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Research and Practice in Thrombosis and... May 2023Thrombin is a key enzyme in the maintenance of normal hemostatic function and is the central product of an interconnected set of simultaneously occurring cellular and... (Review)
Review
Thrombin is a key enzyme in the maintenance of normal hemostatic function and is the central product of an interconnected set of simultaneously occurring cellular and proteolytic events. Antithrombin (AT) is a natural anticoagulant that downregulates different components of the clotting process, particularly thrombin generation. In good health, well-regulated hemostasis is the result of a balance between procoagulant and anticoagulant elements. Cumulative understanding of the regulation of thrombin generation and its central role in hemostasis and bleeding disorders has led to the clinical development of therapeutic strategies that aim to rebalance hemostasis in individuals with hemophilia and other coagulation factor deficiencies to improve bleeding phenotype. The aim of this review is to discuss the rationale for AT lowering in individuals with hemophilia, with a focus on fitusiran, its mechanism of action, and its potential as a prophylactic therapy for individuals with hemophilia A or B, with or without inhibitors. Fitusiran is an investigational small, interfering RNA therapeutic that targets and lowers AT. It is currently in phase III clinical trials and results have shown its potential to increase thrombin generation, leading to enhanced hemostasis and improved quality of life while reducing the overall treatment burden.
PubMed: 37358958
DOI: 10.1016/j.rpth.2023.100179 -
Trauma Surgery & Acute Care Open 2023Antithrombin III (ATIII) deficiency may result from hereditary or acquired reduction in ATIII levels and is associated with an increase in venous thromboembolism (VTE)...
OBJECTIVE
Antithrombin III (ATIII) deficiency may result from hereditary or acquired reduction in ATIII levels and is associated with an increase in venous thromboembolism (VTE) in the general population. VTE is a potentially preventable complication in the critically ill surgical patients. The objective of this study was to evaluate the relation between ATIII levels and VTE in surgical intensive care unit (SICU) patients.
METHODS
All patients admitted to the SICU from January 2017 to April 2018 who had ATIII levels drawn were included in the study. An ATIII level below 80% of normal was considered low. The rate of VTE during the same admission was compared among patients with normal and low levels of ATIII. Prolonged length of stay (LOS >10 days) and mortality were also measured.
RESULTS
Of the 227 patients included, 59.9% were male. The median age was 60 years. Overall, 66.9% of patients had low ATIII levels. Trauma patients had a higher rate of normal ATIII levels, whereas those weighing more than 100 kg had a higher rate of low ATIII levels. Patients with low ATIII levels had higher VTE rates compared with those with normal ATIII levels (28.9% vs. 16%, p=0.04). Patients with low ATIII levels also had prolonged LOS (76.3% vs. 60%, p=0.01) and increased mortality (21.7% vs. 6.7%, p<0.01). Trauma patients with VTE were more likely to have normal ATIII levels (38.5% in low ATIII cohort vs. 61.5% VTE in normal ATIII cohort, p<0.01).
CONCLUSION
Critically ill surgical patients with low ATIII levels have higher incidence of VTE, longer LOS, and higher mortality. In contrast, critically ill trauma patients may have high incidence of VTE even with normal ATIII levels.
LEVEL OF EVIDENCE
III.
PubMed: 37342817
DOI: 10.1136/tsaco-2022-001009 -
Clinical and Applied... 2023Vascular endothelial damage may activate hypercoagulation and contribute to the development of acute kidney injury (AKI). This study aimed to investigate whether early... (Observational Study)
Observational Study
Association Between Thrombin-Antithrombin Complex and Acute Kidney Injury After Pediatric Cardiopulmonary Bypass Surgery: A Single-Center Retrospective Observational Study.
Vascular endothelial damage may activate hypercoagulation and contribute to the development of acute kidney injury (AKI). This study aimed to investigate whether early alteration in coagulation was associated with AKI onset following surgeries involving cardiopulmonary bypass (CPB) in children. This single-center retrospective cohort study included 154 infants and toddlers who underwent cardiovascular surgery with CPB. At admission to the pediatric intensive care unit, the absolute thrombin-antithrombin complex (TAT) level in each patient was measured. Moreover, the presence or absence of AKI onset in the early postoperative period was observed. Of the total participants, 55 (35%) developed AKI. A comparison within the toddler group based on the TAT cut-off value showed that both univariate and multivariable associations were found between increased absolute TAT level and AKI onset (odds ratio, 4.70; 95% confidence interval [1.20-17.90]; = .023). The increase in absolute TAT level in toddlers during the early postoperative period following CPB was associated with AKI onset. However, a further prospective multicenter study with a larger sample size is required for validating these findings.
