Markers Of Endothelial Damage Research Articles

Retinal Microvascular Changes in Association with Endothelial Glycocalyx Damage and Arterial Stiffness in Patients with Diabetes Mellitus Type 2: A Cross-Sectional Study in a Greek Population.

To evaluate the potential association between endothelial glycocalyx damage, as well as arterial stiffness, and the retinal changes on optical coherence tomography (OCT) and OCT-angiography (OCT-A) in patients with type 2 diabetes mellitus (DM). Participants in this cross-sectional study were 65 patients with DM type 2 and 42 age- and gender-matched controls without DM. The demographic and clinical characteristics of the participants were recorded. All patients underwent a thorough ophthalmological examination and multimodal imaging, including fundus photography, OCT, and OCT-A. In addition, evaluation of the endothelial glycocalyx thickness by measuring the perfused boundary region (PBR5-25) of the sublingual microvessel, as well as of the arterial stiffness, by measuring the carotid-femoral pulse wave velocity (PWV), the central aortic pressures and the augmentation index (Aix) was performed. Univariate and multivariate logistic regression analysis was performed for the examination of the potential association between the eye imaging variables and the cardiovascular-related variables. The odds ratios (OR) with the respective 95% confidence intervals (CI) were calculated. A p-value < 0.05 was considered statistically significant. Patients with DM presented significantly higher PBR5-25 compared to controls without DM (p = 0.023). At the univariate analysis, increased PBR5-25 (≥2.19 μm vs. <2.19 μm) was associated with decreased peripapillary VD at the superior quadrant (univariate OR (95% CI) = 0.34 (0.12-0.93), p = 0.037). Multivariate logistic regression analysis showed that increased PWV (≥13.7 m/s vs. <13.7 m/s) was associated with an increased foveal avascular zone (FAZ) area on OCT-A (p = 0.044) and increased FAZ perimeter (p = 0.048). Moreover, increased Aix (≥14.745% vs. <14.745%) was associated with diabetic macular edema (DME) presence (p = 0.050) and increased perifoveal and parafoveal superior and temporal thickness on OCT (p < 0.05 for all associations). Markers of endothelial damage and arterial stiffness were associated with structural and microvascular retinal alterations in patients with DM, pointing out that OCT-A could be a useful biomarker for detecting potential cardiovascular risk in such patients.

Endocan as a biomarker for acute respiratory distress syndrome: A systematic review and meta-analysis.

Endocan is a marker of endothelial damage. Data regarding the association of this proteoglycan and acute respiratory distress syndrome (ARDS) is discrepant. Hence, this study sought to investigate the possible correlation between serum/plasma endocan concentration and ARDS. A systematic review and meta-analysis of international online databases was conducted following PRISMA guidelines. PubMed, SCOPUS, Embase, and Web of Science were searched in March 2023, with the leading search terms being "ARDS" OR "respiratory distress" AND "endocan" and other associated terms. Studies that measured endocan levels in patients with ARDS and compared it with non-ARDS controls or within different severities of ARDS were included. We performed a random-effect meta-analysis for pooling the differences using standardized mean difference (SMD) and 95% confidence interval (CI). We included 14 studies involving 1,058 patients. Those developing ARDS had significantly higher levels of endocan compared to those without ARDS (SMD: 0.47, 95% CI: 0.10-0.84, p = 0.01). Our meta-analysis of three studies found that endocan levels in ARDS nonsurvivors were significantly higher than in survivors (SMD: 0.31, 95% CI: 0.02-0.60, p = 0.03). Three studies investigated endocan levels in different severities of ARDS. Only one of these studies reported significantly higher endocan levels in patients with worsening acute respiratory failure at Day 15. The other two reported no significant association between ARDS severity and circulating endocan levels. Blood endocan levels were significantly higher in patients with ARDS than those without. Additionally, among patients with ARDS, blood endocan values were significantly elevated in nonsurvivors compared to survivors. These findings could help researchers design future studies and solidify these findings and finally, clinicians to take advantage of measuring endocan in clinical settings for assessment of patients with ARDS.

261.14: Endothelial glycocalyx damage marker Syndecan-1 measured during hypothermic oxygenated machine perfusion predicts early allograft dysfunction after liver transplantation.

261.14: Endothelial glycocalyx damage marker Syndecan-1 measured during hypothermic oxygenated machine perfusion predicts early allograft dysfunction after liver transplantation.

The Future of Kawasaki Disease Diagnosis: Liquid Biopsy May Hold the Key.

