Blood coagulation is essential for stopping bleeding but also drives thromboembolic disorders. Factor XII (FXII)-triggered coagulation promotes thrombosis while being dispensable for hemostasis, making it a potential anticoagulant target. However, its physiological role remains unclear. Here, we demonstrate that FXII-driven coagulation enhances innate immunity by trapping pathogens and restricting bacterial infection in mice. Streptococcus pneumoniae infection was more severe in FXII-deficient (F12-/-) mice, with increased pulmonary bacterial burden, systemic spread, and mortality. Similarly, Staphylococcus aureus skin infections and systemic dissemination were exacerbated in F12-/- mice. Reconstitution with human FXII restored bacterial containment. Plasma kallikrein amplifies FXII activation, and its deficiency aggravated S. aureus skin infections, similarly to F12-/- mice. FXII deficiency impaired fibrin deposition in abscess walls, leading to leaky capsules and bacterial escape. Bacterial long-chain polyphosphate activated FXII, triggering fibrin formation. Deficiency in FXII substrate factor XI or FXII/factor XI co-deficiency similarly exacerbated S. aureus infection. The data reveal a protective role for FXII-driven coagulation in host defense, urging caution in developing therapeutic strategies targeting this pathway.

In this review, we aim to highlight recent insights into the mechanisms through which platelets contribute to vascular inflammation. We will discuss how platelets interact with other cellular players in the vascular milieu, their role in shaping inflammatory responses, and the potential therapeutic implications of targeting platelet function in inflammatory vascular diseases.

Platelets are essential components in the processes of hemostasis and thrombosis. Their role is now widely acknowledged as far more complex than merely acting as "band-aids" or helping to "clog a pipe". Platelets are now recognized as crucial mediators in inflammatory reactions, particularly in various diseases of the vasculature, where they contribute to the onset and progression of injury. Through their interactions with leukocytes, vascular cells, and by supporting the coagulation cascade, platelets are able to finely regulate the extent and intensity of vascular damage.

Recent findings underscore the remarkable diversity and functionality of platelets in vascular diseases. Mechanistic studies in preclinical models reveal promising therapeutic opportunities, which require further validation before being translated into clinical practice.

Venous thromboembolism (VTE) after traumatic injury is morbid. Evaluating changes in platelets in injured patients who develop VTE could identify platelet-based strategies for management of thrombotic complications after injury.

In a prospectively designed secondary analysis of a multicenter cohort study conducted by the Consortium of Leaders in the Study of Traumatic Thromboembolism (CLOTT1) study group, injured patients aged 18 to 40 years admitted for a minimum of 48 hours with at least one risk factor for VTE were evaluated. A subset of CLOTT1 patients had platelet aggregometry and thromboelastography performed to examine platelet function (CLOTT2). Patients who developed VTE were compared with those who did not.

Of 7,805 patients from CLOTT1 (mean [SD] age, 29.1 [6.4] years; 1,987 [25.5%] female), 425 (5.4%) developed VTE. Platelet count was lower at each time point for patients with VTE (admission: 242 [234-251] vs. 254 [252-256], p < 0.01; hospital day 1: 157 [150-164] vs. 197 [195-198], p < 0.01; all counts ×10 9 /L). An initial 10-point reduction in platelet count was associated with development of VTE (odds ratio, 1.32 [1.13-1.53]; p < 0.01) controlling for shock, injury severity, coagulopathy, sex, and product transfusion. When evaluating 129 CLOTT2 patients, velocity of platelet aggregation was higher on admission in the VTE group (18.5 vs. 12.8 aggregation units/min; p < 0.01) in response to adenosine diphosphate stimulation. In response to thrombin stimulation, velocity of platelet aggregation was higher at 48 hours (34.4 vs. 12.3 aggregation units/min; p < 0.01), and overall aggregation was higher in the VTE group at 72 hours (area under the curve, 173.2 vs. 129.6; p < 0.01). Thromboelastography results were not different between groups.

This study identified an association of early reduction in platelet count with the development of VTE in injured patients at risk for VTE. P2Y 1/2 and protease-activated receptor 1 receptor stimulation changes in platelet aggregation responses are altered in VTE patients. Interrogating platelet count and functional responses may be beneficial in evaluating thrombotic complications after injury.

Diagnostic Test/Criteria; Level III.

Prothrombotic and proinflammatory responses are crucial in the pathology of myocardial ischemia-reperfusion injury (MIRI). Platelets and neutrophil extracellular traps (NETs) are essential to linking inflammation with thrombosis. Formononetin (FMN), an isoflavone extracted from Astragalus membranaceus, has anti-inflammatory and anti-thrombotic effects and confers benefits on MIRI. However, the mechanisms of FMN against MIRI remain unclear.

This study explored FMN's roles and mechanisms in modulating platelet activation and NETs formation to mitigate MIRI.

A rat model of MIRI by the left anterior descending coronary artery ligation was utilized to evaluate the role of FMN. 60 Sprague-Dawley male rats were randomly divided into 7 groups. Proteomics, flow cytometry, immunofluorescence, ELISA, and western blotting assays were performed to reveal the potential mechanisms of FMN. Neutrophils treated with platelet-rich plasma were applied to further explore the mechanisms of FMN in vitro.

We showed that FMN administration declined myocardial infarct size and improved cardiac function. Moreover, FMN significantly reduced MIRI-induced platelet activation including platelet aggregation, platelet adhesion, platelet granule secretion, and platelet-leukocyte aggregation without affecting tail bleeding time. Additionally, FMN inhibited microthrombus, platelet-neutrophil aggregation, and NETs formation in myocardial tissue. Mechanistically, FMN attenuated MIRI-induced CD36 expression and phosphorylation of ERK5 in platelets. Furthermore, up-regulation of CD36 content in vitro counteracted the potency of FMN to inhibit platelet activation and NETs formation.

FMN mitigates thrombosis and inflammation in MIRI by inhibiting platelet activation and NETs formation via the CD36 pathway. This research offers important insights for future studies on MIRI prevention.

Patients with severe aortic stenosis, undergoing transcatheter aortic valve replacement (TAVR), are more likely to develop thrombotic complications. However, the definite mechanisms underlying the hypercoagulation state remain unclear to date. Our objectives were to explore whether and how neutrophil extracellular traps (NETs) play a procoagulant role in patients after TAVR alone or TAVR with percutaneous coronary intervention within 1 year and further to evaluate their interactions with platelets and endothelial cells.

The levels of plasma NETs, platelets, and endothelial cell activation markers were analyzed by ELISA. NET formation was observed by immunofluorescence. Procoagulant activity was measured by clotting time, fibrin, and TAT (thrombin-antithrombin) complex generation assays. Phosphatidylserine exposure on cells was assessed by flow cytometry.

