-
British Journal of Clinical Pharmacology Nov 2017Antithrombin is increasingly used in paediatric patients, yet there are few age-specific pharmacokinetic data to guide dosing. We aimed to describe the pharmacokinetic...
AIMS
Antithrombin is increasingly used in paediatric patients, yet there are few age-specific pharmacokinetic data to guide dosing. We aimed to describe the pharmacokinetic profile of human (plasma-derived) antithrombin concentrate in paediatric patients.
METHODS
A 5-year retrospective review was performed of patients <19 years of age admitted to our institution who received antithrombin concentrate, were not on mechanical circulatory support and had baseline (predose) and postdose plasma antithrombin activity levels available for analysis. Demographic and laboratory variables, antithrombin dosing information and data on the use of continuous infusion unfractionated heparin were collected. Population pharmacokinetic analysis was performed with bootstrap analysis. The model developed was tested against a validation dataset from a cohort of similar patients, and a predictive value was calculated.
RESULTS
A total 184 patients met the study criteria {46.7% male, median age [years] 0.35 [interquartile range (IQR) 0.07-3.9]}. A median of two antithrombin doses (IQR 1-4) were given to patients (at a dose of 46.3 ± 13.6 units kg ), with median of three (IQR 2-7) postdose levels per patient. Continuous infusion unfractionated heparin was administered in 87.5% of patients, at a mean dose of 34.1 ± 22.7 units kg h . A one-compartment exponential error model best fit the data, and significant covariates included allometrically scaled weight on clearance and volume of distribution, unfractionated heparin dose on clearance, and baseline antithrombin activity level on volume of distribution. The model resulted in a median -1.75% prediction error (IQR -11.75% to 6.5%) when applied to the validation dataset (n = 30).
CONCLUSIONS
Antithrombin pharmacokinetics are significantly influenced by the concurrent use of unfractionated heparin and baseline antithrombin activity.
Topics: Age Factors; Antithrombin III; Antithrombins; Biological Variation, Population; Body Weight; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Fibrinolytic Agents; Heparin; Humans; Infant; Infant, Newborn; Infusions, Intravenous; Male; Models, Biological; Retrospective Studies; Software
PubMed: 28664670
DOI: 10.1111/bcp.13359 -
Biomolecules Jul 2023Adsorbing toxins from the blood to augment membrane-based hemodialysis is an active area of research. Films composed of β-cyclodextrin-co-(methacryloyloxy)ethyl...
Adsorbing toxins from the blood to augment membrane-based hemodialysis is an active area of research. Films composed of β-cyclodextrin-co-(methacryloyloxy)ethyl phosphorylcholine (p(PMβCD-co-MPC)) with various monomer ratios were formed on magnetic nanoparticles and characterized. Surface chemistry effects on protein denaturation were evaluated and indicated that unmodified magnetic nanoparticles greatly perturbed the structure of proteins compared to coated particles. Plasma clotting assays were conducted to investigate the stability of plasma in the presence of particles, where a 2:2 monomer ratio yielded the best results for a given total surface area of particles. Total protein adsorption results revealed that modified surfaces exhibited reduced protein adsorption compared to bare particles, and pure MPC showed the lowest adsorption. Immunoblot results showed that fibrinogen, α1-antitrypsin, vitronectin, prekallikrein, antithrombin, albumin, and C3 correlated with film composition. Hemocompatibility testing with whole blood illustrated that the 1:3 ratio of CD to MPC had a negative impact on platelets, as evidenced by the increased activation, reduced response to an agonist, and reduced platelet count. Other formulations had statistically significant effects on platelet activation, but no formulation yielded apparent adverse effects on hemostasis. For the first time, p(PMβCD-co-MPC)-coated MNP were synthesized and their general hemocompatibility assessed.
Topics: Phosphorylcholine; Magnetite Nanoparticles; Adsorption; Antithrombin III; Blood Coagulation
PubMed: 37627230
DOI: 10.3390/biom13081165 -
JCI Insight Oct 2022Antithrombin, a major endogenous anticoagulant, is a serine protease inhibitor (serpin). We characterized the biological and clinical impact of variants involving...
