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International Journal of Molecular... Apr 2023Liver function influences the plasma antithrombin (AT)-III levels. AT-III is beneficial for patients with portal vein thrombosis (PVT) and low plasma AT-III levels....
Liver function influences the plasma antithrombin (AT)-III levels. AT-III is beneficial for patients with portal vein thrombosis (PVT) and low plasma AT-III levels. However, whether these levels affect prognosis in patients with cirrhosis-associated PVT remains unknown. This retrospective study involved 75 patients with cirrhosis and PVT treated with danaparoid sodium with or without AT-III. The plasma AT-III level was significantly lower in patients with liver failure-related death than in those with hepatocellular carcinoma (HCC)-related death ( = 0.005), although the Child-Pugh and albumin-bilirubin (ALBI) scores were not significantly different between these two groups. Receiver operating characteristic curve analysis of the plasma AT-III levels showed cutoff values of 54.0% at 5-year survival. Low plasma AT-III levels (<54.0%) were associated with significantly worse prognosis than high levels in both overall survival ( = 0.0013) and survival excluding HCC-related death ( < 0.0001). Low plasma AT-III (<54.0%) was also associated with a significantly worse prognosis among patients with Child-Pugh A/B or ALBI grade 1/2 ( < 0.0001). Multivariate analyses indicated that low plasma AT-III levels (<54.0%) were an independent prognostic factor for poor survival outcome. Low plasma AT-III levels may be associated with mortality, particularly liver failure-related death, independent of liver function.
Topics: Humans; Antithrombin III; Portal Vein; Carcinoma, Hepatocellular; Retrospective Studies; Prognosis; Liver Neoplasms; Liver Cirrhosis; Anticoagulants; Venous Thrombosis; Bilirubin; Albumins; Liver Failure
PubMed: 37175438
DOI: 10.3390/ijms24097732 -
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 -
In Vivo (Athens, Greece) 2023The management of refractory ascites is critical for the treatment of patients with decompensated cirrhosis. This study aimed to evaluate the feasibility and safety of... (Observational Study)
Observational Study
Changes in Coagulation and Fibrinolytic Factors in Patients With Cirrhotic Refractory Ascites Undergoing Cell-free and Concentrated Ascites Reinfusion Therapy: A Retrospective Observational Study in Japan.
BACKGROUND/AIM
The management of refractory ascites is critical for the treatment of patients with decompensated cirrhosis. This study aimed to evaluate the feasibility and safety of cell-free and concentrated ascites reinfusion therapy (CART) in patients with cirrhosis and refractory ascites, with a focus on changes in coagulation and fibrinolytic factors in ascitic fluid following CART.
PATIENTS AND METHODS
This was a retrospective cohort study including 23 patients with refractory ascites undergoing CART. Serum endotoxin activity (EA) before and after CART and the levels of coagulation and fibrinolytic factors and proinflammatory cytokines in original and processed ascitic fluid were measured. The Ascites Symptom Inventory-7 (ASI-7) scale was used for subjective symptom assessment before and after CART.
RESULTS
Body weight and waist circumference significantly decreased after CART, whereas serum EA did not significantly change after CART. Similar to the previous reports, ascitic fluid concentrations of total protein, albumin, high-density lipoprotein cholesterol, γ-globulin, and immunoglobulin G levels were significantly increased after CART; mild elevations in body temperature and interleukin 6 and tumor necrosis factor-alpha levels in ascitic fluid were also observed. Importantly, the levels of antithrombin-III, factor VII, and X, which are useful for patients with decompensated cirrhosis, were markedly increased in the reinfused fluid during CART. Finally, the total ASI-7 score was significantly lower following CART, compared with the pre-CART score.
CONCLUSION
CART is an effective and safe approach for the treatment of refractory ascites that allows the intravenous reinfusion of coagulation and fibrinolytic factors in the filtered and concentrated ascites.
Topics: Humans; Ascites; Retrospective Studies; Japan; Ascitic Fluid; Liver Cirrhosis
PubMed: 37103093
DOI: 10.21873/invivo.13199 -
JACS Au Apr 2023The emergence of new SARS-CoV-2 variants and the dangers of long-covid necessitate the development of broad-acting therapeutics that can reduce viral burden. SARS-CoV-2...