Kawasaki disease (KD) is a febrile illness characterised by systemic inflammation of small- and medium-sized blood vessels, which commonly occurs in young children. Although self-limiting, there is a risk of developing coronary artery lesions as the disease progresses, with delay in diagnosis and treatment. Unfortunately, the diagnosis of KD continues to remain a clinical dilemma. Thus, this article not only summarises the key research gaps associated with KD, but also evaluates the possibility of using circulating endothelial injury biomarkers, such as circulating endothelial cells, endothelial microparticles and vascular endothelial cell-free DNA, as diagnostic and prognostic tools for KD: a "liquid biopsy" approach. The challenges of translating liquid biopsies to use in KD and the opportunities for improvement in its diagnosis and management that such translation may provide are discussed. The use of endothelial damage markers, which are easily obtained via blood collection, as diagnostic tools is promising, and we hope this will be translated to clinical applications in the near future.

S100A8/A9hi neutrophils induce mitochondrial dysfunction and PANoptosis in endothelial cells via mitochondrial complex I deficiency during sepsis

S100a8/a9, largely released by polymorphonuclear neutrophils (PMNs), belongs to the S100 family of calcium-binding proteins and plays a role in a variety of inflammatory diseases. Although S100a8/a9 has been reported to trigger endothelial cell apoptosis, the mechanisms of S100a8/a9-induced endothelial dysfunction during sepsis require in-depth research. We demonstrate that high expression levels of S100a8/a9 suppress Ndufa3 expression in mitochondrial complex I via downregulation of Nrf1 expression. Mitochondrial complex I deficiency contributes to NAD+-dependent Sirt1 suppression, which induces mitochondrial disorders, including excessive fission and blocked mitophagy, and mtDNA released from damaged mitochondria ultimately activates ZBP1-mediated PANoptosis in endothelial cells. Moreover, based on comprehensive scRNA-seq and bulk RNA-seq analyses, S100A8/A9hi neutrophils are closely associated with the circulating endothelial cell count (a useful marker of endothelial damage), and S100A8 is an independent risk factor for poor prognosis in sepsis patients.

Syndecan-1 as a prognostic biomarker in COVID-19 patients: a retrospective study of a Japanese cohort

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had a profound global impact, with millions of confirmed cases and deaths worldwide. While most cases are mild, a subset progresses to severe respiratory complications and death, with factors such as thromboembolism, age, and underlying health conditions increasing the risk. Vascular endothelial damage has been implicated in severe outcomes, but specific biomarkers remain elusive. This study investigated syndecan-1 (SDC-1), a marker of endothelial damage, as a potential prognostic factor for COVID-19, focusing on the Japanese population, which is known for its aging demographics and high prevalence of comorbidities.MethodsA multicenter retrospective study of COVID-19 patients in Fukushima Prefecture in Japan who were admitted between February 2020 and August 2021 was conducted. SDC-1 levels were measured along with other clinical and laboratory parameters. Outcomes including thrombosis, 28-day survival, and disease severity were assessed, and disease severity was categorized according to established guidelines.ResultsSDC-1 levels were correlated with disease severity. Patients who died from COVID-19 had greater SDC-1 levels than survivors, and the area under the receiver operating characteristic curve (AUC) analysis suggested the potential of the SDC-1 level as a predictor of mortality (AUC 0.714). K‒M analysis also revealed a significant difference in survival based on an SDC-1 cutoff of 10.65 ng/mL.DiscussionThis study suggested that SDC-1 may serve as a valuable biomarker for assessing COVID-19 severity and predicting mortality within 28 days of hospitalization, particularly in the Japanese population. However, further investigations are required to assess longitudinal changes in SDC-1 levels, validate its predictive value for long-term survival, and consider its applicability to new viral variants.ConclusionsSDC-1 is emerging as a potential biomarker for assessing the severity and life expectancy of COVID-19 in the Japanese population, offering promise for improved risk stratification and patient management in the ongoing fight against the virus.

#1554 The association between gut-derived metabolites and biomarkers of renal and cerebro-vascular damage in type 2 diabetes mellitus patients

