Coagulation Biomarkers Research Articles

The associations between exposure to ambient air pollution and coagulation markers and the potential effects of DNA methylation

Previous studies have illustrated the pivotal role of coagulation biomarkers in the link between air pollution and cardiovascular disease (CVD). However, inconsistencies remain in the conclusions, with limited studies conducted in rural areas of China. We conducted a panel study in rural areas of Henan Province, China. Considering the potential effect modifications of atherosclerotic cardiovascular disease (ASCVD) risks, 104 participants were enrolled, comprising two matched groups: 52 with high ASCVD risks and 52 with low ASCVD risks. DNA methylation at CpG sites and coagulation indices were measured for all participants. Linear mixed-effect regression models were used to evaluate the associations between ambient air pollution, coagulation biomarkers, and DNA methylation. We observed that for every 5-day standard deviation (SD) increment of PM2.5 (11.91μg/m³) and PM10 (13.65μg/m³), fibrinogen increased by 7.70% (95%CI: 2.27, 13.12) and 8.50% (95%CI: 2.46, 14.55), respectively. SO2 (6.95μg/m³) was associated with 40.25% (95%CI: 14.83, 65.67) increase in plasminogen activator inhibitor-1 (PAI-1). Decreased methylation at CpG sites was associated with exposure to air pollution. However, DNA methylation did not mediate the association between ambient air pollution and coagulation. Our study revealed the harmful impact of ambient air pollution on coagulation function but found no significant mediation effects of DNA methylation.

Characterisation of the pharmacokinetic and pharmacodynamic relationship of milvexian in total knee replacement patients

Abstract Background Milvexian, an oral factor XIa inhibitor, is currently being evaluated in patients at risk for thrombotic events due to atrial fibrillation, ischaemic stroke, or acute coronary syndrome. The exposure-response relationship between clinical efficacy and safety endpoints and milvexian pharmacokinetic (PK) metrics was recently submitted as a separate publication. Characterisation of the relationship between the coagulation pharmacodynamic (PD) markers versus milvexian PK metrics at the patient level has yet to be reported. Purpose This analysis characterised the relationship between the coagulation biomarkers, activated partial thromboplastin time (aPTT) and prothrombin time (PT), and milvexian systemic exposure in patients undergoing total knee replacement (TKR) evaluated in the AXIOMATIC-TKR study. Methods A population pharmacokinetic (PopPK) model was previously developed and characterised the PK of milvexian in TKR patients well. The PK/PD relationships between observed aPTT and PT versus PopPK model estimated time-matched milvexian plasma concentrations via nonlinear mixed effects modeling. The relationship between key clinical safety endpoints (e.g., any bleeding or clinically relevant non-major bleeding) and individual PD marker change (e.g., aPTT ratio to baseline) was also explored. Results The aPTT increased with increasing plasma concentration of milvexian over the range of doses evaluated in the study (25mg QD to 200mg BID). An Emax type of model reasonably characterised the PK/PD relationship between the aPTT and model predicted time-matched milvexian plasma concentration, which is consistent with previously observed relationships in healthy volunteers. No change was observed in PT with increased milvexian exposure. No obvious relationship was identified between any (including clinically relevant non-major) bleeding and aPTT ratio to baseline. Conclusions Increased milvexian exposure is directly correlated with aPTT prolongation over the range of doses evaluated in the TKR study. There was no obvious relationship between any (including clinically relevant non-major) bleeding and aPTT ratio. The PK/PD relationship of aPTT without a parallel relationship in PT distinguishes milvexian, a FXIa inhibitor, from previously studied FXa inhibitors. These analyses were a complementary component in dose selection for the milvexian Phase 3 program. Figure 1. PK/PD relationship between aPTT (left) and PT (right) and estimated time-matched plasma concentration (AXIOMATIC-TKR study)

Efficacy and Safety of Rivaroxaban, Apixaban, and Edoxaban for Nonvalvular Atrial Fibrillation Based on Blood Coagulation Activity and Drug Plasma Concentration: SETtsu and North Osaka Multicenter Direct Oral AntiCoagulant (SET DOAC) Registry

