Search Results (263)

Dengue is the most prevalent arthropod-borne viral disease, caused by infection with the dengue virus (DENV). Severe dengue is characterized by significant vasculopathy involving a proinflammatory and procoagulant state associated with increased vascular permeability. However, the host–virus interactions driving this process remain incompletely elucidated. Monocytes (Mø) are primary target cells during DENV infection and actively release extracellular vesicles, like microparticles (MPs), mediating intercellular communication, contributing to dengue pathogenesis. Here, we evaluated whether MPs released by DENV-infected monocytes represent a previously underappreciated mechanism contributing to dengue-associated vascular dysfunction. The vascular endothelium plays a determining role in the response to injury because it functions as a regulatory interface during hemostasis (coagulation–fibrinolysis–inflammation) and by preserving the endothelial barrier. We found that these vesicles transport viral proteins (E and NS1), exhibit a procoagulant profile that promotes thrombin generation, and enhance endothelial vascular cell (EVC) activation. DENV-infected THP-1 Mø MPs interaction induces a shift toward a procoagulant, proinflammatory, and proadherent phenotype, characterized by increased expression of PAR-1, TF, ICAM-1, and VCAM-1, reflecting the establishment of a sustained HMEC-1 EVC activation that compromises vascular barrier integrity. This leads to increased permeability, a hallmark of DENV-associated vasculopathy and a central event in the progression to severe dengue. Full article

Background/Objectives: Tissue factor (TF)-expressing cancer cells and their extracellular vesicles (CaCe-dEVs) are key drivers of cancer-associated hypercoagulability and vascular dysfunction. While low-molecular-weight heparins (LMWHs) and direct FXa inhibitors are standard therapies for cancer-associated thrombosis, their direct effects on cancer cell procoagulant potential and endothelial responses remain incompletely defined. This study compared the impact of LMWHs (enoxaparin, tinzaparin), apixaban, and quercetin on cancer cell viability, thrombin generation, and CaCe-dEVs-induced endothelial injury. Methods: Pancreatic (BXPC3) and breast (MCF7) cancer cells and their vesicles were analyzed for TF expression and thrombin generation. Human umbilical vein endothelial cells (HUVECs) were pretreated with each agent prior to vesicle exposure. Cell viability, thrombin generation, and endothelial morphology were assessed using standard assays and microscopy. Results: Tinzaparin and quercetin significantly reduced cancer cell viability, whereas enoxaparin and apixaban showed no cytotoxicity. None of the agents affected HUVEC viability. All suppressed TF-mediated thrombin generation induced by cancer cells, with tinzaparin being most effective in BXPC3 cells. Quercetin exhibited a partial and limited protective effect on endothelial cells against CaCe-dEVs-induced dysfunction, while LMWHs and apixaban did not prevent endothelial damage. Conclusions: These findings suggest that LMWHs, apixaban, and quercetin modulate cancer-cell-driven hypercoagulability beyond anticoagulation, with quercetin and tinzaparin showing additional cytotoxic potential. Such dual effects may reduce thrombosis risk while impacting tumor progression, meriting further investigation. Full article

The recent rise in whole blood usage for traumatic hemorrhagic shock has renewed interest in the impact of leukocytes on hemostatic function during cold storage. This study investigated whether tissue factor (TF)-bearing extracellular vesicles (EVs) are released from human monocytic cells during cold storage or upon rewarming and whether this process is mechanistically linked to apoptosis. We further examined the contribution of superoxide anion generated by NADPH oxidase (NOX). Methods: THP-1 cells were incubated at 4 °C for up to 24 h with/without test reagents and subsequently rewarmed at 37 °C. Cells were washed by centrifugation before rewarming as required. TF activity in the cell supernatant was quantified, EVs were analyzed by flow cytometry with size-defined gating, and NOX activity normalized to p22^phox was measured by cytochrome c reduction. Results: TF levels and apoptotic cells increased during cold storage. TF release was enhanced 1–2 h after cell lavage following cold exposure, indicating active shedding of TF-bearing EVs rather than passive leakage from damaged membranes. Flow cytometry demonstrated that TF-bearing EVs were distinct from apoptotic vesicles, with a substantial proportion falling within the microvesicle size range. Cold exposure enhanced NOX activity. Both superoxide dismutase (SOD) and catalase inhibited TF release during cold storage; however, only SOD suppressed TF release after cell lavage. Conclusions: TF-bearing EVs are actively shed from human monocytic cells during and after cold storage via a NOX-dependent, superoxide-mediated mechanism. Extracellular SOD suppressed this procoagulant EV release, suggesting a potential strategy to modulate hemostatic alterations associated with cold-stored blood. Full article

