Search Results (122)

Essential oils (EOs) are complex plant-derived mixtures increasingly investigated for their anti-inflammatory, antioxidant, and vasoprotective properties. Thromboinflammation, a process integrating coagulation, platelet activation, endothelial dysfunction, and inflammatory signaling, plays a central role in vascular pathology; however, the contribution of EOs to this process remains insufficiently characterized. This narrative review aims to synthesize current molecular and experimental evidence regarding the effects of EOs and their major bioactive constituents on pathways converging toward thromboinflammation. A focused PubMed/MEDLINE search, supplemented by manual reference screening, was conducted to identify experimental and translational studies on EOs and selected constituents relevant to inflammatory mediators, oxidative stress, endothelial dysfunction, platelet activation, and thrombotic pathways. Available data from predominantly preclinical experimental models indicate that EOs can exert multi-target effects, including modulation of cytokine production, attenuation of oxidative stress, improvement in endothelial function, and inhibition of platelet aggregation, thereby influencing key components of thromboinflammatory pathways. Despite these promising findings, heterogeneity in chemical composition, limited standardization, uncertain exposure relevance, and the predominance of preclinical data remain important limitations. In conclusion, EOs represent a promising but still largely preclinical class of natural compounds capable of modulating interconnected mechanisms relevant to thromboinflammation; however, further translational and clinical studies are required to validate their therapeutic potential. Full article

Acute coronary syndromes (ACS) remain time-critical clinical emergencies in which early diagnosis and accurate risk stratification determine management and outcomes. Although symptoms, electrocardiography, and high-sensitivity cardiac troponin (hs-cTn) provide a reliable framework for detecting myocardial injury, they offer limited insight into plaque instability, thromboinflammatory activity, vascular repair, and post-infarction remodeling. In this narrative review, we examine the biological rationale and current clinical evidence supporting brain-derived neurotrophic factor (BDNF) as a candidate biomarker in ACS, with particular attention to pre-analytical, analytical, and phenotypic sources of heterogeneity. Available studies show that circulating BDNF concentrations vary substantially according to biological matrix, timing of sampling, ACS subtype, and assay methodology, which likely contributes to inconsistent findings across cohorts. Overall, current evidence does not support BDNF as a diagnostic alternative to hs-cTn in rule-in or rule-out pathways. However, BDNF may have value in biological phenotyping and risk stratification by reflecting platelet activation, endothelial dysfunction, inflammatory signaling, and remodeling processes after ACS. Further progress will require standardized pre-analytical procedures, separate assessment of mature BDNF and proBDNF, serial sampling, and validation in large multicenter studies. Full article

Cerebral ischemic stroke is caused by impaired blood flow to the brain parenchyma due to acute vessel occlusion. Although current therapies focusing on rapid restoration of blood flow achieve high rates of recanalization, outcomes remain unfavorable in a significant proportion of patients. Part of this discrepancy is due to intravascular inflammation driven by thrombo-inflammatory mechanisms that add to cerebral tissue loss. Despite being an inevitable consequence of vessel occlusion, altered shear stress remains largely overlooked as a contributor to endothelial dysfunction in stroke. To directly assess the impact of disturbed flow on the endothelial phenotype, human brain endothelial cells were cultured under controlled flow conditions using an ibidi pump system and exposed to flow alternating in both magnitude and direction. Subsequently, the expression of key endothelial proteins, including Claudin-5, PECAM-1, CD62e and endoglin, was analyzed. We show here that the sequence of shear-stress modulation, recapitulating the hemodynamic conditions of large-vessel occlusion and subsequent reperfusion in stroke, is sufficient to cause an inflammatory phenotype in human brain endothelial cells. In addition, we demonstrate that platelet activation induces the mechanosensors Piezo1 and syndecan-1, sensitizing brain endothelial cells to shear-stress alterations characteristic of ischemic stroke. Targeting shear-stress-mediated inflammatory activation of the brain endothelium may therefore offer a complementary strategy in stroke therapy, particularly in large-vessel occlusion with abrupt flow changes. Full article