Background: The therapeutic effects of oral anticoagulant drugs for nonvalvular atrial fibrillation (NVAF) suggest that the three factor Xa (FXa) inhibitors may have distinct safety profiles, though this is not yet fully conclusive. This study investigated the current dosing of rivaroxaban, apixaban, and edoxaban by monitoring drug plasma concentration (PC) and coagulation activity from the viewpoint of the safety. Methods and results: This multicenter clinical study monitored the drug PC and two coagulation biomarkers (fibrinogen and fibrin monomer complex [FMC]) at peak and trough timing in 268 outpatients taking rivaroxaban (n = 72), apixaban (n = 71), and edoxaban (n = 125) for NVAF. Doses were adjusted based on the dose-adjustment criteria of each drug. Referencing our previous study, peak drug PC remained below the cut-off level for predicting bleeding events except in eight patients (rivaroxaban, n = 3; apixaban, n = 2; edoxaban, n = 3) in whom bleeding events occurred. Among them, two (one each on rivaroxaban and edoxaban) had a peak drug PC below the cut-off level. Drug PCs widely varied from peak to trough, whereas FMC levels, reflecting thrombin activity, remained within the normal range (<6.1 µg/mL) regardless of PC variations. These results indicated that the anticoagulant effects of these drugs persisted throughout the day regardless of the drug PC levels, dosage, and dosing frequency. Regarding the change over time in peak PC, the elevation over time developed more in rivaroxaban (29/57; 50.9%, p < 0.05) than in edoxaban (32/101; 31.7%), and rivaroxaban tended to accumulate more than edoxaban. Conclusions: Although drug PC levels of once-daily FXa inhibitors widely varied from peak to trough, FMC levels were maintained within the normal range without daily variations. Rivaroxaban also tended to accumulate over time. The results indicate the low risk of thrombotic events with once-daily FXa inhibitors and its correspondence to the twice-daily regimen.

Coagulation-related genes for thyroid cancer prognosis, immune infltration, staging, and drug sensitivity.

Thyroid cancer (THCA) is the most common endocrine tumor. Coagulation may be associated with the development of cancer, but its role in THCA patients is not yet clear. In this study, we determined the predictive value of coagulation biomarker D-dimer for THCA patient lateral lymph node metastasis (LLNM) through receiver operating characteristics (ROC) analysis and logistic regression analysis. Subsequently, this study used the TCGA database to identify coagulation-related molecular subtypes through consensus clustering analysis and compared their prognosis. We identified coagulation-related genes (CRGs) associated with prognosis in thyroid cancer through gene expression data and clinical information, and constructed a prognostic model by selecting the prognostic CRGs using LASSO regression. Patients were divided into high-risk and low-risk groups based on the median score. Subsequently, prognosis, clinical characteristics, gene mutation occurrence, immune infiltration, function, and drug sensitivity of the two groups were analyzed. We also constructed a nomogram combining the model and clinical features. Finally, the expression of the prognostic CRGs was validated by RT-qPCR. D-dimers had better performance in predicting LLNM(the area under the curve was 0.656 (95% CI 0.580-0.733), with a cut-off value of 0.065 mg/l), and D-dimer>0.065mg/l was an independent predictor of LLNM. Then, we selected 8 prognostic CRGs to construct a predictive model. The prognosis of low-risk group patients was significantly better than that of high-risk group (P<0.001). The results showed significant differences in clinical characteristics, gene mutation occurrence, immune infiltration, function, and drug sensitivity between the high-risk and low-risk groups. We validated by qPCR that these 8 prognostic CRGs were overexpressed in THCA cell lines. Overall, this study provided an in-depth exploration of the potential role of the coagulation in thyroid cancer and its clinical significance, offering a new theoretical basis and research direction for personalized therapy and prognostic evaluation.

Development and validation of a machine learning‐based model of ischemic stroke risk in the Chinese elderly hypertensive population

AbstractMachine learning (ML) has made some significant contributions to stroke prevention, but the stability and accuracy of existing models for clinical applications are uncertain. This study develops and validates an interpretable ML model using metabolic and coagulation biomarkers to predict ischemic stroke in elderly hypertensive patients in Northwest China. The prediction model used 453 electronic medical records for the model building (80% as a training set and 20% as a test set) and 132 for external validation. The final seven key features (D‐dimer, cystatin C, homocysteine, hemoglobin A1c, prothrombin time, low‐density lipoprotein C, and triglyceride glucose‐body mass index) were selected by the advanced approach, elastic net, and classical wrapping approaches. The final model, eXtreme gradient boosting, was identified as having superior performance than the other 9 classifers (random forest, Gaussian process, multilayer perceptron, logistic regression, support vector machine, K‐nearest neighbor, decision tree, Gaussian naive bayes, and ensemble model), with area under the receiver‐operating characteristic curves of 0.97 and 0.94 for the test and external validation sets, respectively. The final model demonstrates excellent stability, accuracy, and clinical usefulness through various metrics and decision curve analysis. Additionally, an online human–machine interface application has been developed for clinical practice to help early identification and intervention for ischemic stroke in elderly hypertensive patients.