The emergence of new SARS-CoV-2 variants and the dangers of long-covid necessitate the development of broad-acting therapeutics that can reduce viral burden. SARS-CoV-2 employs heparan sulfate (HS) as an initial cellular attachment factor, and therefore, there is interest in developing heparin as a therapeutic for SARS-CoV-2. Its use is, however, complicated by structural heterogeneity and the risk of causing bleeding and thrombocytopenia. Here, we describe the preparation of well-defined heparin mimetics by a controlled head-to-tail assembly of HS oligosaccharides having an alkyne or azide moiety by copper-catalyzed azide-alkyne cycloaddition (CuAAC). Alkyne- and azide-containing sulfated oligosaccharides were prepared from a common precursor by modifying an anomeric linker with 4-pentynoic acid and by enzymatic extension with an -acetyl-glucosamine having an azide moiety at C-6 (GlcNAc6N), respectively, followed by CuAAC. The process of enzymatic extension with GlcNAc6N followed by CuAAC with the desired alkyne-containing oligosaccharides could be repeated to give compounds composed of 20 and 27 monosaccharides, respectively. The heparin mimetics could inhibit the binding of the SARS-CoV-2 spike or RBD to immobilized heparin or to Vero E6 cells. The inhibitory potency increased with increasing chain length, and a compound composed of four sulfated hexasaccharides linked by triazoles had a similar potency as unfractionated heparin. Sequence analysis and HS microarray binding studies with a wide range of RBDs of variants of concern indicate that they have maintained HS-binding capabilities and selectivities. The heparin mimetics exhibit no or reduced binding to antithrombin-III and platelet factor 4, respectively, which are associated with side effects.
PubMed: 37101566
DOI: 10.1021/jacsau.3c00042 -
PloS One 2023Antithrombin resistance is a rare subtype of hereditary thrombophilia caused by prothrombin gene variants, leading to thrombotic disorders. Recently, the Prothrombin...
Antithrombin resistance is a rare subtype of hereditary thrombophilia caused by prothrombin gene variants, leading to thrombotic disorders. Recently, the Prothrombin Belgrade variant has been reported as a specific variant that leads to antithrombin resistance in two Serbian families with thrombosis. However, due to clinical data scarcity and the inapplicability of traditional genome-wide association studies (GWAS), a broader perspective on molecular and phenotypic mechanisms associated with the Prothrombin Belgrade variant is yet to be uncovered. Here, we propose an integrative framework to address the lack of genomic samples and support the genomic signal from the full genome sequences of five heterozygous subjects by integrating it with subjects' phenotypes and the genes' molecular interactions. Our goal is to identify candidate thrombophilia-related genes for which our subjects possess germline variants by focusing on the resulting gene clusters of our integrative framework. We applied a Non-negative Matrix Tri-Factorization-based method to simultaneously integrate different data sources, taking into account the observed phenotypes. In other words, our data-integration framework reveals gene clusters involved with this rare disease by fusing different datasets. Our results are in concordance with the current literature about antithrombin resistance. We also found candidate disease-related genes that need to be further investigated. CD320, RTEL1, UCP2, APOA5 and PROZ participate in healthy-specific or disease-specific subnetworks involving thrombophilia-annotated genes and are related to general thrombophilia mechanisms according to the literature. Moreover, the ADRA2A and TBXA2R subnetworks analysis suggested that their variants may have a protective effect due to their connection with decreased platelet activation. The results show that our method can give insights into antithrombin resistance even if a small amount of genetic data is available. Our framework is also customizable, meaning that it applies to any other rare disease.
Topics: Humans; Prothrombin; Genome-Wide Association Study; Rare Diseases; Mutation; Thrombophilia; Antithrombins; Anticoagulants; Thrombosis; Antithrombin III; Phenotype
PubMed: 37098010
DOI: 10.1371/journal.pone.0284084 -
Romanian Journal of Ophthalmology 2023The objective of this case report is to highlight the importance of patent foramen ovale (PFO) as a potential cause of central retinal artery occlusion (CRAO). A...
The objective of this case report is to highlight the importance of patent foramen ovale (PFO) as a potential cause of central retinal artery occlusion (CRAO). A teenage girl presented with a sudden painless onset of vision loss in the right eye, which was accompanied by frontal headaches and vertigo. The patient was referred to the Ophthalmology Department, where subsequent examination revealed a best corrected visual acuity of 20/ 400 and a positive relative afferent pupillary defect (RAPD) in the right eye. Fundoscopy and optical coherence tomography confirmed the diagnosis of central retinal artery occlusion following which investigations to rule out hematologic, vascular, and cardiac causes were performed. Transoesophageal echocardiography revealed PFO as the cause of this cryptogenic stroke. All the necessary blood testing work was performed (complete blood counts, erythrocyte sedimentation rate, C-reactive protein, lipid profile, homocysteine levels, prothrombin time, activated partial thromboplastin time, international normalized ratio, liver, renal and thyroid function tests, antinuclear antibodies, anti-smooth muscle antibodies, anti-mitochondrial antibodies, p-ANCA, c-ANCA, anti-cardiolipin antibodies, protein C, Protein S, activated protein C resistance, anti-thrombin III, VDRL, antibodies for viral retinitis, angiotensin converting enzyme, Mantoux test, detailed urine and electrolyte reports). Transoesophageal echocardiography revealed right to left shunt. This case along with other reported evidence in literature support the strong connection between PFO and CRAO. Closure of symptomatic PFO may result in prevention of severe visual loss. CRAO = central retinal artery occlusion, PFO = patent foramen ovale, RAPD = relative afferent pupillary defect, BCVA = best corrected visual acuity, OCT = Optical coherence tomography, IOP = Intraocular pressures, TTE = transthoracic echocardiography, HM = hand motion, TEE = transesophageal echocardiogram.