Clonal hematopoiesis refers to the clonal expansion of hematopoietic stem and progenitor cells, driven by somatic mutations. Major mutated genes in clonal hematopoiesis include genes involved in epigenetic regulation including DNA methylation and/or chromatin modification (e.g., DNMT3A, TET2, and ASXL1), tumor suppressors (e.g., TP53), signal transduction (e.g., JAK2), and RNA splicing (e.g., SF3B1 and SRSF2). Clonal hematopoiesis includes clonal hematopoiesis of indeterminate potential (CHIP), clonal cytopenia of unknown significance (CCUS), and myelodysplastic syndromes/neoplasms (MDS). CHIP occurs when the frequency of the variant allele equals or exceeds 2% (4% for X-linked genes in males) in the absence of cytopenias. CHIP is common among older persons and is associated with an increased risk of hematologic cancer. CHIP is also associated with an increased risk of atherosclerotic disease including acute myocardial infarction, stroke, cardiac failure, and abdominal aneurysm. Increasing evidence suggests that CHIP is associated with venous thromboembolic disease. Somatic mutations lead to proliferation of hematopoietic progenitor cells and their progeny, resulting in excessive activation of granulocytes and monocytes. It could be postulated that chronic inflammation caused by clonal expansion of myeloid cells carrying mutations in DNMT3A, TET2, and ASXL1 (“DTA”) genes may constitute an independent risk factor in clot formation and endothelial-cell damage. DTA mutations correlate with elevated proinflammatory cytokines such as IL-1β and IL-6 and enhanced activation of inflammasomes. Moreover, JAK2 mutations may have a direct role in the activation of platelets and coagulation. In vivo murine studies have demonstrated that activation of the JAK-STAT signaling pathway promotes neutrophil extracellular trap (NET) formation, contributing to a prothrombotic state. Insights from related clonal disorders such as paroxysmal nocturnal hemoglobinuria and the VEXAS syndrome support the concept that mutation-driven innate immune activation can directly perturb hemostatic balance. This review aims to summarize the association between clonal expansion of hematopoietic cells and thrombotic disease, and highlight how somatic mutations in hematopoietic cells may contribute to vascular disease and thrombogenesis. Full article

The neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) have emerged as potent modulators of immune responses during sepsis, yet their roles remain complex, alternating between protective and permissive depending on timing, tissue compartment, and inflammatory context. This review presents a historical assessment of VIP and PACAP in sepsis research, highlighting the evolution of conceptual advances across five decades. Starting in the 1980s, early studies revealed that VIP levels rise during endotoxemia and correlated with hypotension and mortality, suggesting a deleterious role. By the 1990s, research pivoted toward understanding gut-derived VIP and its interaction with nitric oxide, culminating in the classification of VIP and PACAP as “macrophage deactivating factors” that downregulate TNFα and IL-6. The 2000s further clarified their cell-specific actions through VPAC1/2 and PAC1 receptors, showing anti-inflammatory effects on both innate and adaptive immune cells, while illuminating delivery challenges overcome by liposomal encapsulation. The 2010s expanded this narrative by dissecting receptor dynamics, gut barrier regulation, and VIP’s role in neuroimmune crosstalk and thrombo-inflammation. Most recently, studies in the 2020s provide a nuanced view of how VIP suppresses inflammatory damage but also enables pathogen persistence during live bacterial infection, implicating VIP signaling in trade-offs between tolerance and clearance. Across this chronological framework, VIP and PACAP have oscillated between friend, foe, and frenemy, underscoring the importance of context in leveraging their therapeutic potential in sepsis. Full article

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by persistent low-grade inflammation and a markedly increased risk of cardiovascular diseases (CVD). Leukocytes play an important role not only in host defense but are also increasingly recognized as key contributors to haemostasis and thromboinflammatory processes. In DM, chronic hyperglycaemia, oxidative stress and inflammation lead to leukocyte dysfunction, including enhanced cell activation, impaired mitochondrial function, and dysregulated interactions with platelets and endothelial cells. These alterations promote the thromboinflammatory state that contributes to vascular complications in DM. Thus, the modulation of oxidative stress and inflammation are important. Polyphenols are a class of plant secondary metabolites widely studied for their antioxidant and anti-inflammatory properties. This review comprehensively explores leukocyte dysfunction in DM, its contribution to thromboinflammation, and the mechanistic role of polyphenols in modulating these processes. The evidence presented suggests that polyphenols may contribute to the modulation of thromboinflammatory pathways. Further research in this area is required to enhance our understanding of thromboinflammation in DM and to translate these findings into effective adjunctive strategies, alongside standard pharmacological therapies to reduce CVD risk in individuals with DM. 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

