Search Results (119)

Background/Objectives: The objective of this study was to map and synthesize the current evidence on hemostasis in chronic and acute liver disease within the framework of Patient Blood Management (PBM). Methods: Because research in this field is heterogeneous—spanning mechanistic studies, observational data, randomized controlled trials, guidelines, and expert reviews—a scoping review was selected to comprehensively map concepts. Findings were synthesized narratively to reflect the breadth and heterogeneity of available research. Results: Hemostasis in liver disease is characterized by a fragile state of rebalanced coagulation, where parallel reductions in pro- and anticoagulant factors coexist with variable fibrinolytic disturbances and thrombocytopenia. Conventional coagulation tests (CCTs) do not accurately reflect bleeding risk, whereas viscoelastic assays and thrombomodulin-modified thrombin generation testing provide a more physiologic assessment, though with limitations. Most bleeding events arise from portal hypertension rather than coagulopathy, and the routine prophylactic correction of abnormal results of CCTs is not supported by evidence. PBM-aligned strategies—such as restrictive transfusion, targeted fibrinogen replacement, and use of thrombopoietin receptor agonists (TPO-RAs)—reduce unnecessary blood product use. Thrombosis burden is increasingly recognized in this patient population. Anticoagulation is generally safe when individualized to liver function and clinical context, however significant variability persists in clinical practice, and high-quality data remain limited for advanced disease. Conclusions: Hemostasis in liver disease reflects a dynamic and unstable equilibrium rather than a simple bleeding tendency. Diagnostic and therapeutic strategies grounded in PBM principles improve safety by avoiding unnecessary transfusion and emphasize individualized care. Despite advances in understanding rebalanced hemostasis, major gaps remain in predicting thrombotic risk, standardizing advanced coagulation testing, and defining optimal management across disease stages. Full article

Diabetes mellitus (DM) is a complex metabolic disorder associated with a heightened risk of cardiovascular events, largely driven by a hypercoagulable and hypofibrinolytic state. The pathophysiological interplay between chronic hyperglycemia, oxidative stress, insulin resistance, and systemic inflammation fosters profound alterations in the coagulation cascade, endothelial function, and platelet activity. This narrative review synthesizes evidence from studies published between 2008 and 2026, focusing on coagulation and platelet-related biomarkers selected based on their biological relevance to thrombosis, endothelial dysfunction, and inflammation, as well as the availability of clinical and interventional data across different forms of DM. Although there are numerous biomarkers involved in the pathogenesis of various forms of diabetes, this narrative review critically examines key coagulation biomarkers—including D-dimer, fibrinogen, prothrombin, tissue thromboplastin or tissue factor, P-selectin, soluble urokinase plasminogen activator receptor, thrombomodulin, plasminogen activator inhibitor-1, von Willebrand factor, and β-thromboglobulin—across distinct diabetes subtypes, including type 1, type 2, gestational, and secondary forms linked to endocrinopathies and pancreatic diseases. The literature reveals substantial subtype-specific heterogeneity in hemostatic alterations. For instance, Type 1 DM is characterized by early endothelial dysfunction and platelet activation, while Type 2 DM presents with elevated coagulation factors, impaired fibrinolysis, and a proinflammatory milieu. Gestational DM exhibits pregnancy-specific changes in coagulation, yet distinguishing them from obesity-related effects remains challenging. Secondary diabetes forms, such as those associated with Cushing’s syndrome or pancreatitis, further underscore the diversity in thrombotic risk profiles. Among the coagulation and platelet activation biomarkers reviewed, fibrinogen, P-selectin, and plasminogen activator inhibitor-1 demonstrate the most consistent associations with glycemic control, vascular dysfunction, and therapeutic modulation, particularly in type 2 diabetes, suggesting greater potential for clinical translation. In contrast, evidence for markers such as D-dimer, tissue factor or tissue thromboplastin, and soluble urokinase plasminogen activator receptor remains heterogeneous and insufficient for routine clinical application. By synthesizing mechanistic insights and clinical data, this review highlights the urgent need for subtype-tailored coagulation assessment in diabetes management. A better understanding of the dynamic alterations in coagulation pathways may facilitate earlier detection of vascular complications and inform personalized antithrombotic strategies. Full article

