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Frontiers in Immunology 2023To evaluate the usefulness of urine SERPINC1 and ORM1 as biomarkers for early detection of lupus nephritis (LN).
BACKGROUND
To evaluate the usefulness of urine SERPINC1 and ORM1 as biomarkers for early detection of lupus nephritis (LN).
METHODS
Using proteomics, we screened for potential urine biomarkers that differentiate LN from systemic lupus erythematosus (SLE) patients without nephritis. In addition, urine levels of target biomarkers were measured by ELISA in 13- and 23-week-old MRL-lpr (murine model for LN) and MRL/MpJ mice. Histological analysis was also performed on the kidneys of 23-week-old mice.
RESULTS
Urine SERPINC1 and ORM1 were elevated in SLE patients with newly diagnosed LN compared with SLE patients without LN (SERPINC1, AUC=.892, P<.001; ORM1, AUC=.886, P<.001). Levels of urine SERPINC1 and ORM1 were also significantly higher in MRL-lpr mice than in MRL/MpJ mice at 13 and 23 weeks (SERPINC1: p<.01 and p<.001 at 13 and 23 weeks, respectively; ORM1: p<.01 at 13 and 23 weeks). In contrast, a significant difference in urine albumin between the two groups was only observed at 23 weeks (p<.001) not at 13 weeks (p=.83). Regarding the kidney pathology of MPL-lpr mice, urine ORM1 and urine albumin, but not urine SERPINC1, were positively correlated with the activity index (ORM1, rho =.879, p<.001; albumin, rho =.807, p=.003) and chronicity index (ORM1, rho =.947, p<.001; albumin, rho =.869, p<.001).
CONCLUSION
We propose that urine SERPINC1 and ORM1 are novel biomarkers for early LN.
Topics: Humans; Animals; Mice; Lupus Nephritis; Mice, Inbred MRL lpr; Lupus Erythematosus, Systemic; Albumins; Biomarkers; Antithrombin III
PubMed: 37744355
DOI: 10.3389/fimmu.2023.1148574 -
Annals of Laboratory Medicine Jan 2024Rotational thromboelastometry (ROTEM; TEM International GmbH, Munich, Germany) is a global coagulation test that guides evidence-based platelet transfusion in trauma...
BACKGROUND
Rotational thromboelastometry (ROTEM; TEM International GmbH, Munich, Germany) is a global coagulation test that guides evidence-based platelet transfusion in trauma patients. We evaluated ROTEM parameters for predicting mid-term (five days) platelet transfusion in trauma patients.
METHODS
Maximum clot firmness and clot amplitudes after 5, 10, and 15 mins (A5, A10, and A15, respectively) of fibrin-specific ROTEM (FIBTEM) and extrinsically activated ROTEM (EXTEM) were retrospectively collected from 82 hospitalized, stable, non-bleeding trauma patients after successful initial resuscitation. Platelet-specific ROTEM (PLTEM) was calculated by subtracting FIBTEM from EXTEM. Platelet transfusions were reviewed for five days after ROTEM.
RESULTS
The areas under the curve for FIBTEM, EXTEM, and PLTEM predicting platelet concentrate transfusion of >12 U at mid-term were 0.915-0.923, 0.878-0.896, and 0.551-0.735, respectively. FIBTEM and EXTEM parameters were comparable to those of fibrinogen, fibrin/fibrinogen degradation products, D-dimer, and antithrombin III. Strong correlations (>0.7) were noted between platelet count and EXTEM (A5, A10, and A15) or PLTEM (A5), platelet function (per platelet count) and EXTEM (A10 and A15), and fibrinogen levels and all FIBTEM parameters.
CONCLUSIONS
FIBTEM and EXTEM can reliably predict mid-term platelet transfusion in trauma patients. FIBTEM, EXTEM, and PLTEM parameters correlate with conventional coagulation tests (platelets and fibrinogen).
Topics: Humans; Thrombelastography; Platelet Transfusion; Retrospective Studies; Fibrinogen; Fibrin
PubMed: 37665288
DOI: 10.3343/alm.2024.44.1.74 -
Journal of Diabetes and Its... Aug 2023Diabetes represents a pro-thrombotic condition.
