Search Results (52)

Cerebral malaria (CM) is the severe progression of an infection with Plasmodium falciparum, causing detrimental damage to brain tissue and is the most frequent cause of Plasmodium falciparum mortality. The critical role of brain-infiltrating CD8⁺ T cells in the pathophysiology of CM having been revealed, our investigation focuses on the role of NR2F6, an established immune checkpoint, as a candidate driver of CM pathology. We employed an experimental mouse model of CM based on Plasmodium berghei ANKA (PbA) infection to compare the relative susceptibility of Nr2f6-knock-out and wild-type C57BL6/N mice. As a remarkable result, Nr2f6 deficiency confers a significant survival benefit. In terms of mechanism, we detected less severe endotheliopathy and, hence, less damage to the blood–brain barrier (BBB), accompanied by decreased sequestered parasites and less cytotoxic T-lymphocytes within the brain, manifesting in a better disease outcome. We present evidence that NR2F6 deficiency renders mice more resistant to experimental cerebral malaria (ECM), confirming a causal and non-redundant role for NR2F6 in the progression of ECM disease. Consequently, pharmacological inhibitors of the NR2F6 pathway could be of use to bolster BBB integrity and protect against CM. Full article

Defibrotide, which is approved for treating hepatic veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS), exhibits pleiotropic anti-inflammatory, anti-thrombotic, and fibrinolytic properties, conferring broad endothelial protective effects. Given these mechanisms, defibrotide has potential utility in various conditions involving endothelial injury or activation. In this review we outline the endothelial-protective mechanisms of defibrotide and comprehensively summarize current evidence supporting its applications in hematologic malignancies, including the prevention and treatment of hepatic VOD/SOS, graft-versus-host disease, and transplant-associated thrombotic microangiopathy. Additionally, we discuss its role in mitigating key toxicities linked to chimeric antigen receptor (CAR) T-cell therapies and bispecific antibodies, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). We also explore emerging evidence on defibrotide’s potential in SARS-CoV-2 infection-associated endotheliopathies, including acute COVID-19 and post-acute sequelae of SARS-CoV-2 infection (“long-COVID”), and the endothelial protective activity of defibrotide in these settings. Finally, we highlight potential future applications of defibrotide in hematologic malignancies and viral infections, emphasizing its multimodal mechanism of action. Full article

Endotheliopathy plays an essential role in the pathophysiology of COVID-19. The endothelial activation and stress index (EASIX) indicates endothelial dysfunction. We aimed to investigate the relationship between a high EASIX score and mortality in patients with COVID-19. We retrospectively reviewed COVID-19 patients admitted to the ICU (intensive care unit) of the Ankara Bilkent City Hospital. We recorded hematological and biochemical parameters at the ICU admission and further calculated EASIX with the following equation: EASIX = Lactate dehydrogenase (U/L) × creatinine (mg/dL)/platelet count (10⁹/L). Statistical comparisons were made between the surviving and non-surviving groups in terms of EASIX. The median EASIX score was 1.2 (0.7–2.0) in the survivor group and a median of 2.5 (1.6–4.2) in the non-survivor group (p < 0.001). The mean log2-EASIX was 0.2 ± 0.9 in the survivor group and 1.3 ± 1.2 in the non-survivor group (p < 0.001). Lactate dehydrogenase, creatinine, Troponin I, D-dimer, procalcitonin, ferritin, and IL-6 were statistically significantly higher in the non-survivor group compared to the survivor group. The receiver operating characteristic (ROC) curve analysis showed that the cut-off value of the EASIX score was 2.05 (The area under the curve [AUC] = 0.764, p = 0.001, 95% CI: 0.662–0.847). Our study showed an association between high EASIX scores and poor prognosis in COVID-19 patients. Lactate dehydrogenase, creatinine, Troponin I, D-dimer, procalcitonin, ferritin, IL-6, EASIX, and log2-EASIX were statistically significantly higher in the non-survivor group compared to the survivor group. Being old and having chronic kidney disease increases the risk of death. Eventually, EASIX can be used to predict mortality in COVID-19 patients. Full article