Abstract Background and Aims Due to its numerous complications, type 2 diabetes mellitus (T2DM) has a major impact on the global economic burden and overall mortality. This condition modifies the metabolic microenvironment in targeted organs, such as the kidney and the brain, by its hyperglycemic nature. Gut microbiota seems to have significant interference with the renal-cerebral axis, especially in a dysbiosis state. The aim of the study was to quantify gut derived metabolites by metabolomic techniques and to evaluate their association with markers of endothelial, podocyte and proximal tubule damage and with cerebro-vascular hemodynamic indices. Method The metabolomic profiling was realized on serum and urine samples originated from 90 T2DM patients, divided into three subgroups, such as the following: 30 normal to mildly-, 30 moderately-, and 30 severely increased albuminuria, respectively, and 20 healthy subjects. The samples were examined by using untargeted and targeted ultra-high performance liquid chromatography coupled with electrospray-ionization quadroupole time-of-flight mass spectrometry (UHPLC-QTOF-ESI+-MS), in order to obtain the metabolic profile. The markers of renal damage such as synaptopodin (SP), podocalyxin (PD), N-acetyl-β-D-glucosaminidase (NAG), kidney injury molecule 1 (KIM-1), monocyte chemotactic protein 1 (MCP-1), and intercellular adhesion molecule 1 (ICAM-1) were assessed by ELISA technique. The hemodynamic cerebro-vascular indices were obtained by high resolution Doppler ultrasound of common carotid arteries (CCAs), internal carotid arteries (ICAs), and middle cerebral arteries (MCAs), bilaterally. The correlations between the metabolites, the markers of renal damage, and neurosonological indices were realized by univariable and multivariable linear regression analyses. Results UHPLC-QTOF-ESI+-MS targeted analysis and subsequent statistical assessments revealed a subset of metabolites with a specific pattern for the normal to mildly increased albuminuria subgroup. The metabolites identified as significant were, in serum: arginine (sArg), hippuric acid (sHA), indoxyl sulfate (sIS), butenoylcarnitine (sBCA), sorbitol (sSorb); and in urine, arginine (uArg), butenoylcarnitine (uBCA), indoxyl sulfate (uIS) and p-cresyl sulfate (uPCS). The univariable linear regression analysis revealed that sArg correlated positively with the breath-holding index (BHI) and negatively with intima media thickness (IMT) in ACI, MCP-1 and ICAM-1; sIS, sSorb, and sBCA correlated inversely with these parametes. The multivariable linear regression analysis displayed the specific correlations between metabolites, markers of endothelial dysfunction, and neurosonological indices, such as follows: sArg correlated with IMT and ICAM-1; sIS followed a predictive pattern along with resistance index (RI) in ACIs and ICAM-1; sBCA correlated with IMT and MCP-1 and sSorb correlated with ICAM-1 and BHI. The urine metabolites were correlated with markers of podocyte and proximal tubule dysfunction: uIS and uBCA were correlated with PD and urinary albumin to-creatinin ratio (uACR), and uPCR correlated with KIM-1 and uACR. Conclusion This study revealed a set of metabolites potentially derived from the intestinal microflora which may act as biomarkers for the early detection of both CMA and DKD in T2DM patients. SArg, sIS and, sBCA are indicators of renal endothelial dysfunction. Moreover, sArg and sIS reflect incipient common and internal carotid artery atherosclerosis, suggesting vascular remodeling at these levels. SSorb correlated with BHI, indicating blood-brain barrier dysfunction and CMA development. In urine, uBCA and uIS are indicators of podocytopathy, whereas uPCS is associated with proximal tubule damage in incipient DKD.

Endothelial dysfunction is dampened by early administration of fresh frozen plasma in a rodent burn shock model.

Endothelial dysfunction has been implicated in the pathogenesis of burn shock affecting patients with large thermal injury. In response to injury, glycocalyx components like Syndecan-1 (SDC-1) are shed into circulation and have been used as markers of endothelial damage. Previous work in our laboratory has shown that plasma inclusive resuscitation (PIR) with fresh frozen plasma (FFP) ameliorates endothelial damage. However, there remains a paucity of information regarding optimal timing and dosing of PIR as well as organ-specific endothelial responses to shock. We aimed to examine the impact of PIR on endothelial dysfunction using clinically translatable timing and dosing. Sprague-Dawley rats were used to create thermal burns. Rats were subjected to 40% total body surface area scald burns and were resuscitated with lactated Ringer's (LR) only, LR plus albumin, and LR plus early 1 mL boluses of FFP at 0, 2, 4, and 8 hours postinjury. A late group also received LR plus FFP starting at hour 10 postinjury. Syndecan-1 levels were quantified by enzyme-linked immunosorbent assay, and quantitative real-time polymerase chain reaction analysis characterized transcription of glycocalyx components and inflammatory cytokines in the lung and spleen. Evan's blue dye was used to quantify amount of vascular leakage. Lactated Ringer's plus early FFP reduced Evan's blue dye extravasation when compared with LR only groups, while late FFP did not. When comparing LR only versus LR plus early FFP, SDC-1 levels were reduced in the LR plus early FFP group at hours 8, 12, and 24 (5.23 vs. 2.07, p < 0.001; 4.49 vs. 2.05, p < 0.01; and 3.82 vs. 2.08, p < 0.05, respectively). Lactated Ringer's only groups had upregulation of Exostosin-1 and SDC-1 in the lung compared with LR plus early FFP groups ( p < 0.01 and p < 0.05) and upregulation of cytokines interluekin-10 and interferon γ ( p < 0.001 and p < 0.001). Early administration of LR plus FFP reduces the magnitude of SDC-1 shedding and dampens the cytokine response to injury. The upregulation of glycocalyx components as a response to endothelial injury is also decreased in the lung and spleen by LR plus early FFP administration.