BACKGROUND
Diabetes represents a pro-thrombotic condition.
OBJECTIVES
The primary objective was to evaluate the effects of Vitamin K Antagonist (VKA) compared to direct oral anticoagulants (DOACs) in diabetic and nondiabetic patients with non-valvular atrial fibrillation, newly diagnosed. The secondary objective was to evaluate the effects on the risk of bleeding.
METHODS
We enrolled 300 patients with newly diagnosed atrial fibrillation. One hundred and sixteen patients were taking warfarin, 31 acenocumarol, 22 dabigatran, 80 rivaroxaban, 34 apixaban, and 17 edoxaban. We evaluated: anthropometric parameters, glycated hemoglobin (HbA), fasting and post-prandial glucose (FPG, and PPG), lipid profile, Lp(a), small and dense low-density lipoprotein (SD-LDL), oxidized LDL (Ox-LDL), I-troponin (I-Tn), creatinine, transaminases, iron, red blood cells (RBC); hemoglobin (Hb), platelets (PLT), fibrinogen, D-dimer, anti-thrombin III, C-reactive protein (Hs-CRP), Metalloproteinases-2 (MMP-2), Metalloproteinases-9 (MMP-9), and incidence of bleeding.
RESULTS
We did not record any differences among nondiabetic patients between VKA and DOACs. However, when we considered diabetic patients, we found a slight, but significant improvement of triglycerides and SD-LDL. As regards incidence of bleeding, minor bleeding was more frequent in VKA diabetic group compared to DOACs diabetic group; furthermore, the incidence of major bleeding was higher with VKA in nondiabetic and diabetic group, compared to patients with DOACs. Among DOACs, we recorded a higher incidence of bleeding (minor and major) with dabigatran compared to rivaroxaban, apixaban and edoxaban in nondiabetic and diabetic patients.
CONCLUSION
DOACs seem to be metabolically favourable in diabetic patients. Regarding incidence of bleeding, DOACs with the exception of dabigatran, seem better than VKA in diabetic patients.
Topics: Humans; Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Diabetes Mellitus; Hemorrhage; Rivaroxaban; Stroke
PubMed: 37390799
DOI: 10.1016/j.jdiacomp.2023.108512 -
International Journal of Molecular... Jul 2023Stroke, a complex and heterogeneous disease, is a leading cause of morbidity and mortality worldwide. The timely therapeutic intervention significantly impacts patient... (Review)
Review
Unlocking the Potential of Stroke Blood Biomarkers: Early Diagnosis, Ischemic vs. Haemorrhagic Differentiation and Haemorrhagic Transformation Risk: A Comprehensive Review.
Stroke, a complex and heterogeneous disease, is a leading cause of morbidity and mortality worldwide. The timely therapeutic intervention significantly impacts patient outcomes, but early stroke diagnosis is challenging due to the lack of specific diagnostic biomarkers. This review critically examines the literature for potential biomarkers that may aid in early diagnosis, differentiation between ischemic and hemorrhagic stroke, and prediction of hemorrhagic transformation in ischemic stroke. After a thorough analysis, four promising biomarkers were identified: Antithrombin III (ATIII), fibrinogen, and ischemia-modified albumin (IMA) for diagnostic purposes; glial fibrillary acidic protein (GFAP), micro RNA 124-3p, and a panel of 11 metabolites for distinguishing between ischemic and hemorrhagic stroke; and matrix metalloproteinase-9 (MMP-9), s100b, and interleukin 33 for predicting hemorrhagic transformation. We propose a biomarker panel integrating these markers, each reflecting different pathophysiological stages of stroke, that could significantly improve stroke patients' early detection and treatment. Despite promising results, further research and validation are needed to demonstrate the clinical utility of this proposed panel for routine stroke treatment.
Topics: Humans; Brain Ischemia; Hemorrhagic Stroke; Biomarkers; Serum Albumin; Stroke
PubMed: 37511304
DOI: 10.3390/ijms241411545 -
Thrombosis Research Oct 2023Hereditary antithrombin (AT) deficiency type I causes venous thrombosis due to decreased levels of AT antigen in the blood. We identified one novel and one known...