Compared with pre-TAVR, controls, or severe aortic stenosis without TAVR patients, the plasma NET levels in patients after TAVR alone, especially TAVR with percutaneous coronary intervention, increased from 7 days, peaking at 3 months, and then gradually decreased until the 12th month. Furthermore, neutrophils and plasma from patients post-TAVR are more prone to promote NET formation; NETs from these patients markedly decreased clotting time and increased fibrin and TAT generation. Additionally, a high concentration of NETs induced platelet aggregation and exerted a strong cytotoxic effect on endothelial cells and transformed them into a procoagulant phenotype.

These results lead us to believe that NETs contribute to the hypercoagulability in patients post-TAVR. Our study may provide a new target for preventing thrombotic complications in patients post-TAVR by blocking NET generation.

Neutrophils, conventionally regarded as a homogeneous immune cell population, have emerged as a heterogeneous group of cells with distinct gene profiles and immune properties. Activated neutrophils release a spectrum of bioactive substances, including cytokines, chemokines, proteolytic enzymes, reactive oxygen species and neutrophil extracellular traps (NETs), which are composed of decondensed DNA and antimicrobial proteins. NETs have a pivotal role in innate immunity, including in preventing the ascent of uropathogenic bacteria into the kidneys, as they efficiently trap pathogenic microorganisms. However, although indispensable for defence against pathogens, NETs also pose risks of self-damage owing to their cytotoxicity, thrombogenicity and autoantigenicity. Accordingly, neutrophils and NETs have been implicated in the pathogenesis of various disorders that affect the kidneys, including acute kidney injury, vasculitis, systemic lupus erythematosus, thrombotic microangiopathy and in various aetiologies of chronic kidney disease. Pathological alterations in the glomerular vascular wall can promote the infiltration of neutrophils, which can cause tissue damage and inflammation through their interactions with kidney-resident cells, including mesangial cells and podocytes, leading to local cell death. Targeting neutrophil activation and NET formation might therefore represent a new therapeutic strategy for these conditions.

Type 2 diabetes mellitus (T2DM) is associated with impaired leptomeningeal collateral compensation and poor stroke outcome. Neutrophils tethering and rolling on endothelium after stroke can also independently reduce flow velocity. However, the chronology and topological changes in collateral circulation in T2DM is not yet defined. Here, we describe the spatial and temporal blood flow dynamics and vessel diameter changes in pial arteries and veins and leukocyte-endothelial adhesion following middle cerebral artery (MCA) stroke using two-photon microscopy in awake control and T2DM mice. Relative to control mice, T2DM mice already exhibited smaller pial vessels with reduced flow velocity prior to stroke. Following stroke, T2DM mice displayed persistently reduced blood flow in pial arteries and veins, resulting in a poor recovery of downstream penetrating arterial flow and a sustained deficit in microvascular flow. There was also persistent increase of leukocyte adhesion to the endothelium of veins, coincided with elevated neutrophils infiltration into brain parenchyma in T2DM mice compared to control mice after stroke. Our data suggest that T2DM-induced increase in inflammation and chronic remodeling of leptomeningeal vessels may contribute to the observed hemodynamics deficiency after stroke and subsequent poor stroke outcome.

Venous thromboembolism (VTE), which includes pulmonary embolism (PE) and deep vein thrombosis (DVT), is a serious vascular disease that ranks third in cardiovascular-related deaths. Inflammation along with neutrophil extracellular traps (NETs) play a key role in the pathophysiology of VTE. This review focuses on articles that that evaluate the role of NETs in the development of VTE and their potential as therapeutic targets. Research has demonstrated that when NETs become overactivated, they take part in thrombotic activities, which is the opposite of their defensive functions under healthy conditions. When endothelial cells are activated, neutrophils are recruited very early, releasing NETs and initiating a thrombotic process. NETs promote thrombosis by directly activating factor XII (FXII), ultimately triggering platelet recruitment, and initiating the intrinsic coagulant pathway. Subsequently, monocytes and factors such as tissue factor join the process, further increasing NET formation, the inflammatory reactions and progression of venous thrombus. NETs play a crucial part in the intricate interaction between inflammation and thrombosis, where each triggers the other. High levels of NETs also correlate with the severity of VTE. These properties of NETs make them potential therapeutic targets for VTE prevention and treatment. This article aims to describe NETs, their occurrence, and how they relate to VTE. Taking into account what is now known, the function of NETs as targets for treatment in VTE using various approaches, the benefits and drawbacks of these approaches, and suggestions for the future are examined.

Stroke is an injury occurring due to a sudden interruption of blood supply to the brain. It is the leading cause of disability worldwide and the second most prevalent cause of mortality. The objective of this study is whether momentous inflammatory and coagulation markers may have a correlation with each other in stroke patients.

Sixty stroke patients and twenty sex-age matched normal controls were sampled. Interleukin (IL)-6, IL-1β, sP-selectin, and high-sensitivity C-reactive protein (hsCRP), key inflammatory markers, were selected and measured by ELISA, and tissue factor gene expression level was evaluated by real-time PCR in peripheral blood mononuclear cells.

The serum levels of sP-selectin, IL-1β, IL-6, and hsCRP increased significantly in patients (P-value < 0.05). In the patient group, a significant correlation was observed between these inflammatory markers and coagulant tissue factor gene expression in peripheral blood mononuclear cells (P-values < 0.05), while it was not significant in the control group.

This study proposed that the main inflammatory markers in connection with tissue factor may play a role in the occurrence of thrombosis in stroke patients. Therefore, targeting and inhibiting the key inflammatory factors along with existing anticoagulants may greatly reduce the complications associated with stroke.

Lower extremity deep vein thrombosis (LEDVT) is a common vascular disease, with its pathogenesis mainly involving inflammatory responses and oxidative stress. Liquiritin (LIQ) is a flavonoid that exhibits pharmacological effects such as anti-inflammatory and antioxidant properties. This study aimed to investigate the role of LIQ in LEDVT and its potential mechanisms.

We established an LEDVT model in mice by ligating the inferior vena cava (IVC) and performed in vitro experiments by stimulating human umbilical vein endothelial cells (HUVECs) with IL-1β (10 ng/mL) to simulate endothelial cell injury.

We found that LIQ significantly reduced the size and weight of thrombi and decreased the concentrations of inflammatory factors TNF-α and IL-6 in the IVC of LEDVT mice. Furthermore, LIQ inhibited the secretion of prothrombotic mediators such as tissue factor (TF) and vascular cell adhesion molecule-1 (VCAM-1). Administration of LIQ resulted in a notable reduction in immune inflammatory cells in the IVC of LEDVT mice. LIQ also demonstrated antioxidant properties, as the treatment of LIQ enhanced SOD activity and restored ROS levels to normal in the IVC. Similarly, LIQ reduced the formation of inflammatory factors and the secretion of prothrombotic mediators by HUVECs while inhibiting oxidative stress in HUVECs. Finally, LIQ effectively suppressed the levels of phosphorylated p65 in both the IVC and HUVECs.