Major endothelial damage markers identified from hemadsorption filters derived from treated patients with septic shock - endoplasmic reticulum stress and bikunin may play a role.

In septic patients the damage of the endothelial barrier is decisive leading to circulatory septic shock with disseminated vascular coagulation, edema and multiorgan failure. Hemadsorption therapy leads to rapid resolution of clinical symptoms. We propose that the isolation of proteins adsorbed to hemadsorption devices contributes to the identification of mediators responsible for endothelial barrier dysfunction. Plasma materials enriched to hemadsorption filters (CytoSorb®) after therapy of patients in septic shock were fractionated and functionally characterized for their effect on cell integrity, viability, proliferation and ROS formation by human endothelial cells. Fractions were further studied for their contents of oxidized nucleic acids as well as peptides and proteins by mass spectrometry. Individual fractions exhibited a strong effect on endothelial cell viability, the endothelial layer morphology, and ROS formation. Fractions with high amounts of DNA and oxidized DNA correlated with ROS formation in the target endothelium. In addition, defined proteins such as defensins (HNP-1), SAA1, CXCL7, and the peptide bikunin were linked to the strongest additive effects in endothelial damage. Our results indicate that hemadsorption is efficient to transiently remove strong endothelial damage mediators from the blood of patients with septic shock, which explains a rapid clinical improvement of inflammation and endothelial function. The current work indicates that a combination of stressors leads to the most detrimental effects. Oxidized ssDNA, likely derived from mitochondria, SAA1, the chemokine CXCL7 and the human neutrophil peptide alpha-defensin 1 (HNP-1) were unique for their significant negative effect on endothelial cell viability. However, the strongest damage effect occurred, when, bikunin - cleaved off from alpha-1-microglobulin was present in high relative amounts (>65%) of protein contents in the most active fraction. Thus, a relevant combination of stressors appears to be removed by hemadsorption therapy which results in fulminant and rapid, though only transient, clinical restitution.

Plasma tissue factor pathway inhibitor levels in coronavirus disease 2019 patients: a systematic review and meta-analysis.

PROSPERO CRD42023437353.

Evaluation of Circulating Endothelial Cells as Direct Marker of Endothelial Damage in Allo-Transplant Recipients at High Risk of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome

Sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease (VOD), is a rare but potentially fatal complication following allogenic hematopoietic cell transplantation (allo-HCT). Timely identification of SOS/VOD to allow for prompt treatment is critical, but identifying a VOD-predictive biomarker remains challenging. Given the pivotal role of endothelial dysfunction in SOS/VOD pathophysiology, the CECinVOD study prospectively evaluated levels of circulating endothelial cells (CECs) in patients undergoing allo-HCT with a myeloablative conditioning (MAC) regimen to investigate the potential of CEC level in predicting and diagnosing SOS/VOD. A total of 150 patients from 11 Italian bone marrow transplantation units were enrolled. All participants were age >18 years and received a MAC regimen, putting them at elevated risk of developing SOS/VOD. Overall, 6 cases of SOS/VOD (4%) were recorded. CECs were detected using the Food and Drug Administration-approved CellSearch system, an immunomagnetic selection-based platform incorporating ferrofluid nanoparticles and fluorescent-labeled antibodies, and were defined as CD146+, CD105+, DAPI+, or CD45-. Blood samples were collected at the following time points: before (T0) and at the end of conditioning treatment (T1), at neutrophil engraftment (T2), and at 7 to 10 days postengraftment (T3). For patients who developed VOD, additional samples were collected at any suspected or proven VOD onset (T4) and weekly during defibrotide treatment (T5 to T8). A baseline CEC count >17/mL was associated with an elevated risk of SOS/VOD (P = .04), along with bilirubin level >1.5 mg/mL and a haploidentical donor hematopoietic stem cell source. Postconditioning regimen (T1) CEC levels were elevated (P = .02), and levels were further increased at engraftment (P < .0001). Additionally, patients developing SOS/VOD after engraftment, especially those with late-onset SOS/VOD, showed a markedly higher relative increase (>150%) in CEC count. Multivariate analysis supported these findings, along with a high Endothelial Activation and Stress Index (EASIX) score at engraftment (T2). Finally, CEC kinetics corresponded with defibrotide treatment. After the start of therapy (T4), CEC levels showed an initial increase in the first week (T5), followed by a progressive decrease during VOD treatment (T6 and T7) and a return to pre-SOS/VOD onset levels at resolution of the complication. This prospective multicenter study reveals a low incidence of SOS/VOD in high-risk patients compared to historical data, in line with recent reports. The results from the CECinVOD study collectively confirm the endothelial injury in allo-HCT and its role in in the development of SOS/VOD, suggesting that CEC level can be a valuable biomarker for diagnosing SOS/VOD and identifying patients at greater risk of this complication, especially late-onset SOS/VOD. Furthermore, CEC kinetics may support treatment strategies by providing insight into the optimal timing for discontinuing defibrotide treatment.

