombin content of their products. When reported, the latent antithrombin fractions in their product range from <1% to 40% of total antithrombin compared with <3% in the healthy adult and less in children. The aims of this work were (1) to convey increased awareness to clinicians who may experience defaulted, expected effect after antithrombin supplementation in, for example, heparin anticoagulation during extracorporeal life support and (2) to urge manufacturers to assess and disclose latent antithrombin content in their products.
Topics: Anticoagulants; Antithrombins; Extracorporeal Membrane Oxygenation; Humans
PubMed: 32397894
DOI: 10.1177/0267659120906770 -
Journal of Thrombosis and Haemostasis :... Dec 2020Antithrombin (AT) is a major plasma glycoprotein of the serpin superfamily that regulates the proteolytic activity of the procoagulant proteases of both intrinsic and... (Review)
Review
Antithrombin (AT) is a major plasma glycoprotein of the serpin superfamily that regulates the proteolytic activity of the procoagulant proteases of both intrinsic and extrinsic pathways. Two important structural features that participate in the regulatory function of AT include a mobile reactive center loop that binds to active site of coagulation proteases, trapping them in the form of inactive covalent complexes, and a basic D-helix that binds to therapeutic heparins and heparan sulfate proteoglycans (HSPGs) on vascular endothelial cells. The binding of D-helix of AT by therapeutic heparins promotes the reactivity of the serpin with coagulation proteases by several orders of magnitude by both a conformational activation of the serpin and a template (bridging) mechanism. In addition to its essential anticoagulant function, AT elicits a potent anti-inflammatory signaling response when it binds to distinct vascular endothelial cell HSPGs, thereby inducing prostacyclin synthesis. Syndecans-4 has been found as a specific membrane-bound HSPG receptor on endothelial cells that relays the signaling effect of AT to the relevant second messenger molecules in the signal transduction pathways inside the cell. However, following cleavage by coagulation proteases and/or by spontaneous conversion to a latent form, AT loses both its anti-inflammatory activity and high-affinity interaction with heparin and HSPGs. Interestingly, these low-affinity heparin conformers of AT elicit potent proapoptotic and antiangiogenic activities by also binding to specific HSPGs by unknown mechanisms. This review article will summarize current knowledge about mechanisms through which different conformers of AT exert their serine protease inhibitory and intracellular signaling functions in these biological pathways.
Topics: Anticoagulants; Antithrombin III; Antithrombins; Endothelial Cells; Heparin; Signal Transduction
PubMed: 32780936
DOI: 10.1111/jth.15052