LIQ reduces inflammatory responses and oxidative stress in LEDVT by inhibiting the NF-κB signaling pathway. This finding provides new insights into the prevention and treatment of LEDVT.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal forms of cancer, characterized by a highly desmoplastic tumor microenvironment. One main risk factor is chronic pancreatitis (CP). Progression of CP to PDAC is greatly influenced by persistent inflammation promoting genomic instability, acinar-ductal metaplasia, and pancreatic intraepithelial neoplasia (PanIN) formation. Components of the extracellular matrix, including immune cells, can modulate this progression phase. This includes cells of the innate immune system, such as natural killer (NK) cells, macrophages, dendritic cells, mast cells, neutrophils, and myeloid-derived suppressor cells (MDSCs), either promoting or inhibiting tumor growth. On one hand, innate immune cells can trigger inflammatory responses that support tumor progression by releasing cytokines and growth factors, fostering tumor cell proliferation, invasion, and metastasis. On the other hand, they can also activate immune surveillance mechanisms, which can limit tumor development. For example, NK cells are cytotoxic innate lymphoid cells that are able to kill tumor cells, and active dendritic cells are crucial for a functioning anti-tumor immune response. In contrast, mast cells and MDSCs rather support a pro-tumorigenic tumor microenvironment that is additionally sustained by platelets. Once thought to play a role in hemostasis only, platelets are now recognized as key players in inflammation and cancer progression. By releasing cytokines, growth factors, and pro-angiogenic mediators, platelets help shape an immunosuppressive microenvironment that promotes fibrotic remodeling, tumor initiation, progression, metastasis, and immune evasion. Neutrophils and macrophages exist in different functional subtypes that can both act pro- and anti-tumorigenic. Understanding the complex interactions between innate immune cells, platelets, and early precursor lesions, as well as PDAC cells, is crucial for developing new therapeutic approaches that can harness the immune and potentially also the coagulation system to target and eliminate tumors, offering hope for improved patient outcomes.

Venous thromboembolism (VTE), encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE), is a complex vascular disorder with high morbidity and mortality, driven by Virchow's Triad: blood stasis, hypercoagulability, and endothelial injury. VTE is now recognized as an inflammatory process involving multiple components. Platelets are involved in the process of VTE, contributing to thrombosis initiation, progression, resolution and recurrence through coagulation activation, and interactions with immune and endothelial cells. Anticoagulation remains the cornerstone of VTE treatment; however, antiplatelet agents like aspirin have demonstrated therapeutic potential, particularly following major orthopedic surgeries. Furthermore, emerging platelet-targeted therapies and biomarkers offer new opportunities for improving VTE diagnosis and treatment. This review explores the evolving role of platelets in VTE pathophysiology, assesses current antiplatelet strategies, and highlights novel therapeutic approaches. Advancing platelet research in VTE may lead to safer, more effective interventions, optimizing outcomes for patients with this life-threatening condition.

This study aimed to analyze risk factors for postoperative VTE in pituitary tumor resection patients, focusing on coagulation indicators and their predictive value. This study collected clinical data from 300 patients who underwent pituitary adenoma resection from January 2021 to August 2023 in the Department of Neurosurgery, the Second Clinical College of the Army Medical University, China. Logistic regression modeling was used to identify risk factors for VTE. Restricted cubic spline curves were used to characterize the dose-response relationship between coagulation-related indicators and the risk of venous thromboembolism. The area under the curve (AUC) was calculated using the receiver operating characteristic (ROC) curve to evaluate the predictive power of coagulation-related indicators. Multivariate analysis showed that D-dimer, platelet count and hemoglobin (Hb) were significant predictors of VTE with OR (95% CI) of 1.967 (1.441-2.808), 1.020 (1.013-1.029), and 0.952 (0.914-0.994), respectively. The AUCs for D-dimer, Platelet Count, and Hb were 0.708, 0.731, and 0.712, respectively. The AUC for combining the three coagulation indices was the largest, 0.838. The combined use of D-dimer, Hb, and platelet count can identify high-risk patients early, enabling timely implementation of antithrombotic strategies.

FXII (coagulation factor XII) is best known for its roles in the contact and kallikrein-kinin pathways. FXII is converted to its active enzyme (FXIIa [activated factor XII]) by PKa (plasma kallikrein) or its unique ability to autoactivate on bacterial or other biologic surfaces. In vivo, FXIIa initiates the intrinsic coagulation pathway and promotes inflammation by reciprocal activation of prekallikrein, which cleaves HK (high-molecular-weight kininogen) to liberate bradykinin. CpaA (coagulation targeting metallo-endopeptidase of A baumannii) is a secreted metalloprotease identified in a human clinical isolate of Acinetobacter baumannii that cleaves FXII at O-linked glycosylated sites, inhibiting contact activation. While CpaA facilitates a modest in vivo fitness advantage in mice, the role of CpaA in human infection remains unclear. As such, the objectives of this study were to characterize the structural details of the interaction between CpaA, FXII, and the KKSs (kallikrein-kinin systems) and to determine the downstream consequences on thromboinflammatory responses.

The effect of purified CpaA on the coagulant activity of FXII and the generation of bradykinin was characterized. Neutrophil signaling, flow cytometry, and functional assays were performed to define how CpaA-mediated cleavage of FXII affects innate immune functions. Bacterial killing by human neutrophils was performed with wild-type and mutant A baumannii strains lacking CpaA.

We found that CpaA cleaves both FXII zymogen and FXIIa but not beta Factor XII. However, cleavage of FXIIa by CpaA does not significantly inhibit its clotting activity, demonstrating that CpaA does not inactivate FXIIa, but rather prevents activation of zymogen FXII. CpaA also cleaves HK, resulting in reduced kallikrein activation and bradykinin generation. We previously identified that zymogen FXII interacts with the urokinase receptor on neutrophils and upregulates neutrophil activation. Here, we demonstrate that CpaA cleaves neutrophil FXII, resulting in reduced Akt2 phosphorylation, chemotaxis, oxidative burst, and neutrophil extracellular trap formation. Importantly, CpaA decreases the human neutrophil killing efficiency of A baumannii in culture.

These data identify a role for FXII in responding to bacterial infection and suggest that by inhibiting the contact and KKSs and impairing neutrophil activation, CpaA may blunt the innate immune response and help prevent the elimination of A baumannii from the human host.

Mounting evidence indicates that lung adenocarcinoma (LUAD) patients are at elevated risk for venous thromboembolism (VTE), presenting a major clinical challenge. This study utilized public databases to identify crosstalk genes (CGs) between LUAD and VTE, applied machine learning methods to discover shared diagnostic biomarkers, and explored their underlying mechanisms.