Potential of acetaminophen on the sublingual microcirculation and peripheral tissue perfusion of febrile septic patients: prospective observational study

BackgroundAcetaminophen (ACT) has been studied in septic patients with detectable plasmatic levels of cell-free hemoglobin (Hb), where it demonstrated to inhibit the hemoprotein-mediated lipid peroxidation and oxidative injury, with a potential of beneficial effect on the endothelium. On the basis of this background, the aim of this study was to evaluate the sublingual microcirculation and the peripheral tissue perfusion before-and-after administration of ACT on clinical judgment in a cohort of febrile septic and septic shock patients.MethodsProspective observational study. 50 adult septic and septic shocks treated with ACT for pyrexia, where the sublingual microcirculation and the peripheral tissue perfusion with Near Infrared Spectroscopy (NIRS) and vascular occlusion test (VOT) were evaluated before ACT (t0), after 30 min (t1) and after 2 h (t2). Cell-free Hb and the markers of oxidative stress and endothelial damage were measured at t0 and t2.ResultsThe study showed a significant increase of the density of the perfused small and total vessels of the sublingual microcirculation 30 min after the infusion of ACT; it also showed an increase of the Microvascular Flow Index (MFI) and a decrease in the heterogeneity of the flow.At a peripheral muscular level, we found an acceleration in the reperfusion curve after VOT at t1, expression of a higher reactivity of the microvasculature.ConclusionsACT infusion did not show a clear correlation with cell-free Hb; however, it exhibited protective effect toward the microcirculation that was evident in particular in septic patients. This correlation merits further exploration.

Mechanism matters: mortality and endothelial cell damage marker differences between blunt and penetrating traumatic injuries across three prehospital clinical trials.

Injury mechanism is an important consideration when conducting clinical trials in trauma. Mechanisms of injury may be associated with differences in mortality risk and immune response to injury, impacting the potential success of the trial. We sought to characterize clinical and endothelial cell damage marker differences across blunt and penetrating injured patients enrolled in three large, prehospital randomized trials which focused on hemorrhagic shock. In this secondary analysis, patients with systolic blood pressure < 70 or systolic blood pressure < 90 and heart rate > 108 were included. In addition, patients with both blunt and penetrating injuries were excluded. The primary outcome was 30-day mortality. Mortality was characterized using Kaplan-Meier and Cox proportional-hazards models. Generalized linear models were used to compare biomarkers. Chi squared tests and Wilcoxon rank-sum were used to compare secondary outcomes. We characterized data of 696 enrolled patients that met all secondary analysis inclusion criteria. Blunt injured patients had significantly greater 24-h (18.6% vs. 10.7%, log rank p = 0.048) and 30-day mortality rates (29.7% vs. 14.0%, log rank p = 0.001) relative to penetrating injured patients with a different time course. After adjusting for confounders, blunt mechanism of injury was independently predictive of mortality at 30-days (HR 1.84, 95% CI 1.06-3.20, p = 0.029), but not 24-h (HR 1.65, 95% CI 0.86-3.18, p = 0.133). Elevated admission levels of endothelial cell damage markers, VEGF, syndecan-1, TM, S100A10, suPAR and HcDNA were associated with blunt mechanism of injury. Although there was no difference in multiple organ failure (MOF) rates across injury mechanism (48.4% vs. 42.98%, p = 0.275), blunt injured patients had higher Denver MOF score (p < 0.01). The significant increase in 30-day mortality and endothelial cell damage markers in blunt injury relative to penetrating injured patients highlights the importance of considering mechanism of injury within the inclusion and exclusion criteria of future clinical trials.