Venous thromboembolism (VTE) is a clinically significant complication in patients with breast cancer (BC) and may disrupt treatment continuity while contributing to adverse outcomes. Although BC is generally regarded as a relatively low-risk malignancy for VTE compared with several other cancer types, its high incidence and the increasing use of multimodal therapies have resulted in a growing clinical burden of breast cancer-associated VTE. This review summarizes the epidemiological features, risk factors, biological mechanisms, and advances in the prevention and management of breast cancer-associated VTE. Current evidence indicates that patients with cancer have an approximately 4- to 7-fold higher risk of VTE than the general population, with the risk in BC being particularly pronounced during the first 3–6 months after diagnosis. Older age, metabolic comorbidities, advanced disease, and exposure to multiple anticancer therapies have all been associated with an increased risk of VTE. Mechanistically, tissue factor, procoagulant extracellular vesicles, neutrophil extracellular traps, and inflammatory signaling pathways may contribute to breast cancer-associated VTE by promoting coagulation activation and endothelial dysfunction, while also linking thrombosis to immune evasion and Smetastatic progression. Improved identification of high-risk patients, optimization of dynamic risk assessment, and the implementation of individualized prophylactic and anticoagulant strategies may help improve outcomes in patients with BC. Full article

Mesenchymal stromal cells are increasingly used for their immunomodulatory and regenerative properties, yet their interaction with the hemostatic system remains incompletely understood. This review examines the mechanisms through which these cells influence coagulation within the broader framework of immunothrombosis. Evidence from in vitro studies, animal models, and early clinical observations indicates that mesenchymal stromal cells can promote thrombin generation through tissue factor expression and phosphatidylserine exposure, while also engaging complement pathways, platelets, and innate immune responses. Counter-regulatory mechanisms, including adenosine-mediated platelet inhibition and immune reprogramming after cellular clearance, contribute to a context-dependent biological effect. Functional assays, rather than tissue factor expression alone, appear necessary to estimate the effective procoagulant potential of these products. Clinical data suggest that major thrombotic events remain uncommon, although subclinical activation of coagulation pathways may occur. The hemostatic impact of mesenchymal stromal cells depends on multiple variables, including cell source, dose, route of administration, and host inflammatory status. The available evidence supports a working model in which early coagulation and complement activation may be followed by immune modulation, supporting integrated strategies to optimise both safety and therapeutic efficacy. A central conclusion is that tissue factor, although mechanistically necessary for MSC-associated procoagulant activity, is not by itself an independent predictor of clinical thrombotic risk; the effective coagulation response also depends on phosphatidylserine exposure, membrane context, and host inflammatory conditions. Full article

