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Nephrology, Dialysis, Transplantation :... Apr 2024The risk of diabetic kidney disease (DKD) progression is significant despite treatment with renin-angiotensin system (RAS) blocking agents. Current clinical tools cannot...
BACKGROUND
The risk of diabetic kidney disease (DKD) progression is significant despite treatment with renin-angiotensin system (RAS) blocking agents. Current clinical tools cannot predict whether or not patients will respond to treatment with RAS inhibitors (RASi). We aimed to investigate whether proteome analysis could identify urinary peptides as biomarkers that could predict the response to angiotensin-converting enzyme inhibitor and angiotensin-receptor blockers treatment to avoid DKD progression. Furthermore, we investigated the comparability of the estimated glomerular filtration rate (eGFR), calculated using four different GFR equations, for DKD progression.
METHODS
We evaluated urine samples from a discovery cohort of 199 diabetic patients treated with RASi. DKD progression was defined based on eGFR percentage slope results between visits (∼1 year) and for the entire period (∼3 years) based on the eGFR values of each GFR equation. Urine samples were analysed using capillary electrophoresis-coupled mass spectrometry. Statistical analysis was performed between the uncontrolled (patients who did not respond to RASi treatment) and controlled kidney function groups (patients who responded to the RASi treatment). Peptides were combined in a support vector machine-based model. The area under the receiver operating characteristic curve was used to evaluate the risk prediction models in two independent validation cohorts treated with RASi.
RESULTS
The classification of patients into uncontrolled and controlled kidney function varies depending on the GFR equation used, despite the same sample set. We identified 227 peptides showing nominal significant difference and consistent fold changes between uncontrolled and controlled patients in at least three methods of eGFR calculation. These included fragments of collagens, alpha-1-antitrypsin, antithrombin-III, CD99 antigen and uromodulin. A model based on 189 of 227 peptides (DKDp189) showed a significant prediction of non-response to the treatment/DKD progression in two independent cohorts.
CONCLUSIONS
The DKDp189 model demonstrates potential as a predictive tool for guiding treatment with RASi in diabetic patients.
Topics: Humans; Female; Male; Glomerular Filtration Rate; Middle Aged; Diabetic Nephropathies; Biomarkers; Peptides; Aged; Angiotensin-Converting Enzyme Inhibitors; Renin-Angiotensin System; Prognosis; Disease Progression; Follow-Up Studies; Blood Pressure; Antihypertensive Agents; Hypertension
PubMed: 37930730
DOI: 10.1093/ndt/gfad223 -
Haematologica Oct 2023
Topics: Humans; Antithrombins; Founder Effect; Poland; Antithrombin III; Mutation; Anticoagulants
PubMed: 37021543
DOI: 10.3324/haematol.2022.282459 -
Zeitschrift Fur Geburtshilfe Und... Dec 2023To evaluate the impact of increased Activated Protein C (APC) resistance, decreased antithrombin III activity and hypocomplementemia on the pregnancy outcomes of the...
Impact of Increased Activated Protein-C Resistance, Decreased Antithrombin III Activity and Hypocomplementemia on the Gestational Outcomes of Pregnancies with MTHFR Polymorphisms.
OBJECTIVE
To evaluate the impact of increased Activated Protein C (APC) resistance, decreased antithrombin III activity and hypocomplementemia on the pregnancy outcomes of the patients with methylentetrahydrofolate reductase (MTHFR) polymorphisms.
METHODS
This study was composed of 83 pregnancies with MTHFR polymorphisms. Increased APC resistance, decreased antithrombin III activity and hypocomplementemia were accepted as risk factors for poor gestational outcome.
RESULTS
Having at least one risk factor resulted in significantly higher rates of "APGAR score of<7" at the first ten minutes (p=0.009). Composite adverse outcome rate was also higher in patients with at least one of the defined risk factors despite lack of statistical significance (p=0.241). Rate of newborn with an "APGAR score of<7" at first ten minutes was significantly higher at patients with hypocomplementemia (p=0.03).
CONCLUSION
Hypocomplementemia is a risk factor for poor gestational outcome in pregnancies with MTHFR polymorphisms.
Topics: Pregnancy; Female; Infant, Newborn; Humans; Pregnancy Outcome; Antithrombin III; Oxidoreductases; Activated Protein C Resistance; Methylenetetrahydrofolate Reductase (NADPH2)
PubMed: 37579788
DOI: 10.1055/a-2134-6452 -
Advanced Healthcare Materials Aug 2023Activation of coagulation cascades, especially FX and prothrombin, prevents blood loss and reduces mortality from hemorrhagic shock. Inorganic salts are efficient but...