Biomarkers of endothelial damage and their role in predicting the development of sepsis and septic shock

Introduction. Sepsis is multiple organ dysfunction in response to the generalization of an infectious process. The likelihood of developing sepsis correlates with the value of biochemical parameters, which can serve as prognostic markers. The endothelium, as the structural basis of the circulatory system, is primarily exposed to pathogenetic factors, performing a protective function. The purpose of this review was to summarize the results of assessing the diagnostic and prognostic effectiveness of molecular markers of endothelial damage in the development of inflammation, sepsis and septic shock. Material and methods. The literature search was conducted using the databases PubMed/Medline, Elsevier.com., ResearchGate, RSCI/elibrary, over the past ten years. Results. Using keywords, 215 articles were found and analyzed, from which 70 of the most significant and reliable sources were selected. It was concluded that it is necessary to develop a panel of markers of endothelial damage, which together will provide high reliability and specificity for assessing the risk of developing sepsis and septic shock.

Serum biomarkers of inflammation and vascular damage upon SARS-Cov-2 mRNA vaccine in patients with thymic epithelial tumors.

Thymic epithelial tumors (TET) patients are at high risk of autoimmune and hypoimmune complications. Limited evidence is available on the potential risk of immune-related and inflammatory reactions induced by SARS-Cov-2 vaccine in this patient population. In order to identify subjects at higher risk for vaccine complications, we prospectively evaluated a panel of serum biomarkers related to inflammation (TNF-α, IL-1β,-6,-10,-12, and-17A, IFN-α, β and γ, MPO, MMP-9), and vascular damage (E-and P-selectin, VEGF-A, P-ANCA and MCP-1) in 44 TET patients and in 30 healthy controls along the whole SARS-Cov-2 vaccine cycle. About 50 % of subjects (either TET and controls) showed an increase of serum biochemical markers of inflammation and endothelial damage with a large heterogeneity of values. Such increase appeared early, after the first dose in control subjects and later, after the second dose in TET patients (in which we observed mainly an increase of inflammatory biomarkers). The values normalized after about 3months and did not increase after the third, booster dose. No autoimmune or vascular complications were observed in the study subjects and no difference was observed in terms of vaccine response among subjects showing serum biomarkers increase and those who experienced no changes. Our data highlight the relevance of Sars-Cov-2 vaccine in TET patients, as it resulted safe and prevented severe COVID-19. However, further studies are awaited to explore the mechanisms and the potential consequences of the observed increase of serum inflammatory and vascular damage biomarkers.

Comparison of Blood Biomarkers in Systemic Blood and Varicose Veins: A Cross-sectional Study

Introduction: Varicose Veins (VV) are enlarged, convoluted, and elongated veins that primarily affect the superficial veins in the lower limbs and are one of the most prevalent indications of vascular diseases. The reasons for elevated venous pressure are understood, but the inflammatory cytokines that initiate the ultimate pathways of tissue destruction and are in charge of the clinical characteristics of Chronic Venous Insufficiency (CVI) are yet unknown. Although inflammation plays a crucial role in the process of tissue apoptosis, it also plays a crucial role in tissue repair and regeneration. Aim: To investigate changes in blood markers of varicose vein inflammation and endothelial damage and compare them with systemic markers in VV patients and conclude that they are increased in VV blood. Materials and Methods: The comparative cross-sectional study was conducted in the Department of Biochemistry on 70 patients with primary VV who were scheduled for Outpatient Sclerotherapy at Nootan Medical College and Research Centre, Sankalcahnd Patel Vidyadham in Visnagar, Gujarat, India from April 2021 to June 2023. Chronic lower extremity Venous Disease (CVD) was categorised using the Clinical Aetiology Anatomy Pathophysiology (CEAP) classification method. Blood samples were obtained above the knee from the tortuous and dilated varicose tributaries of the great saphenous vein (local) and from the antecubital (systemic) vein by standard venipuncture. Erythrocytes, leukocytes, platelets, haemoglobin, and haematocrit were determined using an automatic haematology analyser. D-dimer and High sensitivity C-reactive Protein (hsCRP) were determined by an immune turbidimetric assay. IL-6 and von Willebrand factor (vWF) were measured by Enzyme Linked Immunosorbent Assay (ELISA) using commercially available kits according to the manufacturers’ instructions. An Independent samples t-test was used to compare group difference, and p-value ≤0.05 were considered significant in all two-sided statistical tests. Results: Basic haematologic test results {systemic versus (vs) varicose blood samples} were comparable. In VV, the following parameters were significantly increased compared to systemic blood: Haemoglobin (12.85±1.81 g/dL vs. 15.82±1.57 g/ dL, p&lt;0.001), hsCRP (1.34±1.01 mg/L vs. 3.78±1.67 mg/L, p&lt;0.001), IL-6 (2.65±1.07 pg/mL vs. 4.17±1.51 pg/mL, p&lt;0.001), vWF (90.73±16.72% vs. 127.30±19.92, p&lt;0.001). D-dimer was also substantially higher in samples extracted from leg VV than in systemic blood (105.87±17.72 ng/mL vs. 85.61±18.18 ng/mL, p&lt;0.001). Conclusion: Blood from VV has shown a higher level of several inflammatory markers and signs of endothelial dysfunction. This is most likely the result of worsening venous pressure and dilated, convoluted superficial veins that restrict blood flow. The procoagulant qualities of the local blood and damage to the venous wall, leading to a chronic inflammatory response, may accelerate the disease’s progression and thrombotic consequences.