Disease-specific genes for VTE were extracted from comprehensive genomic databases (CTD, DisGeNET, GeneCards, OMIM), while transcriptomic profiles of LUAD and VTE cohorts were retrieved from GEO via GEOquery implementation. Molecular crosstalk analysis identified candidate genes through differential expression algorithms and disease-association metrics. Functional annotation employed GO and KEGG analyses to elucidate the biological significance of identified CGs. LASSO regression analysis of VTE and LUAD matrices yielded overlapping diagnostic biomarkers. Immune contexture was characterized via CIBERSORT deconvolution, followed by correlation analyses between hub genes and immune infiltration profiles. Hub genes expression was corroborated through independent cohort validation and serological quantification. Diagnostic utility was evaluated through receiver operating characteristic (ROC) curve and nomogram. Therapeutic potential was assessed via DSigDB-based drug sensitivity profiling.

Through transcriptomic analysis, we identified 381 CGs, which demonstrated significant enrichment in inflammatory cascades, immunological processes, and coagulation pathways. LASSO regression analysis of LUAD and VTE cohorts revealed TIMP1 and TMEM132A as putative shared diagnostic biomarkers. TMEM132A exhibited significant correlation with immune cell infiltration patterns across both diseases, modulating the immune microenvironment. Validation cohorts and serological assessment confirmed elevated TMEM132A expression in LUAD and LUAD combined with VTE phenotypes. The diagnostic accuracy of TMEM132A was substantiated by ROC curves and nomogram analyses. Pharmacological sensitivity analysis indicated that TMEM132A may serve as a potential target for the therapeutic agents birabresib and abemaciclib.

TMEM132A demonstrates diagnostic utility as a predictive biomarker for VTE occurrence in LUAD, suggesting its potential role as a susceptibility gene in this patient cohort.

Thrombotic diseases remain the major cause of death and disability worldwide, and the contribution of inflammation is increasingly recognized. Thromboinflammation has been identified as a key pathomechanism, but an unsupervised map of immune-cell states, trajectories, and intercommunication at a single-cell level has been lacking. Here, we reveal innate leukocyte substates with prominent thrombolytic properties by employing single-cell omics measures on human stroke thrombi. Using in vivo and in vitro thrombosis models, we propose a pro-resolving monocyte-neutrophil axis, combining two properties: (1) NR4A1hi non-classical monocytes acquire a thrombolytic and neutrophil-chemoattractive phenotype, and (2) blood neutrophils are thereby continuously recruited to established thrombi through CXCL8-CXCR1 and CXCR2 and adopt a hypoxia-induced thrombus-resolving urokinase receptor (PLAUR)+ phenotype. This immunothrombolytic axis results in thrombus resolution. Together, with this immune landscape of thrombosis, we provide a valuable resource and introduce the concept of "immunothrombolysis" with broad mechanistic and translational implications at the crossroad of inflammation and thrombosis.

Patients with spontaneous intracerebral hemorrhage (ICH) are at high risk of venous thromboembolism (VTE). Recent studies have shown the involvement of neutrophil extracellular traps (NETs) in thrombogenesis.To explore the predictive value of serum MPO-DNA (a NETs surrogate) for VTE and the effect of statins on serum MPO-DNA levels and the VTE incidence in ICH patients.This prospective cohort study enrolled 117 ICH patients and 15 healthy controls. Serum MPO-DNA levels were measured via ELISA. The relationship between serum MPO-DNA levels and VTE risk was analyzed. The predictive value of MPO-DNA was evaluated by ROC curves. Effects of statin on NETs and VTE incidence were evaluated.The median MPO-DNA level in patients with VTE was 0.304 (95% CI: 0.231-0.349), significantly higher than the 0.188 (95% CI: 0.159-0.236) in non-VTE patients. Elevated MPO-DNA levels were associated with an increased VTE risk (OR 7.13, 95% CI 2.58-19.75; P < 0.001), and this association persisted after adjustment. The AUC values for MPO-DNA, CRP, and D-dimer were 0.824 (95% CI: 0.719-0.928), 0.618 (95% CI: 0.481-0.754), and 0.786 (95% CI: 0.683-0.888), respectively. Moreover, statin users exhibited reduced MPO-DNA levels (0.174 vs. 0.218; P = 0.007), though VTE incidence differences (13.8% vs. 19.3%) lacked statistical significance.Serum MPO-DNA serves as a sensitive biomarker for VTE prediction in ICH, highlighting NETs as potential therapeutic targets. Statins could attenuate NETosis, but larger trials are required to validate their clinical efficacy and safety in VTE prevention for ICH patients.

Activated neutrophils release Neutrophil Extracellular Traps (NETs), comprising decondensed chromatin, peroxidases, and serine proteases, which aid in host defense but are also implicated in thrombosis and resistance to thrombolysis. Recombinant DNase 1, which degrades NETs, may aid in thrombus dissolution synergistically with fibrinolytics. However, its short half-life and susceptibility to plasma proteases limit its therapeutic applicability. To address these limitations, DNase1 is encapsulated into polymeric nanoparticles (DNPs) using inverse Flash Nanoprecipitation (iFNP), a scalable nanoparticle synthesis technique. Previously only used with model proteins, the study demonstrates for the first time the feasibility of extending iFNP to the encapsulation of therapeutic proteins. Conditions that promote DNase1 solubility, preserve activity, and demonstrate release resulting in ex vivo NET degradation are detailed. Furthermore, the use of neutrophils, the source of NETs, as carriers for DNPs to enhance targeted delivery is investigated. These findings confirm that DNP-loaded neutrophils maintain key functionalities, including viability and oxidative burst, and associate with in vitro blood clots to deliver nanoparticles, and DNase1 protein. This study not only extends the feasibility of applying iFNP to encapsulate therapeutic proteins into polymeric nanoparticles, a promising alternative to lipid nanoparticles, but also contributes to the emerging literature on neutrophils as delivery vectors for nanocarriers.

Several members of protein disulfide isomerase (PDI) family with the CXYC active motif such as PDI, ERp57, ERp72, ERp46, ERp5 and TMX1 have important roles in platelet functions and thrombosis. These members contribute to the network of redox regulation of platelet activities. However, whether other PDI family members without the CXYC motif such as ERp29, have a role in these processes remains unknown.

To determine the role of ERp29 in platelet functions and thrombosis.

The phenotypes of platelet-specific ERp29-deficient (Pf4-Cre/ERp29fl/fl) mice were evaluated using tail bleeding assay and laser-induced and FeCl3-induced arterial injury models, as well as venous thrombosis model. In vitro, the functions of ERp29-deficient platelets were assessed in respect to aggregation, adhesion, spreading, clot retraction, granule secretion and integrin αIIbβ3 activation measured by flow cytometry. Redox state of integrin αIIbβ3 thiols was detected using 3-(N-maleimido-propionyl) biotin (MPB) labeling.