Activation of coagulation cascades, especially FX and prothrombin, prevents blood loss and reduces mortality from hemorrhagic shock. Inorganic salts are efficient but cannot stop bleeding completely in hemorrhagic events, and rebleeding carries a significant mortality risk. The coagulation mechanism of biominerals has been oversimplified in the past two decades, limiting the creation of novel hemostats. Herein, at the interface, the affinity of proteins, the protease activity, fibrinolysis, hydration shell, and dynamic microenvironment are monitored at the protein level. Proteomic analysis reveals that fibrinogen and antithrombin III's affinity for kaolin's interface causes a weak thrombus and rebleeding during hemostasis. Inspiringly, amorphous bioactive glass (BG) with a transient-dynamic ion microenvironment breaches the hydration layer barrier and selectively and slightly captures procoagulant components of kiniogen-1, plasma kallikrein, FXII, and FXI proteins on its interface, concurrently generating a continuous biocatalytic interface to rapidly activate both intrinsic and extrinsic coagulation pathways. Thus, prothrombin complexes are successfully hydrolyzed to thrombin without platelet membrane involvement, speeding production of high-strength clots. This study investigates how the interface of inorganic salts assists in coagulation cascades from a more comprehensive micro-perspective that may help elucidate the clinical application issues of kaolin-gauze and pave the way to new materials for managing hemorrhage.
Topics: Humans; Prothrombin; Kaolin; Proteomics; Salts; Blood Coagulation; Thrombosis; Hemorrhage
PubMed: 37000691
DOI: 10.1002/adhm.202300039 -
Analytica Chimica Acta Oct 2023Glycosaminoglycans (GAGS) are involved in many biological processes through interactions with a variety of proteins, including proteases, growth factors, cytokines,...
Glycosaminoglycans (GAGS) are involved in many biological processes through interactions with a variety of proteins, including proteases, growth factors, cytokines, chemokines and adhesion molecules. Identifying druggable GAG-protein interactions for therapeutic purposes is a challenge for the analytical community. In this context, this work investigates the use of a new miniaturized monolithic affinity column (poly(GMA-co-MBA) grafted with antithrombin III (AT III)) to specifically capture and elute high affinity sequences contained in low molecular weight heparin (enoxaparin) for further on-line characterization. This miniaturized, high binding capacity affinity column allows the specific capture of high-affinity oligosaccharide chains from Enoxaparin, even at low concentrations and with a minimal consumption of AT III. In addition to purification, this elution process enables preconcentration for direct analysis by capillary zone electrophoresis. It was found that many of oligosaccharide chains in enoxaparin were eliminated and that certain chain sequences were retained and enriched. Direct coupling with MALDI-TOF MS was successfully used to further characterize the specifically retained oligosaccharides where nano-ESI-TOF MS failed. After optimization of the sample preparation and ionization parameters, direct on-line analysis was performed by applying the elution volume released from the miniaturized affinity column (≤1 μL) directly to the MALDI plate. Finally, this original miniaturized analytical workflow coupling miniaturized AT III-affinity chromatography to MALDI-TOF MS detection is able to select, enrich and detect and identify high affinity sequences (mainly DP4 in size length with a high degree of sulfation) from low molecular weight heparin samples. A more specific selection of GAG sequences can be achieved by increasing the ionic strength during the washing step of affinity chromatography. This is consistent with the known binding pattern between heparin and AT III.
Topics: Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Enoxaparin; Anticoagulants; Heparin, Low-Molecular-Weight; Glycosaminoglycans; Chromatography, Affinity
PubMed: 37604620
DOI: 10.1016/j.aca.2023.341656 -
International Journal of General... 2023Post-COVID-19 condition is thought to affect 10-20% of people at least 3 months after a diagnosis of COVID-19 and two months of symptoms. Post-COVID-19 condition...
BACKGROUND AND OBJECTIVES
Post-COVID-19 condition is thought to affect 10-20% of people at least 3 months after a diagnosis of COVID-19 and two months of symptoms. Post-COVID-19 condition presents itself with many clinical effects with varying degrees of severity ranging from a mild cough to a life-threatening coagulopathy. Our study aimed to identify a relationship between the titers of anti-SARS-CoV-2 IgG and anticoagulation parameters: antithrombin III (ATIII), protein C (PC) and thrombomodulin (TM).