INTRODUCTION
Hereditary antithrombin (AT) deficiency type I causes venous thrombosis due to decreased levels of AT antigen in the blood. We identified one novel and one known abnormal variant in two unrelated Japanese families with venous thrombosis. In this study, we analyzed the mechanism by which these abnormal variants cause type I AT deficiency.
MATERIALS AND METHODS
Wild-type and variant AT expression vectors were constructed and transiently expressed in human embryonic kidney 293 cells, and AT antigen levels and N-glycosylation of cell lysates and culture medium were evaluated by western blot analysis. Subcellular co-localization of AT was also examined using confocal microscopy, and chase experiments with cycloheximide and MG132 were performed to investigate the degradation pathway of AT variants.
RESULTS
Genetic analysis identified a novel variant, c.613delC (p.Leu205Trpfs79), and the known variant c.283T>C (p.Tyr95His). These AT variants exhibited significantly reduced extracellular secretion compared with the wild-type; N-glycosylation of the AT protein was normal. Co-localization analysis suggested that the transport of these abnormal AT proteins to the Golgi apparatus was impaired. The c.613delC variant was degraded early by the proteasome, suggesting that the c.283T>C variant is stored in the endoplasmic reticulum (ER).
CONCLUSIONS
The AT variants identified here synthesize abnormal AT proteins that exhibit suppressed secretion and impaired transport from the ER to the Golgi apparatus. These results provide clues that could help elucidate the mechanism of type I AT deficiency and facilitate therapy development.
Topics: Humans; Antithrombins; Antithrombin Proteins; Antithrombin III; Antithrombin III Deficiency; Venous Thrombosis
PubMed: 37607435
DOI: 10.1016/j.thromres.2023.08.010 -
Thrombosis and Haemostasis Dec 2023Cirrhotic patients display an increased risk for both bleeding and thrombosis. We investigated platelet activation across Child-Pugh stages (CPSs) and portal...
BACKGROUND
Cirrhotic patients display an increased risk for both bleeding and thrombosis. We investigated platelet activation across Child-Pugh stages (CPSs) and portal hypertension (PH) severity.
MATERIAL AND METHODS
A total of 110 cirrhotic patients were prospectively included. CPS and hepatic venous pressure gradient (HVPG) were determined. Platelet surface expression of P-selectin and activated glycoprotein (GP) IIb/IIIa were measured by flow cytometry before/after stimulation with protease-activated receptor (PAR)-1 (thrombin receptor activating peptide, TRAP) and PAR-4 (AYPGKF) agonists, epinephrine, and lipopolysaccharide (LPS).
RESULTS
Platelet count was similar across CPS but lower with increasing PH severity. Expression of P-selectin and activated GPIIb/IIIa in response to TRAP and AYPGKF was significantly reduced in platelets of CPS-B/C versus CPS-A patients (all 0.05). Platelet P-selectin expression upon epinephrine and LPS stimulation was reduced in CPS-C patients, while activated GPIIb/IIIa in response to these agonists was lower in CPS-B/C (all 0.05). Regarding PH severity, P-selectin and activated GPIIb/IIIa in response to AYPGKF were lower in HVPG ≥20 mmHg patients (both 0.001 vs. HVPG < 10 mmHg). Similarly, activated GPIIb/IIIa was lower in HVPG ≥20 mmHg patients after TRAP stimulation (0.01 vs. HVPG < 10 mmHg). The lower platelet surface expression of P-selectin and activated GPIIb/IIIa upon stimulation of thrombin receptors (PAR-1/PAR-4) in CPS-B/C and HVPG ≥20 mmHg patients was paralleled by reduced antithrombin-III levels in those patients (all 0.05). Overall, PAR-1- and PAR-4-mediated platelet activation correlated with antithrombin-III levels (0.001).
CONCLUSION
Platelet responsiveness decreases with increasing severity of liver cirrhosis and PH but is potentially counterbalanced by lower antithrombin-III levels.