Compared with WT mice, Pf4-Cre/ERp29fl/fl mice exhibited shortened tail-bleeding times, increased platelet accumulation in the two arterial thrombosis models, and enhanced thrombogenesis in the venous thrombosis model. ERp29-deficient platelets had enhanced response in aggregation, ATP release, spreading, clot retraction, αIIbβ3 activation, fibrinogen binding and P-selectin expression. As detected by MPB labeling, the free thiol content of integrin αIIbβ3 in ERp29-deficient platelets were increased compared with WT platelets, suggesting that the role of ERp29 is associated with oxidation of the functional disulfides of integrin αIIb and/or β3 subunits.

ERp29 is the first disulfide isomerase without the CXYC motif that negatively regulates platelet function. This study provides new insight into the redox network controlling thrombosis.

Inflammation and thrombosis are traditionally considered two separate entities of acute host responses to barrier breaks. While inciting inflammatory responses is a prerequisite to fighting invading pathogens and subsequent restoration of tissue homeostasis, thrombus formation is a crucial step of the hemostatic response to prevent blood loss following vascular injury. Though originally designed to protect the host, excessive induction of either inflammatory signaling or thrombus formation and their reciprocal activation contribute to a plethora of disorders, including cardiovascular, autoimmune, and malignant diseases. In this state-of-the-art review, we summarize recent insights into the intricate interplay of inflammation and thrombosis. We focus on the protective aspects of immunothrombosis as well as evidence of detrimental sequelae of thromboinflammation, specifically regarding recent studies that elucidate its pathophysiology beyond coronavirus disease 2019 (COVID-19). We introduce recently identified molecular aspects of key cellular players like neutrophils, monocytes, and platelets that contribute to both immunothrombosis and thromboinflammation. Further, we describe the underlying mechanisms of activation involving circulating plasma proteins and immune complexes. We then illustrate how these factors skew the inflammatory state toward detrimental thromboinflammation across cardiovascular as well as septic and autoimmune inflammatory diseases. Finally, we discuss how the advent of new technologies and the integration with clinical data have been used to investigate the mechanisms and signaling cascades underlying immunothrombosis and thromboinflammation. This review highlights open questions that will need to be addressed by the field to translate our mechanistic understanding into clinically meaningful therapeutic targeting.

Platelets and neutrophils are among the most abundant cell types in peripheral blood. Beyond their traditional roles in thrombosis and haemostasis, they also play an active role in modulating immune responses. Current knowledge on the role of platelet-neutrophil interactions in the immune system has been rapidly expanding. Notably, circulating platelet-neutrophil complexes (PNCs) have been widely detected in various inflammatory diseases and infections, closely associated with inflammatory processes affecting multiple organs. These findings emphasise the critical role of platelet-neutrophil interactions in driving and sustaining inflammatory responses. In this review, we elucidate the mechanisms by which neutrophils and platelets physically interact, leading to mutual activation. Additionally, activated platelets release pro-inflammatory factors that further modulate neutrophil effector functions, enhancing their immune response capabilities. We highlight the role of platelets in promoting the formation of neutrophil extracellular traps (NETs), which, in turn, promote local platelet activation, thereby exacerbating the immune response and sustaining chronic inflammation. Furthermore, we review current evidence on the role of platelet-neutrophil interactions in common autoimmune diseases such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and rheumatoid arthritis (RA). Finally, we identify gaps in understanding the mechanisms of these interactions in the context of other autoimmune diseases and underscore the potential of targeting platelets and neutrophils as a therapeutic strategy for these conditions.

Stroke, encompassing both ischemic and hemorrhagic subtypes, is a leading cause of mortality and disability globally and current treatments remain limited. Neuroinflammation plays a crucial role in the pathophysiology of stroke, influencing both acute injury and long-term recovery.

This review aims to provide a comprehensive overview of neuroinflammation in stroke, detailing the mechanisms, clinical implications, and potential therapeutic strategies.

A detailed literature review was conducted, focusing on recent advancements in understanding the neuroinflammatory processes in stroke, including the roles of thromboinflammation, blood-brain barrier (BBB) disruption, and the immune response.

The initial ischemic insult triggers an inflammatory cascade involving both innate and adaptive immune responses. BBB disruption allows peripheral immune cells and neurotoxic substances to infiltrate the brain, exacerbating neuronal damage and increasing the risk of infections such as pneumonia and urinary tract infections. Thromboinflammation, characterized by platelet activation and immune cell interactions, further complicates the ischemic environment. Proteomic studies have identified key biomarkers that offer insights into neuroinflammatory mechanisms and potential therapeutic targets. Advances in imaging techniques, such as PET and MRI, enable real-time monitoring of neuroinflammation, facilitating personalized treatment approaches.

Neuroinflammation significantly impacts stroke outcomes, presenting both challenges and opportunities for treatment. Current immunologic therapeutic strategies are limited. Future research should aim to further elucidate the complex immune interactions in stroke, refine imaging biomarkers for clinical use, and develop effective interventions to mitigate neuroinflammation.

The article presents a clinical case of peculiarities of clinical manifestations, diagnostic and therapeutic approaches of undiagnosed chronic myeloproliferative disease, on the background of which Budd-Chiari syndrome (BCS) developed. The results of clinical course, examination, and treatment of a patient with BCS as a manifestation of the hidden course of primary myelofibrosis with the presence of somatic mutation (V617F) in Janus-tyrosine kinase-2 (JAK2) gene in myeloid cells are presented. Standard clinical and laboratory examinations, and cytomorphologic and histologic examination of bone marrow were used. The diagnosis of BCS was confirmed by ultrasound (US) Doppler examination of the portal system vessels. Symptomatic therapy resulted in insignificant positive results. The analysis of this clinical case showed that the development of BCS was due to a chronic myeloproliferative disease that was not diagnosed before the development of thrombosis. Hepatic vein thrombosis was accompanied by the development of fulminant cytolytic syndrome. Along with symptomatic therapy, patient K., female, 32 years old, underwent transjugular intrahepatic portosystemic shunting 1 month after the first symptoms of BCS appeared, which contributed to a significant clinical effect. Seven years after the installation of 4 transjugular intrahepatic portosystemic shunts, the patient's condition remains satisfactory. The uniqueness of this clinical case lies in the presence of 2 serious diseases at the same time: myeloproliferative pathology (primary myelofibrosis) JAK2-positive variant and BCS. Timely diagnosis of both hematological diseases and their complication in the form of hepatic vein thrombosis with fulminant cytolytic syndrome allowed timely prescription of adequate treatment with a good clinical response.