MATERIALS AND METHODS
Blood plasma was collected from healthy donors aged 25-45 who had recovered from COVID-19 3-6 months ago and their titers of anti-SARS-CoV-2 IgG and ATIII, PC, and TM were measured.
RESULTS
We found that concentrations and activities of key anticoagulation parameters (ATIII, PC, and TM) measured in donor plasma during the post-COVID-19 varied in relation to the titers of anti-SARS-CoV-2 IgG.
CONCLUSION
While we identified a dysfunction of anticoagulation parameters in patients with post-COVID-19, we aim to explore the subpopulation antibody IgG fraction directly using in vivo and in vitro experiments with the possibility to contribute to the development of treatment options for post-COVID-19 conditions.
PubMed: 38156079
DOI: 10.2147/IJGM.S425496 -
Scientific Reports Oct 2023Antithrombin (AT) deficiency increases the risk for venous thromboembolism, therefore, a highly sensitive assay to identify this condition is crucial. The aim of this... (Meta-Analysis)
Meta-Analysis
Antithrombin (AT) deficiency increases the risk for venous thromboembolism, therefore, a highly sensitive assay to identify this condition is crucial. The aim of this paper was to perform a meta-analysis comparing AT activities measured by different AT activity assays in patients with heparin binding site AT deficiency. In addition, the diagnostic sensitivity of selected assays was compared depending on the available data. An extensive literature search was performed considering results with publication date up to July 10, 2021. Seven relevant English-language observational studies, comparing AT activity measured by different AT activity assays in Caucasian Europeans with either the AT Budapest III or AT Padua I mutation were included in meta-analyses. There was no significant difference in AT activity between Labexpert and Innovance in patients with AT Budapest III (P = 0.567) and AT Padua I (P = 0.265), while AT activity determined by HemosIL was significantly higher compared to Innovance for both mutations (AT Budapest III: P < 0.001; AT Padua I: P < 0.001). These results are in line with the results of comparison of diagnostic sensitivity. In patients with AT Budapest III, the AT activity was also higher when measured with Berichrom compared to Innovance (P = 0.002), however, the results of comparison of diagnostic sensitivity across studies were variable. No significant difference (P = 0.117) in AT activity as well as diagnostic sensitivity was observed between Sta-Stachrom and Innovance. The results of our study suggest that Innovance, Labexpert and Sta-Stachrom are the most sensitive activity assays for detection of AT Budapest III and AT Padua I, whereas HemosIL showed considerably lower sensitivity for these two variants. As revealed in our study, the diagnostic sensitivity of AT activity assays to type II heparin binding site AT deficiency is different, and in some assays mutation dependent.
Topics: Humans; Heparin; Anticoagulants; Blood Coagulation Tests; Antithrombin III Deficiency; Binding Sites; Antithrombins
PubMed: 37794095
DOI: 10.1038/s41598-023-43941-x -
Effect of prothrombin Belgrade mutation, causing antithrombin resistance, on fibrin clot properties.International Journal of Laboratory... Apr 2024Prothrombin Belgrade mutation is the result of the c.1787G>A substitution in the prothrombin gene. It is located in the antithrombin and sodium binding site and leads to...
INTRODUCTION
Prothrombin Belgrade mutation is the result of the c.1787G>A substitution in the prothrombin gene. It is located in the antithrombin and sodium binding site and leads to impaired inactivation of thrombin by antithrombin, resulting in antithrombin resistance and thrombotic disorders. However, it negatively affects sodium binding and may have hypocoagulant effects. Considering that prothrombin Belgrade mutation mechanism is still not fully elucidated and that sodium binding is important for thrombin affinity towards fibrinogen, our aim was to determine whether this mutation affects fibrin clot formation and lysis.
METHODS
Using HEK293T cell line, recombinant wild type and mutated prothrombin were generated by transient transfection. Samples that correspond to plasma of a non-carrier, heterozygous and homozygous carriers were reconstituted using prothrombin deficient plasma and recombinant proteins. Reconstituted samples were used in OHP assay (Overall Hemostasis Potential) to determine kinetic profiles of coagulation and fibrinolysis. Clot turbidity assay was performed to observe kinetics of clot formation and lysis more closely. Fibrin clots formed in reconstituted plasma samples were analyzed by confocal microscopy to determine density of fibrin network. Fibrin clots were additionally observed using electron microscopy to determine thickness of individual fibrin fibers.