Comparison of vascular cell adhesion molecule 1 (VCAM-1) during pregnancy, after placental detachment and during puerperium between normal and pregnancy with COVID-19.

Pregnant women have a number of physiological changes that lower the immune responses to avoid embryonic rejection, which increases the risk of problems after contracting coronavirus disease 2019 (COVID-19). Multiple inflammatory cytokines are dysregulated in this process and expressed inappropriately during systemic inflammatory responses associated with COVID-19. The aim of the study was to compare the levels of vascular cell adhesion molecule 1 (VCAM-1), a marker of endothelial damage in pregnancies with and without COVID-19. A cohort prospective study was conducted at H. Adam Malik General Hospital and the Universitas Sumatera Utara Hospital, Indonesia. Pregnant women without COVID-19 and pregnant women with moderate and severe degrees of COVID-19 were recruited. The level of VCAM-1 was measured at three different time points (during pregnancy, within an hour of placental detachment, and 24 hours postpartum). The ANOVA and Student t-test were used to compare the VCAM-1 levels among different time points and between groups, respectively. The mean VCAM-1 levels at the hospital admission, one hour of placental detachment and 24 hours postpartum in non-COVID-19 and COVID-19 pregnancies were 591.29 vs 1176.27 pg/mL; 558.2 vs 1136.2 pg/mL; and 508.59 vs 985.2 pg/mL, respectively. There was a significant different in VCAM-1 levels in normal pregnancy at the time of hospital admission, one hour after detachment of the placenta and 24 hours postpartum (p=0.04). The mean VCAM-1 levels in pregnant women with COVID-19 also had significant differences between three time points (p=0.033). The levels of VCAM-1 were statically higher among pregnancy in the COVID-19 group compared to the non-COVID-19 group during hospital admission (p=0.023), one hour after placenta detachment (p=0.040) and 24 hours postpartum (p=0.043). The results suggested the usefulness of identifying the VCAM-1 level as a marker of endothelial dysfunction in pregnancy with COVID-19.

SVEGF-R1 in acute non-infectious toxicity syndromes after pediatric allogeneic hematopoietic stem cell transplantation

BackgroundAllogeneic hematopoietic stem cell transplantation (HSCT) is challenged by acute non-infectious toxicities, including sinusoidal obstruction syndrome (SOS), engraftment syndrome (ES) and capillary leak syndrome (CLS) among others. These complications are thought to be driven by a dysfunctional vascular endothelium, but the pathophysiological mechanisms remain incompletely understood, and the diagnoses are challenged by purely clinical diagnostic criteria that are partly overlapping, limiting the possibilities for progress in this field. There is, however, increasing evidence suggesting that these challenges may be met through the development of diagnostic biomarkers to improve diagnostic accuracy of pathogenetically homogenous entities, improved pre-transplant risk assessment and the early identification of patients with increased need for specific treatment. Soluble vascular endothelial growth factor receptor-1 (sVEGF-R1) is emerging as an important biomarker of endothelial damage in patients with trauma and sepsis but has not been studied in HSCT. ObjectivesTo investigate sVEGF-R1 as a marker of endothelial damage in pediatric HSCT patients by exploring associations with SOS, CLS, ES, and acute graft-versus-host disease (aGvHD). MethodsWe prospectively included 113 children undergoing myeloablative HSCT and measured sVEGF-R1 in plasma samples obtained weekly during the early period of transplantation and 3 months post-transplant. ResultsAll over, sVEGF-R1 levels were significantly increased from day +7 after graft infusion, peaking at day +30, most pronounced in patients receiving busulfan. Patients considered to be at increased risk of SOS and therefore commenced on prophylactic defibrotide had significantly elevated levels of sVEGF-R1 before start of conditioning (446 pg/mL vs. 281 pg/mL, p = 0.0035), and this treatment appeared to stabilize sVEGF-R1 levels compared to patients not treated with defibrotide. Thirteen (11.5%) children meeting the modified Seattle criteria for SOS at median day +8 (1–18), had significantly elevated sVEGF-R1 levels on day +14 (489 pg/mL vs. 327 pg/mL, p = 0.007). In contrast. sVEGF-R1 levels in the much broader group of patients (45.1%) meeting EBMT-SOS criteria, including patients with very mild disease, did not overall differ in sVEGF-R1 levels, but higher sVEGF-R1 levels were seen in EBMT-SOS patients with an increased need for diuretic treatment. Importantly, sVEGF-R1 levels were not associated with ES and CLS but were significantly increased on day +30 in patients with grade III-IV aGvHD (OR = 4.2 pr. quartile, p = 0.023). ConclusionVEGF-R1 levels are found to be increased in pediatric patients developing SOS, reflecting the severity of morbidity. sVEGF-R1 were unassociated with both CLS and ES. The potential of sVEGF-R1 as a clinically useful biomarker for SOS should be further explored to improve pre-transplant SOS-risk assessment, SOS-severity grading, and to guide treatment.