Neutrophils, the most abundant leukocytes in human blood, have long been recognized as critical first responders in the innate immune system's defense against pathogens. Some of the more notable innate antimicrobial properties of neutrophils include generation of superoxide free radicals like myeloperoxidase, production of proteases that reshape the extracellular matrix allowing for easier access to infected tissues, and release of neutrophil extracellular traps, extruded pieces of DNA that ensnare bacterial and fungi. These mechanisms developed to provide neutrophils with a vast array of specialized functions to provide the host defense against infection in an acute setting. However, emerging evidence over the past few decades has revealed a far more complex and nuanced role for these neutrophil-driven processes in various chronic conditions, particularly in cardiovascular diseases. The pathophysiology of cardiac diseases involves a complex interplay of hemodynamic, neurohumoral, and inflammatory factors. Neutrophils, as key mediators of inflammation, contribute significantly to this intricate network. Their involvement extends far beyond their classical role in pathogen clearance, encompassing diverse functions that can both exacerbate tissue damage and contribute to repair processes. Here, we consider the contributions of neutrophils to myocardial infarction, heart failure, cardiac arrhythmias, and nonischemic cardiomyopathies. Understanding these complex interactions is crucial for developing novel therapeutic strategies aimed at modulating neutrophil functions in these highly morbid cardiac diseases.

Deep vein thrombosis (DVT) is a prevalent life-threatening complication among hospitalized patients. DVT is characterized by the hypercoagulability and thromboinflammation in which platelet activation and neutrophil extracellular trap (NET) formation are critically involved. Studies have shown that S100A8/A9 is significantly elevated in patients with DVT, and is closely associated with platelet activation and NET formation. Fucoidan, the marine polysaccharide derived from Fucus algae, has potential anti-inflammatory and cardioprotective effects. We found low-molecular-weight fucoidan (LMF) bound to S100A8/A9 with an equilibrium dissociation constant (KD) of 2.368 × 10-8 M. LMF inhibited S100A8/A9-induced platelet hyperactivity and NET formation in vitro, and ameliorated DVT without significantly perturbing hemostasis in vivo. Our results indicate that the alarmin protein S100A8/A9 is a novel target of LMF. LMF may have therapeutic potential in S100A8/A9-induced thromboinflammation in DVT.

Deep vein thrombosis (DVT) is a frequent complication following endovascular thrombectomy (EVT) in patients with acute ischaemic stroke (AIS), potentially leading to fatal pulmonary embolism (PE). Identifying patients early at high risk for DVT is clinically important. This study developed and validated a nomogram combining laboratory findings and clinical characteristics to predict the risk of lower-extremity DVT after EVT in patients with AIS.

This retrospective multicentre observational study was conducted in two tertiary hospitals in China, enrolling 640 patients who underwent ultrasonography for DVT diagnosis within 10 days following EVT. Data on medical history, examination and laboratory results were collected for logistic regression analyses to develop a DVT risk nomogram.

Logistic regression analyses identified critical predictors of DVT: lower limb National Institutes of Health Stroke Scale (NIHSS) score ≥ 2, elevated D-dimer levels (≥ 1.62 mg/L) and prolonged puncture-to-recanalization time (PRT ≥ 66 min). The nomogram demonstrated good discriminative ability (AUC 0.741-0.822) and clinical utility across internal and external validation cohorts. Additionally, the presence of DVT was significantly associated with reduced functional independence at 90 days post-EVT, highlighting the negative impact of DVT on patient recovery (OR = 3.85; 95% CI: 2.18-6.78; p < 0.001).

The study provides a practical clinical tool for early detection and intervention in patients with AIS at high risk for DVT following EVT. Early identification and intervention may help improve outcomes in patients with AIS undergoing EVT.

This nomogram helps in the early detection and proactive management of DVT in AIS patients, which can reduce severe complications and improve patient recovery outcomes.

No patient or public contributions were involved in this study due to its retrospective design, where data were utilised from existing medical records without direct patient interaction.

The mononuclear phagocytic system is recognized as a major scavenger of mRNA-lipid nanoparticles (LNPs), clearing and redirecting these particles away from their intended targets and thus diminishing their delivery efficacy. Understanding the mechanism by which mRNA-LNPs interact with phagocytes and how this interaction affects the mRNA transfection is critical to enhancing the delivery of mRNA. In this study, we temporarily depleted both circulating and resident macrophages (MF) and evaluated the transfection efficiency and biodistribution of mRNA-LNPs. We first demonstrated the enhanced liver expression using two liver-tropic formulations and the significant improvement of the in vivo gene editing efficiency of CRISPR-Cas9 in the Ai14 mouse model after MF depletion, providing a versatile strategy for enhanced mRNA delivery to the liver regardless of the formulation employed. We then extended our investigations to lung-tropic and lymphoid-tropic LNP formulations and discovered that MF depletion abolishes the targeting capacities of these non-liver-tropic formulations, providing insights into the organ targeting of LNPs. Finally, we screened and compared various clinically relevant MF depletion methods, providing the translation potential of this method on enhanced hepatic delivery of mRNA.

In epidemiological studies, higher leukocyte and platelet counts are associated with increased risk of cardiovascular events. Effects of testosterone replacement therapy (TRT) on leukocyte subsets and platelets in men with hypogonadism and association of circulating leukocyte subtypes and platelets during TRT with cardiovascular events remain unknown.

In the TRAVERSE Trial, 5,204 men, 45-80 years with hypogonadism and preexisting or increased risk of cardiovascular disease (CVD) were randomized to transdermal testosterone or placebo gel daily for up to 5 years. We determined the effect of TRT on neutrophils, monocytes, lymphocytes and platelets and association of changes in leukocyte subtypes and platelets with risk of major adverse cardiovascular (MACE) and venous thromboembolism (VTE) events.

TRT was associated with significantly greater increase in neutrophils and monocytes, and greater decrease in lymphocytes and platelets than placebo. Changes in neutrophil (odds ratio for 1 SD increase in cell count (OR) 1.32 [1.01, 1.73]) and monocyte (OR 1.39 [1.08, 1.79]) counts were associated with increased risk of VTE, accounting for TRT. Neutrophil and monocyte counts at baseline and on-treatment were also associated with increased risk of MACE, adjusting for treatment (baseline: neutrophils OR 1.18 [1.06,1.31], monocytes OR 1.16 [1.05,1.29]; on-treatment neutrophils: OR 1.25 [1.12, 1.40]; monocytes: OR 1.18 [1.06,1.31]).

TRT increased circulating neutrophils and monocytes and decreased lymphocytes and platelets in men with hypogonadism. Changes in monocyte and neutrophil counts were associated with increased risk of VTE. Neutrophil and monocyte counts should be considered when evaluating VTE risk in hypogonadal men treated with TRT.

URL:https://clinicaltrials.gov/study/NCT03518034. Unique identifier: NCT03518034. The study was initially registered on March 5, 2018, and the first participant was enrolled on May 23, 2018.