Antithrombin, a major endogenous anticoagulant, is a serine protease inhibitor (serpin). We characterized the biological and clinical impact of variants involving C-terminal antithrombin. We performed comprehensive molecular, cellular, and clinical characterization of patients with C-terminal antithrombin variants from a cohort of 444 unrelated individuals with confirmed antithrombin deficiency. We identified 17 patients carrying 12 C-terminal variants, 5 of whom had the p.Arg445Serfs*17 deletion. Five missense variants caused qualitative deficiency, and 7, including 4 insertion-deletion variants, induced severe quantitative deficiency, particularly p.Arg445Serfs*17 (antithrombin <40%). This +1 frameshift variant had a molecular size similar to that of WT antithrombin but possessed a different C-terminus. Morphologic and cotransfection experiments showed that recombinant p.Arg445Serfs*17 was retained at the endoplasmic reticulum and had a dominant-negative effect on WT antithrombin. Characterization of different 1+ frameshift, aberrant C-terminal variants revealed that protein secretion was determined by frameshift site. The introduction of Pro441 in the aberrant C-terminus, shared by 5 efficiently secreted variants, partially rescued p.Arg445Serfs*17 secretion. C-terminal antithrombin mutants have notable heterogeneity, related to variant type and localization. Aberrant C-terminal variants caused by 1+ frameshift, with similar size as WT antithrombin, may be secreted or not, depending on frameshift site. The severe clinical phenotypes of these genetic changes are consistent with their dominant-negative effects.
Topics: Antithrombin III; Antithrombins; Endoplasmic Reticulum; Serine Proteinase Inhibitors; Serpins
PubMed: 36214221
DOI: 10.1172/jci.insight.161430 -
The International Journal of Artificial... May 2020Antithrombin III deficiency can occur with heparin anticoagulation during extracorporeal membrane oxygenation leading to heparin resistance. Antithrombin III...
BACKGROUND
Antithrombin III deficiency can occur with heparin anticoagulation during extracorporeal membrane oxygenation leading to heparin resistance. Antithrombin III supplementation has been shown to improve anticoagulation; however, there is no consensus on appropriate administration. We described the effect of antithrombin III supplementation on coagulation parameters in adult and pediatric extracorporeal membrane oxygenation patients.
METHODS
We conducted a retrospective cohort study using electronic medical records of patients who received ⩾1 dose of antithrombin III during extracorporeal membrane oxygenation while on continuous heparin. Endpoints included the change in anti-Xa levels and antithrombin III activity at -6 versus 6 h relative to antithrombin III supplementation, and heparin infusion rates at 6 versus 12 h after antithrombin III supplementation.
RESULTS
Eighteen patients receiving 36 antithrombin III administrations were analyzed. Mean (standard deviation) anti-Xa values at -6 versus 6 h were 0.15 (0.07) versus 0.24 (0.15) IU/mL (-value: 0.250) for pediatrics and 0.19 (0.22) versus 0.31 (0.27) IU/mL (-value: 0.052) for adults. Mean (standard deviation) plasma antithrombin III activity at the same intervals were 32% (14.2%) versus 66.8% (25.1%; -value: 0.062) for pediatrics and 30.3% (14%) versus 52.8% (8.1%; -value: 0.094) for adults. Mean (standard deviation) heparin rates at 6 versus 12 h after antithrombin III for pediatrics were 23.6 (6) versus 23.5 (6.5) units/kg/h (-value: 0.728), and 15.3 (6.6) versus 13.5 (8) units/kg/h (-value: 0.188) for adults.
CONCLUSION
Administration of antithrombin III improved anti-Xa levels in both populations, however, did not significantly reduce heparin rates. Our findings suggest that the use of antithrombin III restores heparin responsiveness in patients with low antithrombin III activity and low anti-Xa activity.
Topics: Adult; Anticoagulants; Antithrombin III; Antithrombin III Deficiency; Blood Coagulation Tests; Child; Extracorporeal Membrane Oxygenation; Female; Heparin; Humans; Male; Retrospective Studies; Treatment Outcome
PubMed: 31750755
DOI: 10.1177/0391398819888932 -
Journal of Thrombosis and Haemostasis :... Oct 2023Despite high risk of venous thromboembolism (VTE) in patients with pancreatic cancer, there are little data on contact system activation in these patients.
BACKGROUND
Despite high risk of venous thromboembolism (VTE) in patients with pancreatic cancer, there are little data on contact system activation in these patients.
OBJECTIVES
To quantify contact system and intrinsic pathway activation and subsequent VTE risk in patients with pancreatic cancer.
METHODS
Patients with advanced pancreatic cancer were compared with controls. Blood was drawn at baseline and patients were followed for 6 months. Complexes of proteases with their natural inhibitors, C1-esterase inhibitor (C1-INH), antithrombin (AT), or alpha-1 antitrypsin (α1at), were measured for complexes containing kallikrein (PKa:C1-INH), factor (F)XIIa (FXIIa:C1-INH), and FXIa (FXIa:C1-INH, FXIa:AT, FXIa:α1at). The association of cancer with complex levels was assessed in a linear regression model, adjusted for age, sex, and body mass index. In a competing risk regression model, we assessed associations between complex levels and VTE.