Sickle cell anemia (SCA) is a genetic disorder characterized by chronic hemolysis, primarily driven by red blood cell lysis. Its pathophysiology is centered, though not exclusively, on the increased release of intracellular components, such as hemoglobin degradation products, which are known to stimulate innate immune responses and promote prothrombotic states. Current therapies alleviate symptoms, yet patients remain exposed to a chronic inflammatory milieu punctuated by episodes of acute pain. The recurrence of these crises can be life-threatening due to ischemia–reperfusion injury, hypercoagulability, and respiratory complications. Central mechanisms are marked by elevated hemolysis, heightened inflammatory signaling, and increased procoagulant activity, largely driven by soluble molecules released into the plasma, such as hemoglobin, nuclear molecules and other products. These compounds are recognized from sensors on immune and endothelial cells, named Pattern Recognition Receptors (PRRs), and constitute canonical pathways for intracellular activation. Four main types have been extensively studied in the literature over recent years in both infectious and sterile inflammatory contexts; still, only a few have elucidated the mechanisms underlying acute and chronic inflammation in patients with SCA. Although Toll receptors were shown to be major in triggering immunity, other receptors were found to be important regarding this function, which suggested a multifactorial mechanism for this triggering. Therefore, here, we propose a comprehensive review of previously published findings regarding the expression, activation, and dynamics of Toll-like, NOD-like, and RIG-I–like receptors in the progression of SCA and its associated inflammatory features. Full article

Background: Venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, is increasingly recognized as a thromboinflammatory disorder involving coagulation, innate immunity, endothelial dysfunction, and vascular homeostasis. Emerging evidence suggests that gut microbiome-related inflammatory and metabolic signals may influence pathways potentially relevant to VTE through intestinal barrier dysfunction, microbial translocation, and microbiome-derived metabolites. This review critically examines the direct and indirect evidence relating gut dysbiosis to mechanisms potentially relevant to venous thrombogenesis. Methods: A structured literature search of PubMed, Scopus, and Web of Science was conducted from database inception to February 2026. Observational, translational, experimental, preclinical, and selected genetic studies were narratively synthesized across heterogeneous evidence types. Results: Available evidence suggests that intestinal barrier dysfunction and microbial translocation may increase systemic exposure to lipopolysaccharide and other microbial products, potentially contributing to inflammatory signaling and procoagulant responses. Proposed downstream effects include tissue factor (TF) activation, platelet reactivity, neutrophil extracellular traps (NETs) formation, complement signaling, endothelial perturbation, and impaired balance of anticoagulant and fibrinolytic pathways. Microbiome-derived metabolites, including trimethylamine N-oxide (TMAO), phenylacetylglutamine (PAGln), bile acids, and short-chain fatty acids (SCFAs), have been linked, mainly in experimental or non-VTE settings, to thrombosis-related biology. However, most evidence remains indirect, associative, or experimental, whereas direct human VTE-specific evidence is limited and heterogeneous. Conclusions: The gut microbiome–VTE axis is biologically plausible and supported mainly by mechanistic and indirect evidence, but current data are insufficient to support strong causal conclusions. Further longitudinal, well-phenotyped, mechanistically informed studies are needed to determine whether microbiome-related pathways have measurable clinical relevance in human VTE. Full article

Background: Complicated acute pyelonephritis (AP) is a severe upper urinary tract infection associated with systemic inflammation, organ dysfunction, and the risk of sepsis. The increasing prevalence of antimicrobial-resistant (AMR) organisms can alter clinical management. This study aimed to characterize the biological profile of inpatients with complicated AP and to eventually identify laboratory markers associated with risks of sepsis and AMR infections. Material and Methods: A retrospective observational analysis on 553 adult inpatients diagnosed with complicated AP between 2021 and 2025 was conducted in a tertiary center. Demographic, clinical, and biological parameters were analyzed, including inflammatory markers and renal and hepatic markers. Results: Group characteristics included a mean age of 63.82 ± 15.67 years, and 63% were female. At admission, inflammatory markers were raised, with leukocytosis (15.6 ± 5.8 × 10³/µL), neutrophilia (10.1 ± 4.7 × 10³/µL), and elevated C-reactive protein (CRP) (median 43.2 mg/dL). Coagulation activation was significant with elevated fibrinogen of 747 ± 145 mg/dL and D-dimer with a median level of 1249 ng/mL, of which 58% exceeded 1000 ng/mL. Mild to moderate renal impairment was frequently observed (creatinine 1.69 ± 0.76 mg/dL). In multivariate analysis, no biological parameter proved to be an independent predictor of AMR status among organisms. Discussion and Conclusions: Inpatients with complicated AP showed a pronounced inflammatory and procoagulant biological profile that did not vary between AMR pathogen and non-AMR pathogen infections. This suggests that the clinical value of biomarkers, such as leukocyte and neutrophile, CRP, D-dimer, fibrinogen, procalcitonin, urea, and creatinine, lies primarily in assessing disease severity rather than predicting antimicrobial resistance. The microbiological profile was dominated by Gram-negative pathogens, particularly Escherichia coli, although a heterogeneous spectrum of microorganisms was identified. Full article