Association Between NOX2-Mediated Oxidative Stress, Low-Grade Endotoxemia, Hypoalbuminemia, and Clotting Activation in COVID-19.

Low-grade endotoxemia by lipopolysaccharide (LPS) has been detected in COVID-19 and could favor thrombosis via eliciting a pro-inflammatory and pro-coagulant state. The aim of this study was to analyze the mechanism accounting for low-grade endotoxemia and its relationship with oxidative stress and clotting activation thrombosis in COVID-19. We measured serum levels of sNOX2-dp, zonulin, LPS, D-dimer, and albumin in 175 patients with COVID-19, classified as having or not acute respiratory distress syndrome (ARDS), and 50 healthy subjects. Baseline levels of sNOX2-dp, LPS, zonulin, D-dimer, albumin, and hs-CRP were significantly higher in COVID-19 compared to controls. In COVID-19 patients with ARDS, sNOX2-dp, LPS, zonulin, D-dimer, and hs-CRP were significantly higher compared to COVID-19 patients without ARDS. Conversely, concentration of albumin was lower in patients with ARDS compared with those without ARDS and inversely associated with LPS. In the COVID-19 cohort, the number of patients with ARDS progressively increased according to sNOX2-dp and LPS quartiles; a significant correlation between LPS and sNOX2-dp and LPS and D-dimer was detected in COVID-19. In a multivariable logistic regression model, LPS/albumin levels and D-dimer predicted thrombotic events. In COVID-19 patients, LPS is significantly associated with a hypercoagulation state and disease severity. In vitro, LPS can increase endothelial oxidative stress and coagulation biomarkers that were reduced by the treatment with albumin. In conclusion, impaired gut barrier permeability, increased NOX2 activation, and low serum albumin may account for low-grade endotoxemia and may be implicated in thrombotic events in COVID-19.

Regulating the lncRNA DSCR9/RPLP2/PI3K/AKT axis: an important mechanism of Xinfeng capsules in improving rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic and symmetrical polyarthritis. RA patients often experience inflammatory reaction and hypercoagulable state, which together affect the self-perception of patient (SPP). Currently, inhibiting inflammation and hypercoagulable state are common treatment methods for alleviating RA symptoms. Xinfeng Capsules (XFC) has a long history of treating RA, and can effectively improve the inflammatory response and hypercoagulable state of RA. However, the potential mechanisms have not yet been determined. This study elucidated the action mechanism of XFC in RA inflammation and hypercoagulability through the lncDSCR9/RPLP2/PI3K/AKT axis. Clinical observations indicated that there was a strong link between XFC therapy and improvements in inflammatory and coagulation biomarkers, as well as SPP among RA patients. The subsequent network pharmacology analysis results identified the PI3K/AKT signaling pathway as a potential mediator for XFC treatment of RA. Furthermore, clinical validation and sequencing results revealed that lncRNA DSCR9 expression (a gene implicated in inflammation and coagulation) was negatively correlated with clinical markers of inflammation and coagulation, while positively correlated with SF-36 indicators. Notably, XFC treatment remarkably upregulated lncRNA DSCR9 expression and downregulated PI3K and AKT expressions, showing opposite expression trends to the untreated cases.The regulatory effect of XFC on the lncRNA DSCR9/RPLP2/PI3K/AKT axis in RA was investigated using techniques such as RNA pull-down assay, Western blot analysis, RT-PCR, and EdU assay. Moreover, the administration of the PI3K/AKT agonist RMH can counteract the effects of XFC on p-PI3K, p-AKT, inflammation, and hypercoagulability, reinforcing the role of pathway. Finally, animal studies utilizing HE staining and transmission electron microscopy (TEM) demonstrated that XFC notably decreased PI3K and AKT expressions in adjuvant-induced arthritis (AA) rats, mitigated inflammation and hypercoagulability, and enhanced the ultrastructure of synovial cells. These findings underscored the potential mechanisms of XFC in the treatment of RA. Regulating the lncRNA DSCR9/RPLP2/PI3K/AKT axis may be an important mechanism by which XFC improved RA inflammatory response and hypercoagulable state.