Hemorrhagic shock from traumatic injury results in a massive systemic response with activation of the hypothalamic–pituitary–adrenal (HPA) axis, pro-thrombotic and clot-lysis pathways as well as development of an endotheliopathy. With ongoing hemorrhage, these responses become dysregulated and are associated with worsening coagulopathy, microvascular dysfunction, and increased transfusion requirements. Our transfusion practices as well as our understanding of the molecular response to hemorrhage have undergone significant advancement during war. Currently, resuscitation practices address the benefit of the early recognition and management of acute coagulopathy and advocates for balanced resuscitation with either whole blood or a 1:1 ratio of packed red blood cells to fresh frozen plasma (respectively). However, a significant volume of evidence in the last two decades has recognized the importance of the early modulation of traumatic endotheliopathy and the HPA axis via the early administration of plasma, whole blood, and adjunctive treatments such as tranexamic acid (TXA) and calcium. This evidence compels us to rethink our understanding of ‘balanced resuscitation’ and begin creating a more structured practice to address additional competing priorities beyond coagulopathy. The following manuscript reviews the benefits of addressing the additional interrelated physiologic responses to hemorrhage and seeks to expand beyond our understanding of ‘balanced resuscitation’. Full article

Background/Objectives: Hematopoietic stem cell transplantation (HSCT) in pediatric and young adult (YA) patients can lead to endotheliopathy, such as thrombotic microangiopathy (TMA), sinusoidal obstruction syndrome (SOS), and diffuse alveolar hemorrhage (DAH). Natriuretic peptides have been studied as markers of endotheliopathy and critical illness. We hypothesized that an elevation in NT-proBNP was associated with the development of endotheliopathy (DAH, SOS, or TMA) in the first 100 days following HSCT in pediatric and YA patients. Methods: IRB-exempt status was obtained. This retrospective case–control study reviewed HSCT at our institution from 2016 to 2020. Cases were selected based on an endotheliopathy diagnosis in the first 100 days after HSCT. Cases were matched with controls. Baseline and near-event NT-proBNP levels were compared between cases and matched controls. The effect of NT-proBNP levels on developing endotheliopathy was estimated using conditional logistic regression. Results: Sixty-two patients were included (31 cases, 31 controls). Near-event NT-proBNP was significantly higher in cases compared to controls (median: 473 vs. 187 pg/mL, p = 0.03, Wilcoxon rank–sum test), in contrast to comparison in baseline NT-proBNP (median: 86 vs. 86 pg/mL, p = 0.51). After adjusting for covariates, an association between near-event NT-proBNP and odds of developing endotheliopathy did not achieve statistical significance. However, trends from most common transplant indications suggested an association between an elevated near-event NT-proBNP level and endotheliopathy, particularly in acute lymphoblastic leukemia (ALL) patients. Conclusions: NT-proBNP should be studied further as a biomarker for endotheliopathy in pediatric and YA patients undergoing HSCT. This may be particularly relevant for patients undergoing HSCT for ALL. Full article

Background/Objectives: The complexity of trauma-induced coagulopathy (TIC) is a result of the unique interactions between the patient, trauma, and resuscitation-related causes. The main objective of trauma resuscitation is to create the optimal milieu for both the development of immediate reparatory mechanisms and the prevention of further secondary injuries. Endotheliopathy represents one of the hallmarks of trauma-induced coagulopathy, and comprises endothelial dysfunction, abnormal coagulation, and inflammation, all of which arise after severe trauma and hemorrhagic shock. Methods: We retrospectively and descriptively evaluated 217 patients admitted to the Bucharest Clinical Emergency Hospital who met the Berlin criteria for the diagnosis of multiple trauma. Patients with high suspicion of auto-heparinization were identified according to the dynamic clinical and para-clinical evolution and subsequently tested using rotational thromboelastometry (ROTEM). The ratio between the clot formation time (CT) was used, obtained on the two channels of interest (INTEM/HEPTEM). Results: Among the 217 patients with a mean age of 43.43 ± 15.45 years and a mean injury severity score (ISS) of 36.98 ± 1.875, 42 patients had a reasonable clinical and para-clinical suspicion of auto-heparinization, which was later confirmed by the INTEM/HEPTEM clotting time ratio in 28 cases (12.9% from the entire study population). A multiple linear regression analysis highlighted that serum lactate (estimated 0.02, p = 0.0098) and noradrenaline requirement (estimated 0.03, p = 0.0053) influenced the CT (INTEM/HEPTEM) ratio. Conclusions: There is a subset of multiple trauma patients in which the CT (INTEM/HEPTEM) ratio was influenced only by serum lactate levels and patients’ need for vasopressor use, reinforcing the relationship between shock, hypoperfusion, and clotting derangements. This emphasizes the unique response that each patient has to trauma. Full article