Background and Objectives: Intrauterine growth restriction (IUGR) affects 5–10% of pregnancies and is associated with increased perinatal morbidity and long-term complications for the neonate. Extracellular vesicles (EVs), and in particular, microparticles (MPs), have emerged as potential biomarkers of pregnancy complications; however, the literature on their role in neonates remains limited. To investigate the functional characteristics, concertation in maternal blood and potential role of MPs in IUGR. Materials and Methods: PubMed, Scopus and preprint servers were systematically searched for studies on MPs in correlation with IUGR from 1 August until 18 September 2025. Data on MP characteristics and concentration in maternal blood samples in the context of IUGR were collected. The systematic review is registered in PROSPERO (CRD420251156939). Results: A total of 12 studies fulfilled the inclusion criteria and were included in the review. In IUGR-complicated pregnancies, circulating MPs exhibited preserved procoagulant activity despite minimal quantitative differences compared to controls. Platelet-, endothelial-, and placenta-derived MPs were most frequently studied. Clinically, elevated AV+ placenta-derived MPs were associated with increased risk of IUGR, whereas MPs from isolated IUGR pregnancies showed limited predictive value. Conclusions: MPs play a crucial role in the pathophysiology of IUGR through their interplay in coagulation, inflammation, and vascular dysfunction. They show potential as predictive biomarkers, particularly in cases of preeclampsia-associated IUGR, reflecting systemic maternal endothelial and inflammatory changes. However, their utility in isolated IUGR appears limited, likely due to the predominantly local placental origin of the pathology. Full article

Background/Objectives: Patients with severe hemophilia A on prophylaxis with emicizumab exhibit a mild/moderate bleeding phenotype that requires the use of either recombinant FVIII (rFVIII) or bypassing agents (BPAs) in patients with inhibitors, in the case of breakthrough bleeding or surgery. Since factor IX (FIX) limits the formation of the FIXa–emicizumab–FX complex, exogenously added FIX might enhance complex formation and thrombin generation. This study aimed to compare the procoagulant effects of various FIX concentrates with recombinant activated FVII (rFVIIa), activated prothrombin complex concentrate (aPCC), and rFVIII in SHA patients with and without inhibitors under emicizumab prophylaxis. Methods: Hemostatic changes were monitored using two optimized global coagulation assays: rotational thromboelastometry and calibrated automated thrombin generation. Tubes containing corn trypsin inhibitor (CTI) were used during blood collection to prevent activation. Low concentrations of tissue factor (TF) were used to trigger coagulation in both assays. Results: Ex vivo addition of recombinant FIX concentrates significantly increased the procoagulant activity of emicizumab, achieving levels comparable to therapeutic doses of rFVIIa or rFVIII, and the proportion of active FIXa within the concentrates is a major contributor to their procoagulant function. We assessed the influence of FVIII inhibitors on the hemostatic efficacy of rFIX concentrates and BPAs, finding that rFIX-induced thrombin generation increased in the presence of inhibitors, and no significant differences were observed with BPAs. Conclusions: These findings suggest that FIX concentrates could be an effective alternative to BPAs for emicizumab-treated patients, particularly those with inhibitors. Further studies are needed to confirm their in vivo efficacy and to evaluate thrombotic risk. Full article