SARS-CoV2 pneumonia patients admitted to the ICU: Analysis according to clinical and biological parameters and the extent of lung parenchymal lesions on chest CT scan, a monocentric observational study

Background CT-scan and inflammatory and coagulation biomarkers could help in prognostication of COVID-19 in patients on ICU admission. Objective The objectives of this study were to measure the prognostic value of the extent of lung parenchymal lesions on computed tomography (CT) and of several coagulation and inflammatory biomarkers, and to explore the characteristics of the patients depending on the extent of lung parenchymal lesions. Design Retrospective monocentric observational study achieved on a dataset collected prospectively. Setting Medical ICU of the university hospital of Clermont-Ferrand, France. Patients All consecutive adult patients aged ≥18 years admitted between 20 March, 2020 and 31 August, 2021 for COVID-19 pneumonia. Interventions Characteristics at baseline and during ICU stay, and outcomes at day 60 were recorded. The extent of lung parenchyma lesions observed on the chest CT performed on admission was established by artificial intelligence software. Measurements Several clinical characteristics and laboratory features were collected on admission including plasma interleukin-6, HLA-DR monocytic–expression rate (mHLA-DR), and the extent of lung parenchymal lesions. Factors associated with day-60 mortality were investigated by uni- and multivariate survival analyses. Results 270 patients were included. Inflammation biomarkers including the levels of neutrophils, CRP, ferritin and Il10 were the indices the most associated with the severity of the extent of the lung lesions. Patients with more extensive lung parenchymal lesions (≥ 75%) on admission had higher CRP serum levels. The extent of lung parenchymal lesions was associated with a decrease in the PaO2/FiO2 ratio(p&lt;0.01), fewer ventilatory-free days (p = 0.03), and a higher death rate at day 60(p = 0.01). Extent of the lesion of more than 75% was independently associated with day-60 mortality (aHR = 1.72[1.06; 2.78], p = 0.03). The prediction of death at day 60 was improved when considering simultaneously biological and radiological markers obtained on ICU admission (AUC = 0.78). Conclusions The extent of lung parenchyma lesions on CT was associated with inflammation, and the combination of coagulation and inflammatory biomarkers and the extent of the lesions predicted the poorest outcomes.

Symptom burden, coagulopathy and heart disease after acute SARS-CoV-2 infection in primary practice

SETANTA (Study of HEarT DiseAse and ImmuNiTy After COVID-19 in Ireland) study aimed to investigate symptom burden and incidence of cardiac abnormalities after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)/COVID-19 and to correlate these results with biomarkers of immunological response and coagulation. SETANTA was a prospective, single-arm observational cross-sectional study condcuted in a primary practice setting, and prospectively registered with ClinicalTrials.gov (identifier: NCT04823182). Patients with recent COVID-19 infection (≥ 6 weeks and ≤ 12 months) were prospectively enrolled. Primary outcomes of interest were markers of cardiac injury detected by cardiac magnetic resonance imaging (CMR), which included left ventricular ejection fraction, late gadolinium enhancement and pericardial abnormalities, as well as relevant biomarkers testing immunological response and coagulopathy. 100 patients (n = 129 approached) were included, amongst which 64% were female. Mean age of the total cohort was 45.2 years. The median (interquartile range) time interval between COVID-19 infection and enrolment was 189 [125, 246] days. 83% of participants had at least one persistent symptom, while 96% had positive serology for prior SARS-CoV-2 infection. Late gadolinium enhancement, pericardial effusion, was present in 2.2% and 8.3% respectively, while left ventricular ejection fraction was below the normal reference limit in 17.4% of patients. Von Willebrand factor antigen was elevated in 32.7% of patients and Fibrinogen and D-Dimer levels were found to be elevated in 10.2% and 11.1% of patients, respectively. In a cohort of primary practice patients recently recovered from SARS-CoV-2 infection, prevalence of persistent symptoms and markers of abnormal coagulation were high, despite a lower frequency of abnormalities on CMR compared with prior reports of patients assessed in a hospital setting.Trial Registration: Clinicaltrials.gov, NCT04823182 (prospectively registered on 30th March 2021).

Identification and validation of coagulation and fibrinolytic-related diagnostic biomarkers for ulcerative colitis by bioinformatics analysis.

Abnormalities in coagulation and fibrinolytic status have been demonstrated to be relevant to inflammatory bowel disease. Nevertheless, there is no study to methodically examine the role of the coagulation and fibrinolysis-related genes in the diagnosis of ulcerative colitis (UC). UC-related datasets (GSE169568 and GSE94648) were originated from the Gene Expression Omnibus database. The biomarkers related to coagulation and fibrinolysis were identified through combining differentially expressed analysis and machine learning algorithms. Moreover, Gene Set Enrichment Analysis and immune analysis were carried out. A total of 4 biomarkers (MAP2K1, CREBBP, TAF1, and HP) were identified, and biomarkers were markedly enriched in pathways related to immunity, such as T-cell receptor signaling pathway, primary immunodeficiency, chemokine signaling pathway, etc. In total, the infiltrating abundance of 4 immune cells between UC and control was markedly different, namely eosinophils, macrophage M0, resting mast cells, and regulatory T cells. And all biomarkers were significantly relevant to eosinophils. Our findings detected 4 coagulation and fibrinolysis-related biomarkers (MAP2K1, CREBBP, TAF1, and HP) for UC, which contributed to the advancement of UC for further clinical investigation.