Topics: Humans; P-Selectin; Prospective Studies; Lipopolysaccharides; Blood Platelets; Platelet Glycoprotein GPIIb-IIIa Complex; Platelet Activation; Receptor, PAR-1; Anticoagulants; Liver Cirrhosis; Hypertension, Portal; Epinephrine; Antithrombins; Platelet Aggregation
PubMed: 37517407
DOI: 10.1055/s-0043-1771187 -
Endocrine Jun 2024The study aimed to investigate the potential effect of Antithrombin III (ATIII) between chronic renal insufficiency and chronic coronary artery disease (chronic CAD) in...
PURPOSE
The study aimed to investigate the potential effect of Antithrombin III (ATIII) between chronic renal insufficiency and chronic coronary artery disease (chronic CAD) in type 2 diabetes mellitus (T2DM) patients.
METHODS
T2DM patients hospitalized in ZhongDa Hospital from 2013 to 2018 were enrolled. Relationships between renal function, ATIII, and chronic CAD risk were explored using multivariate regression models. Multiplicative and additive interactions were investigated between ATIII and renal function for CAD risk, and the role of ATIII was determined by bootstrap mediation analysis in patients with chronic renal dysfunction.
RESULTS
A total of 4197 patients were included in the study, with a chronic CAD prevalence of 23.02%. Low ATIII level was statistically associated with chronic renal insufficiency and elevated CAD risk even after adjustments (P < 0.05). A positive correlation between renal function and ATIII was demonstrated, and each 1 SD increase in renal function, ATIII increased by 2.947% (2.406-3.488%, P < 0.001) and 0.969% (0.297-1.642%, P < 0.001) in crude and adjusted models respectively. Patients with decreased renal function and ATIII were at the highest chronic CAD risk (OR = 1.51, 95%CI:1.15-1.98, P < 0.05), while no multiplicative and additive interaction effects were significant. Bootstrap mediation analysis estimated that ATIII mediated approximately 4.27% of the effect of chronic renal insufficiency on chronic CAD risk.
CONCLUSION
ATIII may serve as a mediator between chronic renal insufficiency and chronic CAD, providing mechanistic clues for renal-heart association and new insight into clinical therapies.
Topics: Humans; Male; Female; Middle Aged; Antithrombin III; Renal Insufficiency, Chronic; Coronary Artery Disease; Diabetes Mellitus, Type 2; Aged; Risk Factors
PubMed: 38190026
DOI: 10.1007/s12020-023-03669-0 -
Frontiers in Medicine 2024Limited data are available on the relationship of disseminated intravascular coagulation (DIC) with mortality in patients receiving extracorporeal membrane oxygenation...
BACKGROUND
Limited data are available on the relationship of disseminated intravascular coagulation (DIC) with mortality in patients receiving extracorporeal membrane oxygenation (ECMO). Thus, we investigated the association of DIC score and antithrombin (AT) III with clinical outcomes in patients undergoing ECMO.
METHODS
We analyzed 703 patients who underwent ECMO between January 2014 and May 2022 at Samsung Medical Center. The DIC score was calculated using laboratory findings within 24 h of the ECMO initiation, and ≥ 5 was defined as overt DIC. In addition, the AT III level was measured to identify the correlation with the DIC score.
RESULTS
Among the study patients, 169 (24.0%) were diagnosed with overt DIC (DIC group) during early maintenance therapy. In-hospital mortality was significantly higher in the DIC group than in the non-DIC group (55.0% vs. 36.5%, < 0.001). Bleeding events were significantly higher in the group of patients with a DIC score of 7 or 8 than in the other group (20.8% vs. 8.4%, = 0.038). DIC score negatively correlated with AT III level ( = -0.417, < 0.001). The predictive performance of AT III for overt DIC had statistical significance with a c-static of 0.81 (95% confidence interval (CI), 0.77-0.84, < 0.001).
CONCLUSION
Overt DIC was associated with higher in-hospital mortality and a tendency to bleed in ECMO patients. Furthermore, AT III plasma levels can easily predict overt DIC in patients undergoing ECMO. These findings suggest that monitoring AT III plasma levels may be important in the management of ECMO.
PubMed: 38716413
DOI: 10.3389/fmed.2024.1335826 -
Journal of Gastroenterology and... Jun 2024The development of acute pancreatitis (AP) is strongly linked to blood clotting and fibrinolysis issues. Modern clinical practices now utilize advanced blood markers...