Coagulopathy and traumatic brain injury (TBI) are complexly intertwined. In isolated TBI, coagulopathy may contribute to hemorrhagic lesion development, progression, or recurrence, as it may lead to a particular pattern of coagulopathy called TBI-induced coagulopathy (TBI-IC). We performed a retrospective and descriptive evaluation of 63 patients admitted to the Emergency Clinical Hospital Bucharest with the diagnosis of moderate/severe brain injury. In addition to demographic data, all included patients had a complete paraclinical evaluation that included rotational thromboelastometric (ROTEM) blood-clot analysis. The platelet component (PLTEM) and the endotheliopathy activation and stress index score (EASIX) were calculated. These parameters were presented comparatively according to survival at 30 days and helped define the two study groups: survivors and non-survivors at 30 days. The contribution of platelets to clot strength is derived from maximum clot elasticity (MCE) and maximum clot firmness (MCF). MCE is defined as (MCF × 100)/(100 − MCF), and PLTEM is defined as EXTEM MCE—FIBTEM MCE. EASIX is a novel biomarker recently studied in TBI patients, calculated according to the following formula: lactate dehydrogenase (U/L) × creatinine (mg/dL)/platelets (10⁹ cells/L). Regarding the demographic data, there were no significant differences between the survivors and non-survivors. All ROTEM parameters related to clot amplitude (A5, A10, A20, MCF in EXTEM and FIBTEM channels) were higher in the group of patients who survived. Also, PLTEM was decreased in the group of deceased patients (89.71 ± 22.86 vs. 132.3 ± 16.56 p < 0.0001). The cut-off point determined with the ROC curve is 114.10, with a sensitivity of 94.74% and a specificity of 93.18%, for the detection of the negative prognosis (death at 30 days). The EASIX score was significantly higher in the patients who survived the traumatic event, with a median difference value of 1.15 (p < 0.0001). The ROC analysis of this biomarker highlights a cut-off point of 2.12, with a sensitivity of 88.64% and a specificity of 94.74% (AUC = 0.95, p < 0.0001), for the prediction of mortality. The comparative analysis of the two studied markers was performed using the Cox proportional hazard ratio and highlighted the greater influence that PLTEM has on survival time (b value = −0.05, p < 0.0001) compared to EASIX (b value = 0.49, p = 0.0026). The present retrospective study indicates the potential of the TBI-IC reflecting parameters PLTEM and EASIX as markers of mortality prognosis. Larger prospective studies are needed to confirm their combined prognostic value and use in decision-making and reduction in the burden of disease by adequate allocation of resources in a personalized and timely manner. Full article

This study focuses on understanding the transcriptional heterogeneity of activated platelets and its impact on diseases such as sepsis, COVID-19, and systemic lupus erythematosus (SLE). Recognizing the limited knowledge in this area, our research aims to dissect the complex transcriptional profiles of activated platelets to aid in developing targeted therapies for abnormal and pathogenic platelet subtypes. We analyzed single-cell transcriptional profiles from 47,977 platelets derived from 413 samples of patients with these diseases, utilizing Deep Neural Network (DNN) and eXtreme Gradient Boosting (XGB) to distinguish transcriptomic signatures predictive of fatal or survival outcomes. Our approach included source data annotations and platelet markers, along with SingleR and Seurat for comprehensive profiling. Additionally, we employed Uniform Manifold Approximation and Projection (UMAP) for effective dimensionality reduction and visualization, aiding in the identification of various platelet subtypes and their relation to disease severity and patient outcomes. Our results highlighted distinct platelet subpopulations that correlate with disease severity, revealing that changes in platelet transcription patterns can intensify endotheliopathy, increasing the risk of coagulation in fatal cases. Moreover, these changes may impact lymphocyte function, indicating a more extensive role for platelets in inflammatory and immune responses. This study identifies crucial biomarkers of platelet heterogeneity in serious health conditions, paving the way for innovative therapeutic approaches targeting platelet activation, which could improve patient outcomes in diseases characterized by altered platelet function. Full article