Endovascular therapies have transformed cardiovascular medicine, yet restenosis, thrombosis, and device failure remain common and poorly predictable complications. Increasing evidence suggests that immunothrombotic processes critically shape vascular recovery after device implantation. This includes neutrophil extracellular trap (NET) formation, innate immune polarization, and endothelial damage responses. Concurrently, advances in artificial intelligence (AI) are increasingly enabling continuous multimodal monitoring and adaptive clinical decision-making throughout the medical device life cycle. Here, we propose the concept of immunologically adaptive endovascular devices: a closed-loop paradigm in which patient immune status informs device selection, device–tissue interactions are interpreted via mechanistic biomarkers, and real-world monitoring dynamically updates risk and management. The study introduces (i) an immune–device interaction phenotype taxonomy linking device design features to measurable thrombo-inflammatory trajectories, (ii) a mechanistic framework defining interface signaling processes that enhance or resolve NET-driven responses, (iii) a minimum evidence model encompassing preclinical testing, clinical validation, and post-market surveillance, and (iv) a reference AI architecture for risk prediction, drift detection, and safety monitoring. This study also outlined testable predictions and a translational roadmap toward precision endovascular intervention and next-generation adaptive cardiovascular devices. Full article

Factor XII (FXII) is a central mediator at the intersection of coagulation, fibrinolysis, inflammation, and immunity. It is activated upon contact with negatively charged surfaces, triggering the intrinsic coagulation pathway and driving thrombus formation and stabilization. Beyond clotting, FXII contributes to activation of the kallikrein–kinin system, generation of bradykinin, and modulation of inflammatory and immune responses. Congenital FXII deficiency does not increase bleeding risk, highlighting its unique role and making FXII inhibition an attractive strategy for anticoagulation and immune modulation with a potentially superior safety profile. Preclinical studies provide compelling evidence for this concept. In models of ischemic stroke and traumatic brain injury, FXII blockade significantly reduced infarct volume, improved neurological outcomes, and attenuated neuroinflammation without increasing hemorrhage. Similarly, in extracorporeal circulation and vascular stent implantation, FXII inhibition prevented thrombus formation and reduced fibrin deposition, achieving effects comparable to heparin but with markedly lower bleeding risk. Several classes of FXII inhibitors are currently in development, including antisense oligonucleotides, peptides, recombinant proteins, and monoclonal antibodies. Among them, Ixodes ricinus contact phase inhibitor (Ir-CPI) and recombinant human albumin-fused Infestin-4 (rHA-Infestin-4) have demonstrated strong antithrombotic efficacy in animal models. Most notably, garadacimab, a monoclonal anti-FXIIa antibody, has completed phase 3 trials and received regulatory approval for hereditary angioedema (HAE) prophylaxis, where it markedly reduces attack frequency with a favorable safety profile. This review summarizes current knowledge on FXII biology and evaluates its translational potential as a novel target for anticoagulant and anti-inflammatory therapies. Full article

Pregnancy represents a distinct immunological and physiological state that modifies maternal susceptibility to SARS-CoV-2 and influences the clinical and biological course of COVID-19. Accumulating evidence indicates that the interaction between viral entry determinants, gestation-specific immune modulation, placental endocrine–angiogenic pathways, and systemic inflammatory responses underlies the characteristic manifestations of SARS-CoV-2 infection during pregnancy. This review consolidates current understanding of SARS-CoV-2 viral structure, receptor biology, and the gestational regulation of key entry cofactors, including ACE2, TMPRSS2, NRP1, CTSL and FURIN, within reproductive and placental tissues. The review further integrates documented mechanisms of cytokine-mediated immune dysregulation, endothelial injury, thrombo-inflammation, and steroidogenic alteration observed in affected pregnancies, and examines their contribution to placental malperfusion, preeclampsia-like presentations, fetal growth abnormalities and preterm birth. Published molecular and computational studies characterising trophoblast antiviral defenses, receptor expression patterns, and structural determinants of Spike–ACE2 affinity are synthesised to contextualise the biological basis of placental susceptibility and the rarity of confirmed transplacental transmission. Current evidence on maternal clinical outcomes, fetal and neonatal consequences, vaccination efficacy, therapeutic considerations and contemporary management guidelines is also critically reviewed. By integrating molecular, immunological, pathological and clinical insights, this article provides a comprehensive framework for understanding the interaction between SARS-CoV-2 infection and pregnancy-specific physiology, with implications for risk assessment, preventive strategies and maternal–fetal care. Full article