RESULTS
One hundred nine patients with pancreatic cancer and 22 controls were included. The mean age was 66 years (SD, 8.4) in the cancer cohort and 52 years (SD, 10.1) in controls. In the cancer cohort, 18 (16.7%) patients developed VTE during follow-up. In the multivariable regression model, pancreatic cancer was associated with increased complexes of PKa:C1-INH (P < .001), FXIa:C1-INH (P < .001), and FXIa:AT (P < .001). High FXIa:α1at (subdistribution hazard ratio, 1.48 per log increase; 95% CI, 1.02-2.16) and FXIa:AT (subdistribution hazard ratio, 2.78 highest vs lower quartiles; 95% CI, 1.10-7.00) were associated with VTE.
CONCLUSION
Complexes of proteases with their natural inhibitors were elevated in patients with cancer. These data suggest that the contact system and intrinsic pathway activation are increased in patients with pancreatic cancer.
Topics: Aged; Female; Humans; Male; Anticoagulants; Antithrombin III; Endopeptidases; Kallikreins; Pancreatic Neoplasms; Prospective Studies; Venous Thromboembolism; Middle Aged
PubMed: 37331518
DOI: 10.1016/j.jtha.2023.06.009 -
Thrombosis and Haemostasis May 2022A patient with hematuria in our clinic was diagnosed with urolithiasis. Analysis of the patient's plasma clotting time indicated that both activated partial...
A patient with hematuria in our clinic was diagnosed with urolithiasis. Analysis of the patient's plasma clotting time indicated that both activated partial thromboplastin time (52.6 seconds) and prothrombin time (19.4 seconds) are prolonged and prothrombin activity is reduced to 12.4% of normal, though the patient exhibited no abnormal bleeding phenotype and a prothrombin antigen level of 87.9%. Genetic analysis revealed the patient is homozygous for prothrombin Y510N mutation. We expressed and characterized the prothrombin-Y510N variant in appropriate coagulation assays and found that the specificity constant for activation of the mutant zymogen by factor Xa is impaired approximately fivefold. Thrombin generation assay using patient's plasma and prothrombin-deficient plasma supplemented with either wild-type or prothrombin-Y510N revealed that both peak height and time to peak for the prothrombin mutant are decreased; however, the endogenous thrombin generation potential is increased. Further analysis indicated that the thrombin mutant exhibits resistance to antithrombin and is inhibited by the serpin with approximately 12-fold slower rate constant. Protein C activation by thrombin-Y510N was also decreased by approximately 10-fold; however, thrombomodulin overcame the catalytic defect. The Na-concentration-dependence of the amidolytic activities revealed that the dissociation constant for the interaction of Na with the mutant has been elevated approximately 20-fold. These results suggest that Y510 (Y184a in chymotrypsin numbering) belongs to network of residues involved in binding Na. A normal protein C activation by thrombin-Y510N suggests that thrombomodulin modulates the conformation of the Na-binding loop of thrombin. The clotting defect of thrombin-Y510N appears to be compensated by its markedly lower reactivity with antithrombin, explaining patient's normal hemostatic phenotype.
Topics: Antithrombin III; Antithrombins; Blood Coagulation Disorders, Inherited; Humans; Protein C; Prothrombin; Thrombin; Thrombomodulin
PubMed: 34256393
DOI: 10.1055/a-1549-6407 -
The Journal of Molecular Diagnostics :... May 2022Inherited antithrombin deficiency, the most severe form of thrombophilia, is predominantly caused by variants in SERPINC1. Few causal structural variants have been...
Inherited antithrombin deficiency, the most severe form of thrombophilia, is predominantly caused by variants in SERPINC1. Few causal structural variants have been described, usually detected by multiplex ligation-dependent probe amplification or cytogenetic arrays, which only define the gain or loss and the approximate size and location. This study has done a complete dissection of the structural variants affecting SERPINC1 of 39 unrelated patients with antithrombin deficiency using multiplex ligation-dependent probe amplification, comparative genome hybridization array, long-range PCR, and whole genome nanopore sequencing. Structural variants, in all cases only affecting one allele, were deleterious and caused a severe type I deficiency. Most defects were deletions affecting exons of SERPINC1 (82.1%), but the whole cohort was heterogeneous, as tandem duplications, deletion of introns, or retrotransposon insertions were also detected. Their size was also variable, ranging from 193 bp to 8 Mb, and in 54% of the cases involved neighboring genes. All but two structural variants had repetitive elements and/or microhomologies in their breakpoints, suggesting a common mechanism of formation. This study also suggested regions recurrently involved in structural variants causing antithrombin deficiency and found three structural variants with a founder effect: the insertion of a retrotransposon, duplication of exon 6, and a 20-gene deletion. Finally, nanopore sequencing was determined to be the most appropriate method to identify and characterize all structural variants at nucleotide level, independently of their size or type.