Patient blood samples are invaluable in clinical omics databases, yet current methodologies often fail to fully uncover the molecular mechanisms driving patient pathology. While genome-scale metabolic models (GEMs) show promise in systems medicine by integrating various omics data, having only exometabolomic data remains a limiting factor. To address this gap, we introduce a comprehensive pipeline integrating GEMs with patient plasma metabolome. This pipeline constructs case-specific GEMs using literature-based and patient-specific metabolomic data. Novel computational methods, including adaptive sampling and an in-house developed algorithm for the rational exploration of the sampled space of solutions, enhance integration accuracy while improving computational performance. Model characterization involves task analysis in combination with clustering methods to identify critical cellular functions. The new pipeline was applied to a cohort of trauma patients to investigate shock-induced endotheliopathy using patient plasma metabolome data. By analyzing endothelial cell metabolism comprehensively, the pipeline identified critical therapeutic targets and biomarkers that can potentially contribute to the development of therapeutic strategies. Our study demonstrates the efficacy of integrating patient plasma metabolome data into computational models to analyze endothelial cell metabolism in disease contexts. This approach offers a deeper understanding of metabolic dysregulations and provides insights into diseases with metabolic components and potential treatments. Full article

SARS-CoV-2, the causative agent of the ongoing COVID-19 pandemic, has revealed a broader impact beyond the respiratory system, predominantly affecting the vascular system with various adverse manifestations. The infection induces endothelial dysfunction and immune system dysregulation, creating an inflammatory and hypercoagulable state. It affects both microvasculature and macrovasculature, leading to thromboembolic events, cardiovascular manifestations, impaired arterial stiffness, cerebrovascular complications, and nephropathy, as well as retinopathy—frequently observed in cases of severe illness. Evidence suggests that SARS-CoV-2 infection may result in persistent effects on the vascular system, identified as long-term COVID-19. This is characterized by prolonged inflammation, endotheliopathy, and an increased risk of vascular complications. Various imaging modalities, histopathological studies, and diagnostic tools such as video capillaroscopy and magnetic resonance imaging have been employed to visualize vascular alterations. This review aims to comprehensively summarize the evidence concerning short and long-term vascular alterations following COVID-19 infection, investigating their impact on patients’ prognosis, and providing an overview of preventive strategies to mitigate associated vascular complications. Full article

The therapeutic management and short-term consequences of the coronavirus disease 2019 (COVID-19) are well known. However, COVID-19 post-acute sequelae are less known and represent a public health problem worldwide. Patients with COVID-19 who present post-acute sequelae may display immune dysregulation, a procoagulant state, and persistent microvascular endotheliopathy that could trigger microvascular thrombosis. These elements have also been implicated in the physiopathology of postural orthostatic tachycardia syndrome, a frequent sequela in post-COVID-19 patients. These mechanisms, directly associated with post-acute sequelae, might determine the thrombotic consequences of COVID-19 and the need for early anticoagulation therapy. In this context, heparin has several potential benefits, including immunomodulatory, anticoagulant, antiviral, pro-endothelial, and vascular effects, that could be helpful in the treatment of COVID-19 post-acute sequelae. In this article, we review the evidence surrounding the post-acute sequelae of COVID-19 and the potential benefits of the use of heparin, with a special focus on the treatment of postural orthostatic tachycardia syndrome. Full article