Objectives: Head and neck tumors have been associated with varying risks for venous thromboembolism (VTE). Through a cross-tumor comparison, we assessed site-specific coagulation-related gene expression changes in head and neck squamous cell carcinoma (HNSCC) compared to squamous cell tumors in the esophagus (ESCCa) and lung (LUSC). Further, we assessed the relationship between clinicopathologic features of HNSCC and coagulome gene expression. Methods: RNA-sequencing data from primary tumor tissues of HNSCCa, ESCCa, and LUSC were obtained from The Cancer Genome Atlas (TCGA). Three previously identified pro-thrombotic genes (F3, SERPINE1, and SERPINB2) were analyzed and, for pan-cancer comparisons, gene expression was Z-standardized and summarized as a composite coagulome score. For HNSCCa-specific analyses, gene expression was compared using log2 RSEM counts, contrasting between HPV status, primary tumor site, tumor stage, grade, and demographic characteristics. Results: HNSCCa demonstrated the highest composite coagulome activation (mean Z-score = 0.29, 95% CI: 0.23–0.35) compared with LUSC and ESCCa (mean Z-scores = −0.27 and −0.16, respectively; p < 0.001). Among 487 HNSCCa tumors, HPV-negative tumors exhibited significantly higher composite coagulome expression than HPV-positive tumors (mean ± SD, 11.25 ± 1.39 vs. 10.14 ± 1.30; p < 0.001). Oral cavity tumors demonstrated the highest coagulome expression, while oropharyngeal tumors were most suppressed. Higher histologic grade was inversely associated with coagulome expression (p < 0.001). Patient age, sex, and race were not significantly associated with coagulome expression. Conclusions: HNSCCa exhibits a tumor-specific pro-thrombotic expression profile with substantial heterogeneity driven by HPV status and primary tumor site. Despite elevated tumor-specific pro-coagulant signaling, these findings reflect tumor-specific pro-thrombotic potential rather than clinical VTE risk in HNSCCa, which likely remains context-dependent and may require additional inflammatory or treatment-related triggers to clinically manifest. Full article

Background: Thrombocytopenia is traditionally perceived as a bleeding-predominant condition; however, growing evidence indicates that many thrombocytopenic states are paradoxically associated with an increased risk of venous and arterial thrombosis. This dual hemostatic derangement poses major therapeutic challenges when anticoagulant or antiplatelet therapy is indicated, particularly in complex settings such as cancer-associated thrombosis, immune thrombocytopenia, and advanced liver disease. Methods: We conducted a narrative review of the literature published between January 2021 and May 2025 using PubMed and guideline repositories. Search terms included thrombocytopenia, anticoagulation, antiplatelet therapy, cancer-associated thrombosis, immune thrombocytopenia, and cirrhosis. International guidelines from ASH, ISTH, ASCO, EHA, ESC, and AHA were prioritized. Evidence was synthesized to define platelet-based safety thresholds and disease-specific management strategies. Results/Discussion: Thrombocytopenia does not uniformly confer protection against thrombosis. Platelet activation, endothelial dysfunction, inflammatory signaling, impaired fibrinolysis, and procoagulant microparticles contribute to a prothrombotic milieu despite reduced platelet counts. Most guidelines support full-dose anticoagulation at platelet counts ≥ 50 × 10⁹/L, with dose modification between 25 and 50 × 10⁹/L and treatment interruption below 25 × 10⁹/L, depending on thrombotic risk. Antiplatelet therapy requires stricter individualization, particularly regarding dual antiplatelet therapy. Conclusions: Management of antithrombotic therapy in thrombocytopenic patients requires a dynamic, individualized approach balancing ischemic and bleeding risks. Pragmatic algorithms may guide clinical decision-making while prospective data remain limited. Full article