According to the literature, cardiovascular diseases (CVDs)-including myocardial infarction, stroke, and venous thromboembolism (VTE)-are among the leading causes of mortality and morbidity worldwide. Evidence suggests that CVDs share common risk factors and pathophysiological mechanisms. Similar to the Mosaic Theory of Hypertension proposed by Irvine Page in 1949, the pathophysiology of VTE is multifactorial, involving multiple interacting processes. The concept of immunothrombosis, introduced by Engelmann and Massberg in 2009, describes the interplay between the immune system and thrombosis. Both thrombosis and hemostasis share core mechanisms, including platelet activation and fibrin formation. Additionally, immune mediators-such as monocytes, neutrophil extracellular traps (NETs), lymphocytes, selectins, and various molecular factors-play a critical role in thrombus formation. This review highlights inflammation as a key risk factor for pulmonary embolism (APE). Immunity is central to the complex interactions among the coagulation cascade, platelets, endothelium, reactive oxygen species (ROS), and genetic factors. Specifically, we examine the roles of the endothelium, immune cells, and microRNAs (miRNAs) in the pathophysiology of APE and explore potential therapeutic targets. This review aims to elucidate the roles of the endothelium, immune cells, and miRNAs in the pathophysiology of APE and explore potential future perspective.

This study aims to explore the association between deep vein thrombosis (DVT) of the lower limbs at admission and the time from injury to admission (TFITA), providing clinical references for the prevention of DVT at admission.

Data was collected from patients who were admitted to our hospital for hip fractures between January 2017 and December 2023. Univariable and multivariable logistic regression analyses were conducted to examine the relationship between TFITA and DVT at admission, using both continuous and categorized variables based on thresholds for TFITA. Propensity score matching (PSM) and subanalyses stratified by TFITA and characteristics of DVT at admission were further employed to investigate the relationship. Additionally, restricted cubic splines (RCS) analysis was performed to determine whether a non-linear association exists between TFITA and DVT at admission.

A total of 1230 patients were included in the statistical analysis, comprising 116 patients with DVT at admission and 1114 without. Both Univariable and multivariable logistic regression analyses indicated a positive association between TFITA and DVT at admission before and after matching. Subanalyses revealed significant associations for older age, low-energy injuries, high D-dimer levels, and low platelet counts subgroup with TFITA and DVT at admission. RCS analysis indicated no non-linear relationship between TFITA and DVT at admission.

For patients with hip fractures, longer TFITA is positively correlated with the incidence of DVT at admission. These findings support the potential of TFITA as an intervention strategy for managing DVT at admission.

Venous thromboembolism (VTE) is a grave medical condition characterized by the blockage of distant blood vessels due to blood clots or detached vessel wall fragments, leading to ischemia or necrosis of the affected tissues. With the recent introduction of immunothrombosis, the significance of immune cells in the process of thrombus formation has gained prominent attention. Complex cross-talk occurs between immune cells and blood cells during infection or inflammation, with immune cells actively participating in blood clot formation by promoting platelet recruitment and thrombin activation. Nevertheless, comprehensive studies on the genetic association between immune cells phenotypes and VTE remain scarce. This article employed Mendelian randomization (MR) to investigate the association between the incidence of VTE and a range of 731 immune cell types, along with 91 blood cell perturbation phenotypes, utilizing single nucleotide polymorphisms as instrumental variables.

Through the utilization of publicly available genetic data, a two-sample bi-directional MR analysis was conducted. Sensitivity analyses included Cochran's Q test, MR-Egger intercept test, MR-pleiotropy residual sum and outlier (MR-PRESSO) and leave-one-out analysis. For significant associations, replication analysis was conducted using GWAS data from deep vein thrombosis (DVT) and pulmonary embolism (PE).

We firstly investigated the causal relationship between 731 immune cells and VTE risk. All the GWAS data were obtained from European populations and from men and women. The IVW analysis revealed that CD20 on naive-mature B cell, CD20 on IgD- CD38dim B cell, and CD20 on unswitched memory B cell may increase the risk of VTE (P < 0.05). CD28- CD8dim T cell %T cell, CD64 on monocyte and CD64 on CD14 + CD16- monocyte may be protective factors against DVT (P < 0.05). Then disturbed blood cells types as exposure were analyzed to examine its association with occurrence of VTE. Initial and replication analysis both revealed that environmental KCl-impacted red blood cells and butyric acid-impacted platelet accelerated incidence of VTE (P < 0.05), while colchicine -impacted eosinophil, KCl-impacted reticulocyte and Lipopolysaccharide (LPS) -impacted neutrophil reduced VTE risk (P < 0.05). Sensitivity analyses confirmed the robustness and reliability of these positive findings.

Our study presents evidence of a causal link between six immune cell phenotypes and VTE. Additionally, we have identified two types of blood cells that are associated with both VTE and DVT, and three types of blood cells that are relevant to both VTE and PE.

Not applicable.

Hypercoagulation and thrombin generation are major risk factors for venous thrombosis. Sustained thrombin signaling through protease-activated receptor (PAR) 4 promotes platelet activation, phosphatidylserine exposure, and subsequent thrombin generation. A single nucleotide polymorphism in PAR4 (rs2227376) changes proline to leucine extracellular loop 3, which decreases PAR4 reactivity and is associated with a lower risk for venous thromboembolism (VTE) in a genome wide association studies meta-analysis.

The goal of this study was to determine the mechanism for the association of rs2227376 with a reduced risk of VTE using mice with a homologous mutation (PAR4-P322L).

Venous thrombosis was examined using our recently generated PAR4-P322L mice in the inferior vena cava stasis and stenosis models. Coagulation and clot stability were measured using rotational thromboelastometry. Thrombin-generating potential was measured in platelet-rich plasma. Phosphatidylserine surface expression and platelet-neutrophil aggregates were analyzed using flow cytometry.

Mice heterozygous (PAR4P/L) or homozygous (PAR4L/L) at position 310 had reduced sizes of venous clots at 48 hours. PAR4P/L and PAR4L/L platelets had progressively decreased phosphatidylserine in response to thrombin and convulxin, in addition to decreased thrombin generation and decreased PAR4-mediated platelet-neutrophil aggregation.

The leucine allele in extracellular loop 3, PAR4-322L, leads to fewer procoagulant platelets, decreased endogenous thrombin potential, and reduced platelet-neutrophil aggregation. This decreased ability to generate thrombin and bind to neutrophils offers a mechanism for PAR4's role in VTE, highlighting a key role for PAR4 signaling.

Early failure of a pancreatic allograft due to complete thrombosis has an incidence of approximately 10% and is the main cause of comorbidity in pancreas transplantation. Although several risk factors have been identified, the exact mechanisms leading to this serious complication are still unclear. In this review, we define the roles of the individual components involved during sterile immunothrombosis-namely endothelial cells, platelets, and innate immune cells. Further, we review the published evidence linking the main risk factors for pancreatic thrombosis to cellular activation and vascular modifications. We also explore the unique features of the pancreas itself: the vessel endothelium, specific vascularization, and relationship to other organs-notably the spleen and adipose tissue. Finally, we summarize the therapeutic possibilities for the prevention of pancreatic thrombosis depending on the different mechanisms such as anticoagulation, anti-inflammatory molecules, endothelium protectors, antagonism of damage-associated molecular patterns, and use of machine perfusion.