Topics: Female; Adolescent; Humans; Foramen Ovale, Patent; Echocardiography, Transesophageal; Retinal Artery Occlusion
PubMed: 37089812
DOI: 10.22336/rjo.2023.12 -
Blood Apr 2023
Topics: Antithrombins; Factor IXa; Antithrombin III; Anticoagulants
PubMed: 37079331
DOI: 10.1182/blood.2023019793 -
Journal of Blood Medicine 2023This study aims to investigate the prevalence of inherited thrombophilia in women with recurrent pregnancy loss during the first trimester of pregnancy. The study was...
PURPOSE
This study aims to investigate the prevalence of inherited thrombophilia in women with recurrent pregnancy loss during the first trimester of pregnancy. The study was assessed the potential role of inherited thrombophilia in recurrent miscarriages and evaluate the consequences of this condition on the reproductive outcomes of affected women.
MATERIAL AND METHODS
This study was an analytical descriptive carried out in Khartoum, Sudan. The research comprised 98 controls who had given birth twice or more without experiencing a miscarriage and 120 patients. Each patient had done more than two miscarriages especially when the pregnancy is at its beginning trimester. (APCR), and (PS) were investigated using the clotting approach. There was an assessment of biological activities of (ATIII), (PC), and (PS) for both groups using the chromogenic method.
RESULTS
The average age of the patients was 34, which was higher than the average age of the controls (33.5). The patient group had a much higher rate of multiple miscarriages among the women.: 35 (29.17%), 45 (37.50%), and 40 (33.33%). The incidence of PC deficiencies was determined to be 1.02% (1/98), whereas neither ATIII nor PS deficiencies were seen in the control group (0/98). APCR was more prevalent in the control group (4.10% or 4/98).
CONCLUSION
Despite contradicting evidence to the contrary in the literature, our findings imply that most miscarriages occur when pregnancy is at the first trimester when a woman is pregnant and they are all caused by thrombophilia.
PubMed: 37041968
DOI: 10.2147/JBM.S401469 -
Bulletin of Experimental Biology and... Mar 2023The effects of inhalations of an oxygen-xenon (70%/30%) mixture were studied in two models of acute respiratory distress syndrome caused by intratracheal administration...
The effects of inhalations of an oxygen-xenon (70%/30%) mixture were studied in two models of acute respiratory distress syndrome caused by intratracheal administration of 0.5 mg/kg LPS or 0.04 ml acidin-pepsin (pH 1.2). Inhalation of the oxygen-xenon mixture inhibited the development and reduced the intensity of the inflammatory process in the lung tissue, which was assessed by the dynamics of lung weight and body weight of animals: the therapeutic exposure decreased both parameters. It was found that the thrombogenic stimulus, pathognomonic for the development of acute respiratory distress syndrome, decreased under the effect of oxygen-xenon inhalations, while the level of natural anticoagulant antithrombin III increased.
Topics: Humans; Respiratory Distress Syndrome; Lung; Oxygen; Administration, Inhalation
PubMed: 37040041
DOI: 10.1007/s10517-023-05755-9 -
Clinical and Translational Science Jul 2023Antithrombin-III (AT-III) concentrates have been used in the immediate postoperative period after liver transplantation to prevent critical thrombosis. We aimed to... (Randomized Controlled Trial)
Randomized Controlled Trial
Antithrombin-III (AT-III) concentrates have been used in the immediate postoperative period after liver transplantation to prevent critical thrombosis. We aimed to investigate a more appropriate method for AT-III concentrate administration to maintain plasma AT-III activity level within the target range. In this randomized controlled trial, 130 adult patients undergoing living-donor liver transplantation were randomized to either the intermittent group or continuous group. In the intermittent group, 500 international units (IU) of AT-III concentrate were administered after liver transplantation and repeated every 6 h for 72 h. In the continuous group, 3000 IU of AT-III were continuously infused for 71 h after a loading dose of 2000 IU over 1 h. Plasma AT-III activity level was measured at 12, 24, 48, 72, and 84 h from the first AT-III administration. The primary outcome was the target (80%-120%) attainment rate at 72 h. Target attainment rates at other timepoints and associated complications were collected as secondary outcomes. A total of 107 patients were included in the analysis. The target attainment rates at 72 h post-dose were 30% and 62% in the intermittent group and continuous group, respectively (p = 0.003). Compared to the intermittent group, patients in the continuous group reached the target level more rapidly (12 vs. 24 h, median time, p < 0.001) and were more likely to remain in the target range until 84 h. For maintaining the target plasma AT-III activity level after living-donor liver transplantation, continuous infusion of AT-III seemed to be more appropriate compared to the conventional intermittent infusion regimen.
Topics: Adult; Humans; Antithrombin III; Liver Transplantation; Living Donors; Anticoagulants; Thrombosis
PubMed: 37038357
DOI: 10.1111/cts.13521