Tumor metastasis is closely associated with coagulation and inflammation, particularly via thrombin–PAR1 signaling. However, the potential of natural polysaccharides such as rhamnan sulfate (RS) to modulate these pathways and suppress metastasis remains unclear. We aimed to investigate the effects of orally administered RS derived from Monostroma nitidum on melanoma metastasis and its underlying mechanisms. Male C57BL/6J mice were orally administered water or RS daily. On day 8, saline or B16 melanoma cells were injected intravenously. Mice were treated for 21 days and divided into four groups (control, RS-only, M + W, and M + RS; n = 5/group). Metastasis and related molecular factors were analyzed in plasma, lung, and aortic tissues. Significant lung and aortic metastases were observed in the M + W group but were markedly suppressed in the M + RS group. RS reduced the expression of inflammatory factors (e.g., IL-6, PAR1), proteases, leukocyte activation markers, complement factors, angiogenic factors, and EMT-related factors. Conversely, thrombin, thrombomodulin, plasmin, TAFIa, and tight junction proteins were increased in RS-treated mice. RS suppresses melanoma metastasis by modulating thrombin–PAR1-mediated inflammation and associated pathways. These findings suggest RS as a potential therapeutic agent, although further mechanistic and clinical studies are required. Full article

Yamakagashi (Rhabdophis tigrinus) is a widely distributed snake species in Japan. Yamakagashi causes venom-induced consumption coagulopathy (VICC) when the amount of infused venom is high, and bites can be fatal if antivenom treatment is delayed. However, yamakagashi antivenom is an unapproved treatment, and its storage capacity is limited, preventing its prompt administration. Therefore, we investigated the application of commercially available drugs, namely tranexamic acid and antithrombin III, in the treatment of VICC caused by yamakagashi venom in a rat model. Furthermore, we investigated the combination of each drug with recombinant thrombomodulin α. Administration of tranexamic acid or antithrombin III alone failed to extend rat survival or correct changes in blood coagulation markers, such as prothrombin time, fibrinogen concentrations, and D-dimer levels, in yamakagashi venom-treated rats. However, combined administration of recombinant thrombomodulin α and tranexamic acid extended rat survival and partially restored blood coagulation markers. Therefore, the combination of recombinant thrombomodulin α and tranexamic acid might represent a useful therapeutic regimen for yamakagashi venom exposure. Full article

Background: To evaluate the effects of preoperative topical ripasudil, a Rho-associated protein kinase (ROCK) inhibitor, on Schlemm’s canal (SC) morphology in patients with primary open-angle glaucoma (POAG). Methods: This study included 95 SC specimens obtained during trabeculectomy from 95 patients with POAG. Based on preoperative treatment, patients were divided into two groups: ripasudil (−) group (n = 68) receiving four topical medications [FP receptor agonist, β-blocker, carbonic anhydrase inhibitor (CAI), and α₂ agonist], and ripasudil (+) group (n = 27) receiving the same four medications plus ripasudil. SC morphology parameters were assessed in thrombomodulin (TBM)-stained sections, including length parameters [TBM-positive/negative and opened/closed SC lengths] and area parameters [TBM-positive/negative and opened SC areas]. Between-group comparisons were performed using unpaired t-tests, and multiple regression analysis was conducted to adjust for age, gender, preoperative intraocular pressure (IOP), and oral CAI use. Results: The ripasudil (+) group had significantly longer total SC length (TSC: 302.5 µm) than the ripasudil (−) group (273.0 µm, p = 0.023). Among area parameters, the ripasudil (+) group showed significantly larger opened SC area (OSC-A: 2689 µm² vs. 1881 µm², p = 0.008) and TBM-negative opened SC area (NOSC-A: 716 µm² vs. 305 µm², p = 0.001), whereas TBM-positive opened SC area (POSC-A) was not significantly different between groups (2001 µm² vs. 1575 µm², p = 0.096). After multivariate adjustment, ripasudil use remained significantly associated with longer TSC (p = 0.011) and larger OSC-A (p = 0.014) and NOSC-A (p = 0.001). Conclusions: Preoperative use of topical ripasudil was associated with preservation of SC lumen morphology, particularly in regions lacking SC endothelium. These findings provide a theoretical basis for therapeutic strategies employing ROCK inhibitors to maintain SC morphology and function. Full article