Topics: Infant; Humans; Child; Retrospective Studies; Cardiopulmonary Bypass; Risk Factors; Postoperative Complications; Acute Kidney Injury
PubMed: 37340684
DOI: 10.1177/10760296231184465 -
BMC Pregnancy and Childbirth Jun 2023Multiple etiologies contribute to recurrent pregnancy loss (RPL) including immunological, endocrine, anatomical, genetic and infection but more than 50% of cases remain...
BACKGROUND
Multiple etiologies contribute to recurrent pregnancy loss (RPL) including immunological, endocrine, anatomical, genetic and infection but more than 50% of cases remain unexplained. Evidences of thrombotic and inflammatory processes were observed at maternal-fetal interface and considered pathological findings in most RPL cases including unexplained cases. This study aimed to evaluate the association between RPL and several risk factors: platelet parameters, coagulation factors, antiphospholipid syndrome, and thyroid function.
METHODS
This is an unmatched case-control study that included 100 RPL and 100 control women. Anthropometric and health data were collected and a gynecologist examined participants to assure fitting the inclusion criteria. Platelet parameters [including Mean Platelet Mass (MPM), Concentration (MPC) and Volume (MPV)] and ratios (MPV/Platelet, MPC/Platelet, MPM/Platelet, Platelet/Mononuclear cells), coagulation markers [Protein C (PC), Protein S (PS), Antithrombin III, D-dimer], antiphospholipid antibodies [Anti-phospholipid (APA), Anti-cardiolipin (ACA) and anti-B2-glycoprotein 1], Lupus anticoagulant, Antinuclear antibodies, and thyroid function (Thyroid stimulating hormone and anti-thyroid peroxidase) were measured.
RESULTS
Mean ages of cases and controls at marriage were 22.5 years for both, and their current ages were 29.4 and 33.0, respectively. 92% of cases and 99% of controls aged blow 30 years at marriage. 75% of cases have 3-4 miscarriages and 9% have ≥ 7 miscarriages. Our results indicated significantly lower male/female age ratio (p = .019), PC (p = .036) and PS (p = .025) in cases compared to controls. Plasma D-dimer (p = .020) and antiphospholipid antibodies [ACA (IgM and IgG), APA (IgM)] were significantly higher in cases compared to controls. No significant differences were observed between cases and controls concerning APA (IgG), anti-B2-glycoprotein 1 (IgM and IgG), Lupus anticoagulant, Antinuclear antibodies, platelet parameters, thyroid markers, family history of miscarriage, consanguineous marriage, and other health data.
CONCLUSIONS
This is the first study that investigated the association between platelet, coagulation, antiphospholipid, autoimmune and thyroid parameters, and RPL in Palestinian women. Significant associations between male/female age ratio, PC, PS, D-dimer, ACA (IgM, IgG), APA (IgM) and RPL were observed. These markers could be used in evaluating RPL. These findings confirm the heterogeneous nature of RPL and emphasize the need for further studies to find out risk factors for RPL.
Topics: Pregnancy; Female; Humans; Male; Aged; Young Adult; Adult; Antiphospholipid Syndrome; Lupus Coagulation Inhibitor; Case-Control Studies; Antibodies, Antinuclear; Arabs; Antibodies, Antiphospholipid; Abortion, Habitual; Glycoproteins; Immunoglobulin G; Immunoglobulin M
PubMed: 37340363
DOI: 10.1186/s12884-023-05764-6 -
Biochemistry and Biophysics Reports Sep 2023SARS-CoV-2 causes substantial extrapulmonary manifestations in addition to pulmonary disease. Some of the major organs affected are cardiovascular, hematological and...