Background/Objectives: In clinical practice today, platelet concentrates are often used for topical surgical applications. They are biomaterials that can accelerate healing processes associated with oral and maxillofacial surgery as well as in several other clinical applications through the action of growth factors released by platelets at the surgical site. However, in most cases, the exact quantification of the released growth factors is challenging in both the short and long term. The aim of this study was to determine if early platelet activation and degranulation occur during the collection and utilization of platelet-rich plasma (PRP) in the surgical room, where, before its application, PRP undergoes a procedure of gelification via reactions with procoagulant agents. Methods: PRP was prepared from the blood samples of 39 patients following the modified Whitman protocol. The samples were then analyzed at four different time points (1, 6, and 24 h during preparation and clinical application in the surgery room) using flow cytometry and enzyme-linked immunosorbent assays (ELISAs) to investigate the platelet activation/degranulation and TGFβ release in the supernatant (SN) during storage and clinical application. The mean platelet count in the whole blood was 267.5 ± 48.58 × 10³/mL (range: 189–334 × 10³/mL), and the mean concentration was 2925.5 ± 833.37 × 10³/mL (range: 748–3453 × 10³/mL). Results: The activation and degranulation of platelet cells (measured via monoclonal antibodies: CD62p and CD63, respectively) demonstrated a progressive increase at 1 h, 6 h, 24 h, and after gelification. The TGFβ dosage in the supernatant (SN) at different times exhibited a similar trend, with a mean release of 18.36 ng/mL at 1 h, 21.96 ng/mL at 6 h, and 29.45 ng/mL at 24 h. After the gelification of the PRP, a significant reduction was observed, with a value of 15.52 ng/mL. Conclusions: The results reveal that the protocol used for the preparation, storage, and application of the PRP ensures a good-quality hemoderivative and that the platelet concentrate must be applied with the correct timing to support tissue healing processes. Full article

Isothiazolinones are commonly used biocides that are extensively used in industrial areas and household products. The extensive usage of isothiazolinones raises concerns regarding their adverse human health effects. Isothiazolinones are readily absorbed and enter circulation. However, the potential systemic effects of isothiazolinones on the circulatory system remain unclear. Here, we examined whether the isothiazolinones, benzisothiazolinone (BIT) and octylisothiazolinone (OIT) affected platelets. In isolated platelets, BIT and OIT depleted intracellular glutathione, which led to mitochondrial reactive oxygen species (ROS) accumulation. Excessive mitochondrial ROS led to mitochondrial dysfunction, altering intracellular calcium and adenosine triphosphate homeostasis. These intracellular events activated phospholipid scramblase, externalizing phosphatidylserine, thereby enhancing procoagulant activity, as evidenced by thrombin generation. Overall, OIT showed a more potent effect than BIT. Notably, supplementation with N-acetyl-L-cysteine mitigated BIT- and OIT-induced effects, suggesting a thiol-dependent mechanism. Taken together, BIT and OIT stimulated the platelet-mediated coagulation pathway, which may increase prothrombotic risk and contribute to cardiovascular disease. These results could improve our understanding of the systemic adverse effects after isothiazolinone exposure. Full article

Fiber-forming polymers are increasingly used to control blood coagulation, either by accelerating the onset of hemostasis or by limiting thrombogenic events in contact with blood. Despite rapid progress in materials engineering, a unified view linking the molecular mechanisms of the coagulation cascade with specific design strategies of procoagulant and anticoagulant polymeric fibers is still missing. In this review, we summarize current knowledge on how natural and synthetic polymers interact with plasma proteins, platelets, and coagulation factors, emphasizing the role of fiber morphology, surface chemistry, charge distribution, and functionalization. Particular attention was paid to systems based on natural polysaccharides (e.g., chitosan, alginate, and cellulose derivatives), as well as synthetic polymers (e.g., PLA, PCL, polyurethanes, and zwitterionic materials). Two possible courses of action were described: their bioactivity may activate the contact pathway and/or support platelet adhesion or their ability to minimize protein adsorption and inhibit thrombin generation. We discuss how metal–polymer coordination, surface immobilization of heparin or nitric oxide donors, and nanoscale texturing modulate coagulation kinetics in opposite directions. Finally, we highlight emerging fiber-based strategies for achieving either rapid hemostasis or long-term hemocompatibility and propose design principles enabling precise tuning of coagulation responses for wound dressings, vascular grafts, and blood-contacting devices. This general compendium of knowledge on blood–material interactions provides a foundation for further design of biomaterials based on fiber-forming polymers and the development of manufacturing processes. Full article