Comprehensive laboratory assessment of lonoctocog alfa versus octocog alfa in severe haemophilia A.

Lonoctocog alfa is a single-chain factor VIII (FVIII) molecule with high binding affinity to von-Willebrand-factor. While it is well known that its plasma activity is underestimated by one-stage clotting assays (OSCA), there is a lack of knowledge on the post-infusion performance of lonoctocog alfa in global coagulation assays or its potential impact on the haemostatic balance in vivo. To characterize lonoctocog alfa versus octocog alfa in pre- and post-infusion samples obtained from patients undergoing repeated investigation of incremental recovery (IR). Eighteen patients with severe haemophilia A (lonoctocog alfa: 10, octocog alfa: 8) were included. A panel of factor-specific and global coagulation assays was applied, comprising a FVIII OSCA, two FVIII chromogenic substrate assays (CSA), rotational thrombelastography and thrombin generation (TG). Potential activation of coagulation was assessed by measuring plasma thrombin markers and levels of activated protein C. Comparable IRs were found for lonoctocog alfa and octocog alfa (2.36 [IU/dL]/[IU/kg] vs. 2.55 [IU/dL]/[IU/kg], respectively). Lonoctocog alfa activities were found to be underestimated by the FVIII OSCA while also the two FVIII CSAs showed statistically significant assay discrepancies on lonoctocog alfa. Effects of both FVIII products on rotational thrombelastography were less distinct than those on TG parameters. No elevated pre- or significantly shifting post-infusion plasma levels of coagulation biomarkers were detected. Lonoctocog alfa and octocog alfa showed comparable recovery and safety in vivo as well as similar impacts on TG in vitro. Observed assay discrepancies on lonoctocog alfa demonstrated variability of results also between different FVIII CSAs.

Depressive symptom clusters and biomarkers of monocyte activation, inflammation, and coagulation in people with HIV and depression.

We assess associations of somatic and cognitive/affective depressive symptom clusters with monocyte activation (soluble (s)CD14, sCD163), systemic inflammation (interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP)), and coagulation (D-dimer, fibrinogen) in people with HIV (PWH) on suppressive antiretroviral therapy with depression. Utilizing baseline data from a randomized controlled trial, we found no significant associations in linear regression models examining individual depressive symptom clusters; however, models examining both clusters simultaneously showed that the somatic cluster was positively associated with inflammation biomarkers, while the cognitive/affective cluster was negatively associated with inflammation and coagulation biomarkers (suggesting a cooperative suppression effect). Our findings indicate a differential association with depressive symptom clusters and biological mechanisms underlying cardiovascular disease (CVD) in HIV, which may be driven by unique components of each depressive symptom cluster. This line of research could identify subgroups of PWH with depression at elevated CVD risk needing early CVD prevention approaches. Supported by R01 HL126557.

Metabolic pathways altered by air pollutant exposure in association with coagulation function among the rural elderly

Air pollution exposure has been linked with coagulation function. However, evidence is limited for the relationships between air pollution, coagulation function and metabolomics in humans. We recruited a panel of 130 rural elderly from the Chayashan township in China, all of whom were free of pre-existing cardiovascular diseases and had provided residential address information. We conducted clinical examinations and collected blood samples from these rural elderly for the detection of coagulation biomarkers (e.g, activated partial thromboplastin time, fibrinogen, thrombin time, and prothrombin time) and untargeted metabolites in both December 2021 and August 2022. We used mini ambient air quality monitor to measure the mean levels of five air pollutants (e.g., PM2.5, SO2, NO2, CO and O3) during 1 to 2 weeks before blood sample collection. The Mummichog pathway analysis was used to identified potential metabolic features and pathways. In this study, we identified 5 pathways associated with both air pollution and coagulation function, and further pinpointed eight metabolic features within these pathways. The majority of these features were lipids, including arachidonic acid and linoleic acid. Overall, the findings of this study offer insights into potential mechanisms, particularly lipid metabolism, that may underlie the association between air pollution and coagulation function.