SARS-CoV-2 causes substantial extrapulmonary manifestations in addition to pulmonary disease. Some of the major organs affected are cardiovascular, hematological and thrombotic, renal, neurological, and digestive systems. These types of muti-organ dysfunctions make it difficult and challenging for clinicians to manage and treat COVID-19 patients. The article focuses to identify potential protein biomarkers that can flag various organ systems affected in COVID-19. Publicly reposited high throughput proteomic data from human serum (HS), HEK293T/17 (HEK) and Vero E6 (VE) kidney cell culture were downloaded from ProteomeXchange consortium. The raw data was analyzed in Proteome Discoverer 2.4 to delineate the complete list of proteins in the three studies. These proteins were analyzed in Ingenuity Pathway Analysis (IPA) to associate them to various organ diseases. The shortlisted proteins were analyzed in MetaboAnalyst 5.0 to shortlist potential biomarker proteins. These were then assessed for disease-gene association in DisGeNET and validated by Protein-protein interactome (PPI) and functional enrichment studies (GO_BP, KEGG and Reactome pathways) in STRING. Protein profiling resulted in shortlisting 20 proteins in 7 organ systems. Of these 15 proteins showed at least 1.25-fold changes with a sensitivity and specificity of 70%. Association analysis further shortlisted 10 proteins with a potential association with 4 organ diseases. Validation studies established possible interacting networks and pathways affected, confirmingh the ability of 6 of these proteins to flag 4 different organ systems affected in COVID-19 disease. This study helps to establish a platform to seek protein signatures in different clinical phenotypes of COVID-19. The potential biomarker candidates that can flag organ systems involved are: (a) Vitamin K-dependent protein S and Antithrombin-III for hematological disorders; (b) Voltage-dependent anion-selective channel protein 1 for neurological disorders; (c) Filamin-A for cardiovascular disorder and, (d) Peptidyl-prolyl -trans isomerase A and Peptidyl-prolyl -trans isomerase FKBP1A for digestive disorders.
PubMed: 37304132
DOI: 10.1016/j.bbrep.2023.101493 -
Journal of Anaesthesiology, Clinical... 2023The hemostatic system undergoes extensive alterations following surgical trauma leading to a hypercoagulable state. We assessed and compared the changes in platelet...
BACKGROUND AND AIMS
The hemostatic system undergoes extensive alterations following surgical trauma leading to a hypercoagulable state. We assessed and compared the changes in platelet aggregation, coagulation, and fibrinolysis status during normotensive and dexmedetomidine-induced hypotensive anesthesia in patients undergoing spine surgery.
MATERIAL AND METHODS
Sixty patients undergoing spine surgery were randomly allocated into two groups: normotensive and dexmedetomidine-induced hypotensive groups. Platelet aggregation was assessed preoperatively, 15 min after induction, 60 min, and 120 min after skin incision, at the end of surgery, 2 h and 24 h postoperatively. Prothrombin time (PT), activated partial thromboplastin time (aPTT), platelet count, antithrombin III, fibrinogen, and D-dimer levels were measured preoperatively, 2 h and 24 h postoperatively.
RESULTS
Preoperative platelet aggregation (%) was comparable between both groups. Platelet aggregation significantly increased intraoperative at 120 min after skin incision and postoperatively in the normotensive group compared to the preoperative value ( < 0.05) but it was insignificantly decreased during the intraoperative induced hypotensive period in the dexmedetomidine-induced hypotensive group ( > 0.05). Postoperative PT, aPTT significantly increased and platelet count, and antithrombin III significantly decreased in the normotensive group compared to the preoperative value ( < 0.05) but they were not significantly changed in the hypotensive group ( > 0.05). Postoperative D-dimer significantly increased in the two groups compared to the preoperative value ( < 0.05).
CONCLUSION
Intraoperative and postoperative platelet aggregation significantly increased in the normotensive group with significant alterations of the coagulation markers. Dexmedetomidine-induced hypotensive anesthesia prevented the increased platelet aggregation that occurred in the normotensive group with better preservation of platelet and coagulation factors.
PubMed: 37250254
DOI: 10.4103/joacp.JOACP_111_21 -
Medicina (Kaunas, Lithuania) Apr 2023: Thrombophilia in pregnant women is a condition whose incidence is constantly increasing worldwide, and, under these conditions, the development of preventive...
: Thrombophilia in pregnant women is a condition whose incidence is constantly increasing worldwide, and, under these conditions, the development of preventive procedures is becoming essential. In this study, we aimed to evaluate thrombophilia in pregnant women in the western part of Romania and to establish anthropometric characteristics, socioeconomic features, and genetic and risk factors. : 178 pregnant women were divided into three study groups, according to the type of thrombophilia, aiming to carry out the genetic profile and the acquired one. Anthropometric measures and biological tests were performed. : The mixed type of thrombophilia predominates. The particularities of pregnant women diagnosed with thrombophilia are higher age, living in an urban environment, with normal BMI, approximately 36 weeks of gestational period, and having at least one miscarriage. Regarding the most frequent thrombophilic genetic markers, we obtained the MTFHR gene mutation C677T and A1298C, followed by the PAI-1 4G/5G gene mutation. Smoking represents an aggravating factor in the evolution of this pathology, manifested through the increase of D-dimers and the decrease in antithrombin values, simultaneously with the increase in therapeutic need. : The predominance of MTHFR and PAI-1 4G/5G gene polymorphism is a particularity of pregnant women with thrombophilia from the western part of Romania. Smoking is confirmed as an important risk factor in spontaneous abortion.