Background and Objectives: Severe COVID-19 frequently fulfills Sepsis-3 criteria and is characterized by thrombo-inflammation and endothelial injury. We evaluated whether a bedside endothelial activation index (EAI = D-dimer/fibrinogen) identifies biologically distinct phenotypes and relates to interleukin-6 (IL-6) response after therapeutic plasma exchange (TPE), and whether baseline IL-6 predicts a ≥50% IL-6 reduction. Methods: Retrospective single-center ICU cohort of adults with SARS-CoV-2 infection, sepsis-related organ dysfunction, and ≥1 TPE session (n = 51). Patients were stratified by median EAI (low vs. high). Outcomes included peri-procedural biomarker/physiology changes (post–baseline), IL-6 responder status (≥50% reduction), correlations with IL-6 reduction (%), and multivariable predictors of response. Results: Compared with low EAI (n = 25), high EAI (n = 26) had higher baseline D-dimer (6.2 vs. 2.2 µg/mL) and lower fibrinogen (2.9 vs. 7.1 g/L) (both p < 0.001). Low EAI showed larger CRP decreases (ΔCRP −84.0 vs. −2.3 mg/L; p = 0.001) and larger fibrinogen falls (Δ −3.1 vs. −0.4 g/L; p < 0.001), while high EAI had larger D-dimer decreases (Δ −2.5 vs. −0.6 µg/mL; p = 0.004) and a modest SOFA improvement (Δ −0.3 vs. +0.1; p = 0.026). IL-6 responders (n = 20) had higher baseline IL-6 than non-responders (365.2 vs. 47.1 pg/mL; p < 0.001). Baseline IL-6 independently predicted response (per doubling: OR 1.94, 95% CI 1.27–2.95; p = 0.002), while age reduced odds (OR 0.91/year, 95% CI 0.84–0.99; p = 0.032). IL-6 reduction correlated with ΔCRP (ρ = −0.41; p = 0.003) and ΔPaO₂/FiO₂ (ρ = 0.37; p = 0.01). Conclusions: EAI stratifies distinct thrombo-inflammatory patterns around TPE, while baseline IL-6 is the dominant predictor of achieving large IL-6 reductions. To emphasize the novelty and clarify the study objective, this exploratory analysis used a phenotype-stratified framework to test whether a simple bedside endothelial activation index could enrich biological response assessment to adjunctive TPE. The prespecified primary outcome was achievement of a ≥50% IL-6 reduction after completion of the TPE course; secondary outcomes included peri-procedural biomarker, oxygenation, SOFA, and ICU endpoints. Full article

COVID-19 not only affects the respiratory system but also increases the risk of cerebrovascular complications, including ischemic stroke. Experimental and clinical data suggest that cytokine dysregulation and polymorphisms of thrombophilia-related genes (MTHFR, MTR, and MTRR) may jointly promote hypercoagulation, endothelial dysfunction, and thromboinflammation, thereby contributing to post-COVID ischemic stroke. This study included 160 patients treated at Zangiota Infectious Diseases Hospitals (2021–2023): 60 patients with ischemic stroke in the acute or post-COVID period (experiment group), 50 COVID-19 patients without ischemic stroke (comparison group), and 50 ischemic stroke patients without COVID-19 (control group). Clinical–neurological and immunological parameters were assessed, and polymorphisms in thrombophilia/folate cycle genes (MTHFR C677T, MTR, and MTRR) were genotyped by PCR/real-time PCR. Statistical analysis included χ² tests, t-tests, logistic regression with odds ratios (OR) and 95% confidence intervals (CI); Hardy–Weinberg equilibrium was verified. A strong association was identified between the MTHFR C677T polymorphism and ischemic stroke on the background of COVID-19 (OR = 5.4; 95% CI: 2.1–13.8; p < 0.001). The TNF-α rs1800629 polymorphism was also significantly associated with COVID-19-related cerebrovascular events (OR = 3.27; 95% CI: 1.4–7.6; p = 0.006). Carriage of two or more minor alleles produced a synergistic effect, markedly increasing the risk of post-COVID ischemic stroke (OR = 5.59; 95% CI: 2.3–13.6; p < 0.001). These polymorphisms were linked to hyperhomocysteinemia, endothelial dysfunction, and mechanisms contributing to multifactorial arterial ischemic events. The combined assessment of thrombophilia and folate cycle-related genotypes and clinical indicators may provide a potential framework for improved risk stratification. Polymorphisms in MTHFR may appear to represent important genetic determinants of ischemic stroke following COVID-19, particularly in the context of arterial ischemic mechanisms. Full article