RESULTS
No significant difference found in OHP, OCP, OFP, and fibrin network density between wild type, heterozygous, and homozygous carrier reconstituted plasma samples. There were significant differences between samples for slope and slope time parameters in kinetic profiles and fibrin fiber thickness.
CONCLUSIONS
Results indicate that prothrombin Belgrade mutation has no significant impact on fibrinolysis, however it may affect kinetics of clot formation and its architecture.
Topics: Humans; Fibrin; Prothrombin; Antithrombins; Thrombin; HEK293 Cells; Thrombosis; Fibrinolysis; Anticoagulants; Antithrombin III; Mutation; Sodium
PubMed: 37918971
DOI: 10.1111/ijlh.14195 -
Frontiers in Genetics 2023Hereditary antithrombin-III deficiency can significantly increase the risk for thrombosis, which is common in limb deep vein and pulmonary cases. However, thrombotic...
Hereditary antithrombin-III deficiency can significantly increase the risk for thrombosis, which is common in limb deep vein and pulmonary cases. However, thrombotic microangiopathy (TMA) caused by hereditary antithrombin deficiency is rare. We reported the case of a 32-year-old Chinese female patient with TMA with renal injury caused by decreased antithrombin-III activity due to a new mutation (chr1-173884049 c.50A>G) in , which encodes antithrombin-III. In this case, the patient had no history of relevant drug use, diabetes, or monoclonal plasma cells in the bone marrow puncture. Consequently, TMA of the kidney was considered secondary to hereditary antithrombin-III deficiency. Gene detection was the only clue that led us to suspect that TMA was caused by hereditary antithrombin deficiency. Our findings indicated that for patients with repeated findings of antithrombin-III activity less than 50%, the possibility of antithrombin-III deficiency and complete gene detection must be considered immediately after excluding the use of anticoagulants and lack of availability to facilitate early detection, diagnosis, and intervention.
PubMed: 37829283
DOI: 10.3389/fgene.2023.1278511 -
Journal of Thrombosis and Haemostasis :... Jan 2024Normalization of antithrombin activity may prevent catheter-associated thrombosis in critically ill children at high risk of bleeding.
BACKGROUND
Normalization of antithrombin activity may prevent catheter-associated thrombosis in critically ill children at high risk of bleeding.
OBJECTIVES
To characterize the temporal pattern of antithrombin activity, assess its association with catheter-associated thrombosis and clinically relevant bleeding, and evaluate its relationship with thrombin generation in these children.
METHODS
In this prospective cohort study, critically ill children <18 years old at high risk of bleeding with central venous catheter were eligible. Antithrombin activity and thrombin generation were measured from platelet-poor plasma and after in vitro antithrombin supplementation. Systematic surveillance ultrasound was performed to diagnose thrombosis. Children were followed for bleeding.
RESULTS
We enrolled 8 infants (median age: 0.2 years, IQR: 0.2, 0.3 years) and 72 older children (median age: 14.3 years, IQR: 9.1, 16.1 years). Mean antithrombin on the day of catheter insertion was 64 IU/dL (SD: 32 IU/dL) in infants and 83 IU/dL (SD: 35 IU/dL) in older children. Antithrombin normalized by the day of catheter removal. Thrombosis developed in 27 children, while 31 children bled. Thrombosis (regression coefficient: 0.008, 95% CI: -0.01, 0.03) and bleeding (regression coefficient: -0.0007, 95% CI: -0.02, 0.02) were not associated with antithrombin. Antithrombin was not correlated with in vivo change in endogenous thrombin potential (correlation coefficient: -0.07, 95% CI: -0.21, 0.08). In vitro supplementation reduced endogenous thrombin potential (correlation coefficient: -0.78; 95% CI: -0.95, -0.23).
CONCLUSION
These findings may not support normalization of antithrombin activity to prevent catheter-associated thrombosis in critically ill children at high risk of bleeding.
Topics: Child; Infant; Humans; Adolescent; Antithrombins; Central Venous Catheters; Prospective Studies; Thrombin; Critical Illness; Anticoagulants; Antithrombin III; Upper Extremity Deep Vein Thrombosis; Hemorrhage
PubMed: 37797693
DOI: 10.1016/j.jtha.2023.09.023