Portal vein thrombosis (PVT) is commonly encountered in patients with cirrhosis, challenging our understanding of its development, particularly the ambiguous contribution of inflammation. This study utilized Mendelian randomization (MR) to explore the causal impact of circulating inflammatory markers on PVT.Employing a two-sample MR framework, we merged genome-wide association study (GWAS) meta-analysis findings of 91 inflammation-associated proteins with independent PVT data from the FinnGen consortium's R10 release. A replication analysis was performed using a distinct GWAS dataset from the UK Biobank. Inverse variance weighting, MR-Egger regression, weighted median estimator, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier were used for analysis, supplemented by multivariable MR (MVMR) to adjust for cirrhosis effects.Findings indicate a significant inverse association between the genetically inferred concentration of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and PVT risk, evidenced by an odds ratio (OR) of 0.37 (95% confidence interval [CI]: 0.21-0.67; p = 9.2 × 10-4; adjusted for multiple testing p = 0.084). This association was corroborated in the replication phase (OR = 0.39, 95% CI: 0.17-0.93; p = 0.03) and through MVMR analysis (OR = 0.34, 95% CI: 0.15-0.79; p = 0.012). Sensitivity analyses disclosed no evidence of heterogeneity or pleiotropy.Our investigation emphasizes the 4E-BP1 as a protective factor against PVT, underscoring its potential relevance in understanding PVT pathogenesis and its implications for diagnosis and therapy.

Since their discovery in 2004, neutrophil extracellular traps (NETs) have been at the center of multidisciplinary attention. Although a key tool in neutrophil-mediated immunity, these filamentous, enzyme-enriched DNA-histone complexes can be detrimental to tissues and have been identified as an underlying factor in a range of pathological conditions. Building on more than 20 years of research into NETs, this review places thrombosis, the pathological formation of blood clots, in the spotlight. From this point of view, we discuss the structure and formation of NETs, as well as the interaction of their components with the hemostatic system, dissecting the pathways through which NETs exert their marked effect on formation and the dissolution of thrombi. We pay distinct attention to the latest developments in the research of a key player in NET formation, peptidyl-arginine-deiminase (PAD) enzymes: their types, sources, and potential cross-play with the hemostatic machinery. Besides these molecular details, we elaborate on the link between pathological thrombosis, NETs, and widespread conditions that represent a debilitating public health burden worldwide, such as sepsis and neoplasms. Finally, future implications on the treatment of thrombosis-related conditions will be discussed.

Sepsis is a complex syndrome resulting from an aberrant host response to infection. A hallmark of sepsis is the failure of the immune system to restore balance, characterized by hyperinflammation or immunosuppression. However, the net effect of immune system imbalance and the clinical manifestations are highly heterogeneous among patients. In recent years, research interest has shifted from focusing on the pathogenicity of microorganisms to the molecular mechanisms of host responses which is also associated with biomarkers that can help early diagnose sepsis and guide treatment decisions. Despite significant advancements in medical science, sepsis remains a major challenge in healthcare, contributing to substantial morbidity and mortality worldwide. Further research is needed to improve our understanding of this condition and develop novel therapies to improve outcomes for patients with sepsis. This review explores the related signal pathways of sepsis and underscores recent advancements in understanding its mechanisms. Exploration of diverse biomarkers and the emerging concept of sepsis endotypes offer promising avenues for precision therapy in the future.

This retrospective study aimed to investigate the effect of mild-to-moderate COVID-19 on the risk of deep vein thrombosis (DVT) in patients with hip fractures. Hip fractures are common in the elderly, and previous research has shown that they accounted for 58.3% of traumatic fractures in older inpatients during the COVID-19 pandemic in China. Meanwhile, the relationship between COVID-19 and DVT is complex. Some studies have reported that the incidence of DVT in critically ill COVID-19 patients can be as high as 46%, and 20% in those with moderate-to-severe cases. However, the impact of mild-to-moderate COVID-19 on DVT risk in hip fracture patients remains unclear.

Adult patients who underwent surgery for hip fractures between December 8, 2022, and January 9, 2023, were included in the study. All patients were tested for SARS-CoV-2 nucleic acid and were assessed for DVT preoperatively using doppler ultrasonography (DUS). Logistic regression was used to identify risk factors for DVT.

The records of 98 patients with hip fractures, were included in the analysis, of whom 63 were SARS-CoV-2 positive and 35 were SARS-CoV-2 negative. Pre-operative DUS showed that 36/98 patients (37%) had DVT, including 25/63 (40%) patients with COVID-19, and 11/35 (31%) patients without COVID-19. Multivariable logistic regression analysis showed that pre-operative leukocyte count and platelet-to-lymphocyte ratio (PLR) were independent risk factors for DVT, whereas mild-to-moderate COVID-19 was not an independent risk factor for DVT. In patients with hip fractures, COVID-19 did not significantly increase the risk of DVT.

Therefore, in patients with hip fractures, DVT prevention measures should be implemented routinely, regardless of COVID-19 status.

Adults older than 45 years old are at higher risk of developing venous blood clotting known as venous thrombosis/thromboembolism than a cohort <45 years old. Complement activation, which can be mediated by oxidative stress, plays a central role in venous thrombosis. Yet, whether RBCs contribute to complement activation triggering thrombosis in aging and in patients with venous thrombosis/thromboembolism remains an open question. RBCs from healthy Mid-life stage (55-68 years old) adults and patients with venous thrombosis/thromboembolism showed higher deposition of the complement C3 and the anaphylatoxin C3a, and NADPH oxidase (Nox)1 expression than a younger cohort (21-30 years old). Increased C3/C3a deposition on RBCs from mid-life stage adults and patients with venous thrombosis/thromboembolism triggered prothrombin activation via Nox1-dependent reactive oxygen species (ROS) generation, and G protein-coupled receptor kinase 2 (GRK2) activation. Interaction of C3/C3a positive RBCs from mid-life stage adults with endothelial cells led to increased endothelial ROS production. TGF-β1-stimulated GRK2 and Nox1 activation in RBCs from the younger and older adults exacerbated RBC C3/C3a deposition and C3/C3a-mediated prothrombotic activation, which appears to result from ROS-mediated increased RBC phosphatidylserine exposure. Using human RBCs, and Rpl13a snoRNA knockout aged mice, we show that Rpl13a snoRNAs, the master regulators of ROS levels and oxidative stress response, regulate human and murine RBC C3a deposition and prothrombic activation in aging by modulating Nox1 mRNA expression. In vivo Rpl13a snoRNA knockout in aged mice decreased thrombi size by blunting RBC C3a deposition, and RBCs-triggering prothrombin activation. These findings point out to a novel role of RBC Rpl13a snoRNAs in dysregulating RBC ROS-induced C3a deposition promoting venous thrombosis in aging.