Effects of batroxobin on the antithrombotic system in patients with cerebral venous thrombosis: Clues to mechanisms.

More evidence supports the benefits of batroxobin combined with anticoagulation in correcting acute cerebral venous thrombosis (CVT). The dynamic fluctuations of peripheral blood platelets, fibrinolysis, and coagulation biomarkers during this therapy were analyzed. We investigated batroxobin's effects on the antithrombotic system under two regimens. The pretreatment group included patients on anticoagulants for at least 1 week before starting batroxobin. The simultaneous treatment group began both treatments upon admission. The control group received only anticoagulation. Batroxobin was given on alternate days at doses of 10BU, 5BU, and 5BU, totaling three doses. Anticoagulation was continuous. Baseline data were T0; the next day after each batroxobin dose was T1, T2, and T3. Data from these four time points was analyzed. The time-point paired sample T-test results of the pretreatment group [n = 60; mean age (SD), 43.3(16.5); 38 (63.35%) women] showed that batroxobin significantly inhibited ADP-induced platelet aggregation rate (T1-T0: p = 0.015; T2-T0: p = 0.025; T3-T0: p = 0.013), decreased fibrinogen level (T1-T0: p < 0.001; T2-T0: p < 0.001; T3-T0: p < 0.001), and increased D-dimer (T1-T0:p < 0.001; T2-T0: p < 0.001; T3-T0: p < 0.001), TT (T1-T0:p = 0.046; T2-T0: p = 0.003; T3-T0: p < 0.001), and APTT (T1-T0:p = 0.021; T2-T0: p = 0.012; T3-T0: p = 0.026). Compared to the control group, the simultaneous treatment group showed significantly higher TT (T2: p = 0.002; T3: p = 0.004) and D-dimer (T1: p < 0.001; T2: p < 0.001; T3: p < 0.001) values, while fibrinogen (T2: p < 0.001; T3: p < 0.001) levels were significantly lower. Using batroxobin can alleviate the amplitude of changes in coagulation indicators other than TT caused by anticoagulants. The above conclusions are consistent with the results of repeated measurement data analysis. Batroxobin can significantly inhibit ADP-induced platelet aggregation rate, increase D-dimer, decrease fibrinogen, and prolong TT and APTT in the presence of anticoagulant agents. Using batroxobin can reduce the amplitude of changes in coagulation indicators caused by anticoagulants. These results reveal the potential mechanism of batroxobin combined with anticoagulation in the safe and effective treatment of CVT.

Predelivery Haemostatic Biomarkers in Women with Non-Severe Postpartum Haemorrhage.

Background: Postpartum haemorrhage (PPH) is a frequent complication of childbirth that is difficult to predict. Predelivery coagulation biomarkers may help to guide preventive strategies. Our objective was to evaluate the association of predelivery haemostatic biomarkers with non-severe PPH. Methods: A nested case-control study was conducted within the « Study of Biological Determinants of Bleeding Postpartum » in order to compare different haemostatic biomarkers in plasma from pregnant women with non-severe PPH (cases) and controls without PPH matched for age, body mass index, term, and mode of delivery. Blood was collected at entry in the delivery room. Global haemostatic assays (thrombin generation assay (TGA) and plasmin generation assay (PGA)) were then performed on freshly thawed aliquots of platelet-poor plasma. Results: A total of 370 pregnant women (185 cases and 185 controls) were included. Median [interquartile range] predelivery platelet count was lower in PPH cases than in controls (217 [181-259] versus 242 [196-280] G/L). TGA and PGA parameters were similar between cases and controls. In a subset analysis of vaginal deliveries (n = 144), median predelivery TGA thrombin peak was lower, and median predelivery PGA lag phase was longer in cases compared to controls. In multivariable analysis, only predelivery platelet count was independently associated with non-severe PPH. Conclusions: Predelivery platelet count is associated with non-severe PPH. Differences in other haemostatic parameters are tenuous, questioning their usefulness in predicting non-severe PPH.