Flap reconstruction remains a cornerstone after oncologic resection, trauma, and complex wounds, yet partial necrosis, venous congestion, and delayed healing continue to drive morbidity and unplanned re-exploration. Even when macroscopic inflow and outflow are re-established, distal and border-zone tissue may remain constrained by microcirculatory dysfunction. This review frames flap compromise as a biomimetics-relevant failure of a hierarchical transport network and summarizes the vascular repair mechanisms that regenerative interventions aim to replicate. We outline key concepts governing flap perfusion, including angiosomes, choke vessels, endothelial barrier failure, mural cell support, and immune regulation within the angiogenic niche, and relate these to no-reflow, thrombo-inflammation, and impaired vascular regeneration. We then synthesize regenerative strategies aimed at durable reperfusion, spanning recombinant factors, gene and nucleic acid delivery, cell-based therapies, cell-free biologics, including extracellular vesicles and platelet-derived products, pharmacologic modulators, and biomaterial platforms that localize and sustain bioactivity. Translation will require functional perfusion endpoints, standardized reporting of delivery parameters, and safety-conscious designs that minimize aberrant angiogenesis and vector-related risks in post-resection settings. Full article

Platelet hyperreactivity is a central driver of thromboinflammatory diseases, including ischemic stroke, cardiovascular disorders, and autoimmune conditions. Current antiplatelet therapies primarily target surface receptors or coagulation pathways and are frequently limited by drug resistance, bleeding risk, and inadequate control of metabolically or inflammation-driven platelet dysfunction. Emerging evidence reveals that platelets possess a fully functional autophagic machinery that critically regulates mitochondrial quality, redox balance, granule secretion, cytoskeletal remodeling, and activation thresholds. This intracellular pathway represents a previously underrecognized but highly druggable regulatory axis in platelet biology. In this review, we examine the molecular framework governing autophagy in platelets, with emphasis on mTOR, AMPK, PI3K/AKT, and mitophagy signaling networks, and discuss how basal and activation-induced autophagy determine thrombotic behavior under physiological and pathological conditions. We then integrate clinical and preclinical evidence demonstrating how dysregulated platelet autophagy contributes to thrombotic risk in ischemic stroke, cardiovascular disease, metabolic disorders, and autoimmune diseases. Importantly, we highlight how pharmacological agents, including mTOR inhibitors, AMPK activators, natural autophagy enhancers, and lysosomal inhibitors, modulate platelet function through autophagy-dependent mechanisms. These findings position platelet autophagy as a promising intracellular therapeutic target that complements conventional antiplatelet strategies. We further discuss the translational challenges of autophagy-targeted therapy, including context dependency, lack of platelet-specific modulators, delivery strategies, and the need for reliable biomarkers to guide personalized intervention. By framing platelet autophagy as a druggable pathway rather than a biological curiosity, this review outlines a precision-targeted therapeutic framework for managing thromboinflammatory diseases through intracellular modulation of platelet behavior. Full article

Host defense peptides (HDPs), ancestral effectors of innate immunity, have emerged as pleiotropic regulators transcending their antimicrobial origins. This review critically examines the complex interplay among HDPs, hemostasis, and tissue repair. We analyze molecular mechanisms governing interactions with platelets and endothelial cells, highlighting a fundamental paradigm shift: platelets and megakaryocytes are active synthesizers of a specific peptide repertoire rather than passive carriers. Functional dualities are elucidated, contrasting LL-37-driven platelet agonism via glycoprotein VI (GPVI) against the amyloid-like stabilization of fibrin by defensins. Based on these mechanisms, we propose a framework wherein HDPs function as concentration-dependent molecular switches between physiological repair and pathological thromboinflammation. Furthermore, the review addresses the hypothesis of “adaptive thrombopoiesis,” where systemic peptide surges act as danger signals to reprogram the function of newly formed platelets. Finally, therapeutic implications are evaluated, emphasizing the design of protease-resistant peptidomimetics to harness protective effects while mitigating vascular toxicity. Full article