Predictive value of thrombin-antithrombin III complex and tissue plasminogen activator-inhibitor complex biomarkers in assessing the severity of early-stage acute pancreatitis.
BACKGROUND AND AIM
The development of acute pancreatitis (AP) is strongly linked to blood clotting and fibrinolysis issues. Modern clinical practices now utilize advanced blood markers like thrombin-antithrombin III complex (TAT), plasmin-α2-plasmin inhibitor complex, thrombomodulin (TM), and tissue plasminogen activator-inhibitor complex (t-PAIC) to assess thrombosis risk. Our study used a highly sensitive chemiluminescence technique to measure these markers in AP patients, aiming to determine their early predictive value for AP severity.
METHODS
There were 173 patients with AP, all of whom developed symptoms within 72 h; 102 individuals had onset symptoms within 48 h. The biomarkers were measured upon admission before determining the severity of AP.
RESULTS
The levels of TAT, plasmin-α2-plasmin inhibitor complex, TM, and t-PAIC were significantly higher in the severe acute pancreatitis (SAP) group compared with the mild acute pancreatitis and moderate severe acute pancreatitis groups. For the patients within 72 h of onset, TAT, TM, and t-PAIC predicted the occurrence of SAP. For the patients within 48 h of onset, TAT and t-PAIC predicted the occurrence of SAP. The area under the curve (AUC) of prediction models is similar to Bedside Index for Severity in Acute Pancreatitis (BISAP) but significantly higher than C-reactive protein (P < 0.05). Notably, t-PAIC had a larger AUC than TAT, BISAP, and C-reactive protein.
CONCLUSION
In the initial 48 h, plasma TAT and t-PAIC levels may predict the development of SAP. Within 72 h, plasma levels of TAT, TM, and t-PAIC may predict the development of SAP, and the TAT + TM + t-PAIC prediction model achieved a maximum AUC of 0.915, comparable to BISAP.
PubMed: 38822643
DOI: 10.1111/jgh.16641 -
Scientific Reports Dec 2023Disseminated intravascular coagulation (DIC) is a frequent complication in patients with sepsis and is associated with increased mortality. Anticoagulant therapy may be...
Risk stratification utilizing sequential organ failure assessment (SOFA) score, antithrombin activity, and demographic data in sepsis-associated disseminated intravascular coagulation (DIC).
Disseminated intravascular coagulation (DIC) is a frequent complication in patients with sepsis and is associated with increased mortality. Anticoagulant therapy may be appropriate for certain patients with DIC, particularly those with increased disease severity and deficiency in the physiologic anticoagulant antithrombin. We retrospectively analyzed post-marketing survey data from 1562 patients with sepsis-associated DIC and antithrombin activity of 70% or less. All the patients were treated with antithrombin concentrates. Baseline sequential organ failure assessment (SOFA) score, DIC score, and antithrombin activity were assessed. Cox multivariate regression analysis, Kaplan-Meier curve analysis, and receiver operating characteristic (ROC) curve analysis were performed to evaluate the performance of variables used to assess mortality. Furthermore, a decision tree was constructed to classify the risk of 28-day mortality. COX multivariate regression analysis demonstrated a significant association of age, sex, baseline SOFA score, baseline antithrombin activity, and the presence of pneumonia or skin/soft tissue infection with increased mortality. The area under the curve of SOFA score or antithrombin activity for mortality was 0.700 and 0.614, respectively. Kaplan-Meier analysis demonstrated that mortality was significantly higher in patients with SOFA score ≥ 12 and antithrombin activity < 47%. The decision tree analysis accurately classified the risk of death into high (> 40%), medium (40%-20%), and low (< 20%) categories in 86.1% of the cohort. Twenty eight-day mortality can be strongly predicted using baseline SOFA score, antithrombin activity, infection site, age, and sex as variables in the clinical decision tree for patients with sepsis-associated disseminated intravascular coagulation (DIC).
Topics: Humans; Antithrombins; Organ Dysfunction Scores; Disseminated Intravascular Coagulation; Retrospective Studies; Anticoagulants; Antithrombin III; Sepsis; Risk Assessment; Demography
PubMed: 38110515
DOI: 10.1038/s41598-023-49855-y