Tissue Factor Levels Used as Coagulation Biomarkers in Diabetic and Hypertensive Patients

Background: Tissue factor is a key initiator of the clotting process, and elevated levels are associated with abnormal thrombogenesis. Patients with chronic conditions like diabetes and hypertension may exhibit increased tissue factor concentrations, which can lead to serious complications. This study aims to determine tissue factor levels among diabetic patients, diabetics with uncontrolled hypertension, and healthy volunteers, to explore the potential of tissue factor as a diagnostic biomarker. Methods: Tissue factor concentrations were measured using enzyme-linked immunosorbent assay (ELISA), and glycated hemoglobin type 1A (HbA1c) levels were estimated with the Cobas instrument. The study population included diabetic patients, diabetics with uncontrolled hypertension, and healthy volunteers. Statistical analysis was performed using SPSS version 26, with comparisons made between the groups. Results: The results showed significantly higher tissue factor concentrations in patients compared to healthy volunteers. The mean tissue factor level in patients was 100.12 (±26.92) pg/mL, while in healthy volunteers, it was 59.17 (±19.24) pg/mL (p &lt; 0.001). Diabetic patients with elevated HbA1c levels had higher tissue factor concentrations compared to healthy volunteers (mean HbA1c: 6.95 (±1.853)% vs. 4.28 (±0.327)%). Moreover, patients with both diabetes and hypertension had the highest tissue factor levels, with a mean of 130.89 (±14.33) pg/mL (p &lt; 0.001). No significant differences in tissue factor levels were observed based on gender or age (p &gt; 0.05). Conclusion: Elevated tissue factor levels were observed in patients with diabetes and hypertension, particularly in those with poorly controlled conditions. This elevation suggests an increased risk of coagulation disorders, potentially affecting vital organs such as the heart, brain, and kidneys. Tissue factor could serve as a valuable diagnostic biomarker, allowing for early intervention in patients at risk of developing serious complications.

Synergistic impact of innate immunity hyper-activation and endothelial dysfunction on the magnitude of organ failure in the infection-sepsis continuum

ObjectivesIdentifying host response biomarkers implicated in the emergence of organ failure during infection is key to improving the early detection of this complication. MethodsTwenty biomarkers of innate immunity, T-cell response, endothelial dysfunction, coagulation, and immunosuppression were profiled in 180 surgical patients with infections of diverse severity (IDS) and 53 with no infection (nIDS). Those better differentiating IDS/nIDS in the area under the curve were combined to test their association with the sequential organ failure assessment score by linear regression analysis in IDS. Results were validated in another IDS cohort of 174 patients. ResultsC-reactive protein, procalcitonin, pentraxin-3, lipocalin-2 (LCN2), tumoral necrosis factor-α, angiopoietin-2, triggering receptor expressed on myeloid cells-1 (TREM-1) and interleukin (IL)-15 yielded an area under the curve ≥0.75 to differentiate IDS from nIDS. The combination of LCN2, IL-15, TREM-1, angiopoietin-2 (Dys-4) showed the strongest association with sequential organ failure assessment score in IDS (adjusted regression coefficient; standard error; P): Dys-4 (3.55;0.44; <0.001), LCN2 (2.24; 0.28; <0.001), angiopoietin-2 (1.92; 0.33; <0.001), IL-15 (1.78; 0.40; <0.001), TREM-1(1.74; 0.46; <0.001), tumoral necrosis factor-α (1.60; 0.31; <0.001), pentraxin-3 (1.12; 0.18; <0.001), procalcitonin (0.85; 0.12; <0.001). Dys-4 provided similar results in the validation cohort. ConclusionsThere is a synergistic impact of innate immunity hyper-activation (LCN2, IL-15, TREM-1) and endothelial dysfunction (angiopoietin-2) on the magnitude of organ failure during infection.

Biomarkers of inflammation and coagulation after minimally invasive mitral valve surgery: a prospective comparison to conventional surgery

STRUCTURED ABSTRACT Objectives Minimally invasive cardiac surgery techniques are increasingly used but have longer cardiopulmonary bypass time, which may increase inflammatory response and negatively affect coagulation. Our aim was to compare biomarkers of inflammation and coagulation as well as transfusion rates after minimally invasive mitral valve repair and mitral valve surgery using conventional sternotomy. Design A prospective non-randomized study was performed enrolling 71 patients undergoing mitral valve surgery (35 right mini-thoracotomy and 36 conventional sternotomy procedures). Blood samples were collected pre- and postoperatively to assess inflammatory response. Thromboelastometry (ROTEM) was performed to assess coagulation, and transfusion rates were monitored. Results The minimally invasive group had longer cardiopulmonary bypass times compared to the sternotomy group: 127 min ([115–146] vs 79 min [65–112], p < 0.001) and were cooled to a lower temperature during cardiopulmonary bypass, 34 °C vs 36 °C (p = 0.04). IL-6 was lower in the minimally invasive group compared to the conventional sternotomy group when measured at the end of the surgical procedure, (38 [23–69] vs 61[41–139], p = 0.008), but no differences were found at postoperative day 1 or postoperative day 3. The transfusion rate was lower in the minimally invasive group (14%) compared to full sternotomy (35%, p = 0.04) and the chest tube output was reduced, (395 ml [190-705] vs 570 ml [400–1040], p = 0.04). Conclusions Our data showed that despite the longer use of extra corporal circulation during surgery, minimally invasive mitral valve repair is associated with reduced inflammatory response, lower rates of transfusion, and reduced chest tube output.