Changes in plasma endocan level are related to circulatory but not respiratory failure in critically ill patients with COVID-19

The aim of this prospective, observational study was to assess whether changes in the level of endocan, a marker of endothelial damage, may be an indicator of clinical deterioration and mortality in critically ill COVID-19 patients. Endocan and clinical parameters were evaluated in 40 patients with acute respiratory failure on days 1–5 after admission to the intensive care unit. Endocan levels were not related to the degree of respiratory failure, but to the presence of cardiovascular failure. In patients with cardiovascular failure, the level of endocan increased over the first 5 days (1.63, 2.50, 2.68, 2.77, 3.31 ng/mL, p = 0.016), while in patients without failure it decreased (1.51, 1.50, 1.56, 1.42, 1.13 ng/mL, p = 0.046). In addition, mortality was more than twice as high in patients with acute cardiovascular failure compared to those without failure (68% vs. 32%, p = 0.035). Baseline endocan levels were lower in viral than in bacterial infections (1.57 ng/mL vs. 5.25 ng/mL, p < 0.001), with a good discrimination between infections of different etiologies (AUC of 0.914, p < 0.001). In conclusion, endocan levels are associated with the occurrence of cardiovascular failure in COVID-19 and depend on the etiology of the infection, with higher values for bacterial than for viral sepsis.

Easix Score Correlates With Endothelial Dysfunction Biomarkers and Predicts Risk of Acute Graft-Versus-Host Disease After Allogeneic Transplantation

Plasma biomarkers of endothelial dysfunction have been postulated for the diagnosis and prognosis of acute graft-versus-host disease (aGVHD). However, their use is not validated in clinical practice yet. The endothelial activation and stress index (EASIX), a simple score based on routine laboratory parameters, is considered to be an indirect marker of endothelial damage. High value of EASIX was correlated with worse non-relapse mortality (NRM) and overall survival (OS) and a high risk of sinusoidal obstructive syndrome and transplant-associated thrombotic microangiopathy (TA-TMA). This study investigates the predictive value of plasma biomarkers and the EASIX score for the prediction of aGVHD. We assessed vascular cell adhesion molecule-1 (VCAM-1), tumor necrosis factor receptor 1 (TNFR1), and VWF:Ag plasma levels and the EASIX score before allogeneic hematopoietic stem cell transplantation (allo-HSCT) and on days 0, 3, 7, 14, and 21 in an experimental cohort (n = 33). EASIX was transformed to a base-2 logarithm to perform the analysis. For the most relevant biomarkers, we estimate the optimal cutoff values and the discriminatory ability to differentiate patients with high-risk of aGVHD. The conclusions obtained in the experimental cohort were validated in a large cohort of 321 patients at the same institution. Plasma biomarkers and EASIX showed similar post-transplantation dynamics consisting of a progressive increase. Multivariate analysis showed an association between high TNFR1 levels and Log-2 EASIX score on day 7 after transplantation with an increased likelihood of developing aGVHD (hazard ratio [HR] = 1, P = .002; HR = 2.31, P = .013, respectively). Patients with TNFR1 ≥1300 ng/mL (HR = 7.19, P = .006) and Log2-EASIX ≥3 (HR = 14.7, P <.001) at day 7 after transplantation were more likely to develop aGVHD with high predictive accuracy (C-index of 74% and 81%, respectively). In the validation cohort, patients with Log2-EASIX ≥3 on day 7 after transplantation presented a significantly higher incidence of grade II-IV aGVHD (HR = 1.94, P = .004) independent of GVHD prophylaxis (HR = 0.38, P = .004), conditioning regimen (HR = 0.59, P =.02) and type of donor (HR = 2.38, P = .014). Differential degree of endothelial damage can be measured using both EASIX score and plasma biomarkers in the early post-transplantation period. Patients at risk of developing aGVHD could be easily identified by a high EASIX score. Both indicators of endothelial activation represent a promising approach to predict aGVHD.