Topics: Antithrombin III Deficiency; Antithrombins; Exons; Humans; Introns; Retroelements
PubMed: 35218943
DOI: 10.1016/j.jmoldx.2022.01.009 -
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 -
COPD 2022We aimed to explore the role of antithrombin III (AT-III) activity in diagnosing patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and...
We aimed to explore the role of antithrombin III (AT-III) activity in diagnosing patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and chronic bronchitis, and its relationship with all-cause mortality of AECOPD patients. We performed univariate and multivariate Cox regression analyses of the factors determining all-cause mortality. We recruited 279 patients with AECOPD and 91 with chronic bronchitis. On admission, patients with AECOPD had lower AT-III activity (80.7 vs. 86.35%, = 0.002) and higher neutrophil percentages (70.12 vs. 66.40%, = 0.02) than those with chronic bronchitis. The patients who died were older (78 vs. 73 years, < 0.001); had higher CRP (39.05 vs. 5.65 mg/L, < 0.001), D-dimer (1.72 vs. 0.46 mg/L, < 0.001), FIB (3.56 vs. 3.05 g/L, = 0.01) levels; and exhibited lower AT-III activity (71.29 vs. 82.94%, < 0.001) than the survivors. The AT-III area under the receiver operating characteristic curve for predicting COPD all-cause mortality was 0.75 ( < 0.001), optimal cutoff point 79.75%, sensitivity 86.8%, and specificity 57.1%. Multivariate Cox regression analyses showed that increased levels of CRP (HR = 1.005, = 0.02), D-dimer (HR = 1.17, = 0.01), WBC count (HR = 1.11, = 0.002), and reduced AT-III activity (HR = 0.97, = 0.02) were independent prognostic factors for all-cause mortality. Patients with AT-III ≤ 79.75% were 4.52 times ( = 0.001) more likely to die than those with AT-III > 79.75%. AT-III activity was lower in patients with AECOPD than in those with chronic bronchitis and is potentially useful as an independent predictor of all-cause mortality in patients with AECOPD: reduced AT-III activity and increased CRP and D-dimer levels indicate a higher risk of all-cause mortality.
Topics: Humans; Antithrombin III; Biomarkers; Bronchitis, Chronic; Disease Progression; Hospital Mortality; Prognosis; Pulmonary Disease, Chronic Obstructive
PubMed: 36469629
DOI: 10.1080/15412555.2022.2106200 -
The International Journal of Artificial... Feb 2019Extracorporeal circulation devices are coated with a biocompatible polymer coating agent (BPCA) that has a hydrophilic blood-contacting layer, but hemofilters are not....
OBJECTIVE:
Extracorporeal circulation devices are coated with a biocompatible polymer coating agent (BPCA) that has a hydrophilic blood-contacting layer, but hemofilters are not. We aimed to investigate the antithrombotic properties of a BPCA-coated hemofilter.
METHODS:
Four experiments using BPCA-coated circuits and non-coated hemofilters and four experiments using BPCA-coated circuits and BPCA-coated hemofilters were performed with whole human blood and compared by measuring the circuit pressure every 5 min, antithrombin activity every 40 min, and thrombin-antithrombin complex every 40 min, for a total of 240 min of recirculation.
RESULTS:
The mean time required for the pressure at the inlet of the hemofilter to increase sharply was longer in BPCA-coated than in non-coated hemofilters (66 ± 11 min vs 25 ± 9 min, p < 0.01). The mean antithrombin activity value at 200 and 240 min of recirculation was significantly higher in the experiments with BPCA-coated versus non-coated hemofilters (43.3 ± 2.87 vs 33.3 ± 5.74, p = 0.04; 42.8 ± 3.59 vs 31.0 ± 5.35, p = 0.01, respectively); the antithrombin activity values at the other time points were not significantly different. Furthermore, all thrombin-antithrombin complex values in experiments with the BPCA-coated hemofilters achieved overrange at 80 min of recirculation, whereas those with the non-coated hemofilter achieved overrange at 40 min.
CONCLUSION:
This study suggests that BPCA-coated hemofilters can inhibit antithrombin consumption, contributing to antithrombotic effects in extracorporeal circulation circuits.
Topics: Acrylates; Antithrombin III; Antithrombins; Blood Coagulation; Blood Coagulation Tests; Coated Materials, Biocompatible; Hemofiltration; Humans; Hydrophobic and Hydrophilic Interactions; In Vitro Techniques; Peptide Hydrolases; Polymers; Sulfones; Thrombosis
PubMed: 30486706
DOI: 10.1177/0391398818815480