Impact of different energy sources on coagulation biomarkers and silent cerebral events in balloon-based ablation for atrial fibrillation

BackgroundDifferent energy sources of balloon-based ablation for pulmonary vein isolation (PVI) cause different kinds of endothelial damage and coagulation responses associated with thromboembolic risk. ObjectivesTo compare the impact of different balloon-based ablation, cryo-balloon ablation (CBA) and laser balloon ablation (LBA), on coagulation/fibrinolysis biomarkers and silent cerebral events (SCEs) in paroxysmal atrial fibrillation (PAF). MethodsPAF patients who underwent PVI using either CBA (n=52) or LBA (n=53) without radiofrequency touch-up ablation were eligible. Time-course (day-0 [before ablation], day-1, day-2, and day-28) of myocardial enzymes and inflammatory and coagulation/fibrinolysis biomarkers was evaluated during the perioperative period. Brain MRI was performed within 2 days after the procedure to evaluate SCEs. ResultsThere was no difference in patient characteristics between CBA and LBA.CBA had greater myocardial injury (troponin-I and creatine kinase MB) and lower inflammatory reaction (WBC and neutrophil/lymphocyte ratio) than LBA. The coagulation biomarkers maximally increased by day-2 and then decreased in both groups. In day-28, the serum prothrombin fragment 1+2 and D-dimer levels in LBA were significantly higher than the values in CBA. The fibrinolysis biomarker (plasmin-α2 plasmin inhibitor complex) did not increase after the procedure in either group. The incidence of SCEs was comparable between CBA and LBA (11% vs. 15%, p=0.591). No thromboembolic event was observed. ConclusionCBA and LBA had different effects on myocardial injury, inflammatory reaction, and coagulation activity but did not affect the incidence of thromboembolic events. LBA had significantly higher coagulation activity in day-28 and may require more careful post-procedural anticoagulation than CBA.

Predictive value of C reactive protein (CRP) and D-dimer in patients with advanced cervical cancer treated with sintilimab and anlotinib.

e17525 Background: The Sintilimab plus Anlotinib in patients with advanced cervical cancer trial was a single-arm, phase II study that showed promising activity of the programmed death-1 (PD-1) inhibitor sintilimab plus the vascular endothelial growth factor receptor inhibitor Anlotinib in patients with advanced cervical cancer. We aimed to identify prognostic values of inflammation biomarkers and coagulation biomarkers in advanced cervical cancer treated with Sintilimab and Anlotinib. Methods: We conducted a post-hoc analysis of the data from the ALTER-C201 study (Clinical trial information: ChiCTR1900023015). The predictive value of coagulation variables and inflammation variables was evaluated by receiver operating characteristic (ROC) curves. Through Cox hazards regression models, prognostic factors were determined for overall survival (OS). Survival curves were visualized by Kaplan–Meier method and compared through Log-rank analysis. Results: We involved 41 patients and followed up for 38.0 (range, 0.6–44.0) months. According to the ROC curve, the predictive values of baseline CRP and D-dimer are better than other indicators, with area under the curve (AUC) values of 0.748 and 0.848, respectively. The cut-off values for D-dimer and CRP are 1.75ug/ml and 10.9mg/L, respectively. Through regression analysis, we demonstrated that CRP (HR 2.591; 95%CI 1.099–6.106; P = 0.030) and D-dimer (HR 2.669; 95%CI 1.154–6.173; P = 0.022) were independent prognostic factors. Compared to patients with CRP ≥ 10.9mg/L, those with CRP &lt; 10.9mg/L have a longer OS (28.93 months, 95% CI, 15.23 to not reached v 10.57 months, 95% CI, 6.14 to not reached; log-rank test, P = 0.007). Compared to patients with D-dimer ≥ 1.75ug/ml, those with D-dimer &lt; 1.75ug/ml have a longer OS (28.93 months, 95% CI, 17.09 to not reached v 10.73 months, 95% CI, 4.63 to not reached; log-rank test, P = 0.005). Conclusions: CRP and D-dimer predict survival in advanced cervical cancer patients undergoing combined ICI/ VEGF-TKI therapy. We advocate further work to validate utilisation of CRP and D-dimer as prognostic biomarkers for advanced cervical cancer in clinical practice.