The coronavirus SARS-CoV-2 is the causative pathogen of the COVID-19 pandemic that has been causing global upheaval since 2019. The widespread administration of vaccines has partially deterred the spread of SARS-CoV-2, yet the virus is mutating its genome to reduce its antigenicity and evade the human herd immunity. It seems that SARS-CoV-2 will co-exist with the human population for many decades to come. While most infected individuals only experience mild to moderate symptoms, some develop severe pulmonary and systemic disease that can result in hospitalization or even death. The natural history model of SARS-CoV-2 infection has been proposed which includes three sequential stages: the early infection stage, pulmonary stage, and hyper-inflammatory stage. Recently, it has been observed that many people who recovered from an acute infection still experience persistent symptoms for weeks or months, a condition known as long COVID. Furthermore, some COVID-19 patients display escalated rates of both macro- and micro-thrombosis due to endotheliopathy. Hence, we added the thrombosis and convalescent stages to the natural history model, encompassing the entire period from early infection to long COVID. The early infection stage is characterized by symptomatic or asymptomatic elevation of viral titers. Some patients progress to the pulmonary stage characterized by opacities in chest X-rays and computed tomography. The thrombosis stage is characterized by heightened rates of pulmonary thrombosis and consistently elevated D-dimer levels. The hyper-inflammatory stage is characterized by storms of cytokines, such as IL-6, IL-17, and interferons, which is a systemic effect. In the convalescent stage, some people recover completely, while others suffer from long COVID with persistent symptoms such as fatigue, shortness of breath, or brain fog. The natural history model of SARS-CoV-2 infection can be used to elucidate treatment and care. Full article

Background: Plasma levels of von Willebrand factor (VWF) are significantly elevated in patients with coronavirus disease 2019 (COVID-19). However, dynamic changes and prognostic value of this biomarker in hospitalized patients with COVID-19 have not been determined. Methods: A total of 124 patients infected with SARS-CoV-2 were prospectively recruited for the study. Serial blood samples were obtained at the time of admission (D1), 3–4 days following standard-care treatments (D2), and 1–2 days prior to discharge or any time collected prior to death (D3). Plasma VWF antigen, ADAMTS13 antigen, and ADAMTS13 proteolytic activity, as well as the ratio of VWF/ADAMTS13 were determined, followed by various statistical analyses. Results: On admission, plasma levels of VWF in COVID-19 patients were significantly elevated compared with those in the healthy controls, but no statistical significance was detected among patients with different disease severity. Plasma ADAMTS13 activity but not its antigen levels were significantly lower in patients with severe or critical COVID-19 compared with that in other patient groups. Interestingly, the ratios of plasma VWF antigen to ADAMTS13 antigen were significantly higher in patients with severe or critical COVID-19 than in those with mild to moderate disease. More importantly, plasma levels of VWF and the ratios of VWF/ADAMTS13 were persistently elevated in patients with COVID-19 throughout hospitalization. Kaplan–Meier and Cox proportional hazard regression analyses demonstrated that an increased plasma level of VWF or ratio of VWF/ADAMTS13 at D2 and D3 was associated with an increased mortality rate. Conclusions: Persistent endotheliopathy, marked by the elevated levels of plasma VWF or VWF/ADAMTS13 ratio, is present in all hospitalized patients following SARS-CoV-2 infection, which is strongly associated with mortality. Full article

Although coronavirus disease 2019 (COVID-19) is considered a systemic disease associated with vascular inflammation and eventual destruction of the protective endothelial glycocalyx (eGC), biomarkers of eGC damage are not yet available in the clinic. The most prominent components of eGC are sulphated glycosaminoglycans (sGAGs) attached to core proteoglycans. We hypothesised that the amount of sGAG fragments shed in urine (as a surrogate for systemic eGC damage) would correlate with disease severity and outcome. Total urinary sGAG concentration was measured using an in-house optimised 1,9-dimethylmethylene blue (DMMB) assay, which is highly accurate and insensitive to interferences. The median urinary sGAG concentration was significantly higher in 67 hospitalised patients with COVID-19 compared to 72 hospitalised patients with community-acquired pneumonia (CAP). In both groups, urinary sGAG concentrations predicted a combined endpoint (including intubation and death) with an area under the receiver operator characteristic curve of 0.72 (95% CI 0.55–0.88, p = 0.01) and 0.70 (95% CI 0.57–0.83, p = 0.007), respectively. In conclusion, the inexpensive and easy-to-perform DMMB assay provides a surrogate parameter for eGC damage that may be useful for risk stratification of patients with COVID-19 and CAP. Full article