Topics: Humans; Female; Pregnancy; Infant; Pregnant Women; Plasminogen Activator Inhibitor 1; Romania; Thrombophilia; Abortion, Spontaneous; Methylenetetrahydrofolate Reductase (NADPH2); Mutation
PubMed: 37241083
DOI: 10.3390/medicina59050851 -
Healthcare (Basel, Switzerland) May 2023We aimed to investigate the effects of antithrombin III administration on the prognosis of severe trauma patients with disseminated intravascular coagulation (DIC).
BACKGROUND
We aimed to investigate the effects of antithrombin III administration on the prognosis of severe trauma patients with disseminated intravascular coagulation (DIC).
METHODS
Medical records of a total of 4023 patients who were admitted to the intensive care unit (ICU) at the single regional trauma center from January 2016 to December 2020 were retrospectively analyzed. After the exclusion of young patients (<15 years old), mild trauma (ISS < 16), non DIC, etc., a total of 140 patients were included in the study. These patients were classified into antithrombin III-administered and non-antithrombin III-administered groups. Clinical data, including laboratory findings, trauma- and ICU-related severity scores, prognosis (including length of hospital stay), and need for organ support, were retrospectively collected. We evaluated the characteristics of the two groups, and compared and analyzed the vital signs, laboratory findings, prognosis, and clinical outcomes of each group. With this, we analyzed the effect of antithrombin III administration in severe trauma patients with DIC.
RESULTS
Of the 140 patients, 61 were treated with antithrombin III. No significant difference was observed in the baseline characteristics between the two groups for initial laboratory results, initial vital signs, or trauma-related severity scores. The improvement of the sequential organ failure assessment (SOFA) score, a prognostic marker, was significantly greater in the administered group ( = 0.009). Additionally, the antithrombin-administered group showed a larger improvement in the SOFA score than the non-administered group ( = 0.002). However, there was no statistical difference between the two groups for the frequency or duration of organ support treatments (renal replacement therapy, mechanical ventilation), mortality, or length of hospital stay.
CONCLUSION
Antithrombin III administration in severe trauma patients with DIC improved SOFA scores and aided in multi-organ dysfunction recovery. Appropriate indications should be studied to maximize the drug's improvement effect in patients with severe trauma in the future.
PubMed: 37239762
DOI: 10.3390/healthcare11101476 -
Biomolecules May 2023The interaction between coagulation factors Xa and IXa and the activated state of their inhibitor, antithrombin (AT),have been investigated using X-ray diffraction...
The interaction between coagulation factors Xa and IXa and the activated state of their inhibitor, antithrombin (AT),have been investigated using X-ray diffraction studies. However, only mutagenesis data are available for non-activated AT. Our aim was to propose a model based on docking and advanced-sampling molecular dynamics simulations that can reveal the conformational behavior of the systems when AT is not binding a pentasaccharide. We built the initial structure for non-activated AT-FXa and AT-FIXa complexes using HADDOCK 2.4. The conformational behavior was studied using Gaussian accelerated molecular dynamics simulations. In addition to the docked complexes, two systems based on the X-ray structures were also simulated, with and without the ligand. The simulations revealed large variability in conformation for both factors. In the docking-based complex of AT-FIXa, conformations with stable Arg150-AT interactions can exist for longer time periods but the system also has a higher tendency for reaching states with very limited interaction with the "exosite" of AT. By comparing simulations with or without the pentasaccharide, we were able to gain insights into the effects of conformational activation on the Michaelis complexes. RMSF analysis and correlation calculations for the alpha-carbon atoms revealed important details of the allosteric mechanisms. Our simulations provide atomistic models for better understanding the conformational activation mechanism of AT against its target factors.
Topics: Antithrombins; Factor Xa; Heparin; Molecular Dynamics Simulation; Protein Conformation; Antithrombin III; Oligosaccharides; Kinetics
PubMed: 37238665
DOI: 10.3390/biom13050795 -
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