Background/Objectives: Sepsis heterogeneity limits advances in immunotherapy. Increasing use of artificial intelligence (AI) and machine learning (ML) attempts to turn multi-dimensional data into meaningful clusters, indicating biological mechanisms. We provide an overview of the existing evidence on AI-derived sepsis subtyping, exploring treatment response to available immune modulating therapies. Methods: On 1 October 2025, we conducted a structured search on all relative publications on MEDLINE and undertook a narrative review. Results: Multiple subphenotyping algorithms were identified, using clinical, biological, and omics data, across different cohorts, mainly through secondary analyses of randomized trials. The main classification was between hyper- and hypoinflammatory subphenotypes. Statins, corticosteroids, activated protein C, or thrombomodulin displayed differential effects on the outcome of these subphenotypes. Conclusions: Further research is required to prospectively validate findings and to offer pragmatic solutions to patients who need them the most. Issues of validity, equity, ethics, and feasibility are discussed. Full article

Background: Ischemia–reperfusion injury is a major contributor to early graft dysfunction after kidney transplantation and is associated with endothelial damage, reflected by circulating soluble thrombomodulin (sTM). This exploratory study aimed to assess very early graft-level changes in renal vein sTM during reperfusion using a paired-kidney design, in which kidneys from the same donor were preserved using different strategies: static cold storage (SCS) and hypothermic machine perfusion (HMP). Methods: Renal vein blood samples were collected intraoperatively at 1 and 30 min after reperfusion. Plasma sTM concentrations were determined using ELISA. Early graft function was monitored during the first 7 days post-transplantation. Results: Cold ischemia time was longer in the HMP group than in the SCS group (20 ± 8 h vs. 13 ± 6 h, p < 0.05). At 1 min post-reperfusion, sTM levels were comparable between groups. In the HMP group, sTM decreased significantly between 1 and 30 min after reperfusion, whereas no change was observed in the SCS group. Between-group differences at either time point did not reach statistical significance. Early renal function parameters improved in both groups, with no significant inter-group differences. No cases of delayed graft function or graft thrombosis occurred. Conclusions: Kidney preservation strategy may modulate very early graft-level endothelial responses during reperfusion, reflected by renal vein sTM dynamics. Although a limited sample size may have reduced the ability to detect between-group differences, very early renal vein sTM measurements may provide insight into ischemia–reperfusion injury. Clinical relevance requires validation in larger studies. Full article

Both primary and secondary hemostasis consist of finely regulated pathways, forming a blood clot to stop bleeding. These orchestrated mechanisms involve multiple plasma- and platelet/endothelial-derived receptors, factors, enzymes, and proteins, such as the von Willebrand factor (vWF), fibrinogen, and thrombin. Over-activation or improper resolution of the coagulation cascade leads to severe pathological disorders, arterial and venous. Despite the fact that the genetic etiology of thrombophilia has gained the main research interest, there is growing evidence that the disturbed redox network of key hemostatic pathways signals thrombus formation. Oxidized LDL in dyslipidemias and many endogenous and exogenous compounds act as pro-oxidant stimuli that lead to post-translational modifications of proteins, such as sulfenylation, nitrosation, disulfide formation, glutathionylation, etc. Oxidation of cysteine and methionine residues of vWF, fibrinogen, and thrombomodulin has been detected at thrombotic episodes. Increased homocysteine levels due to, but not restricted to, methylenetetrahydrofolate reductase gene (MTHFR) mutations have been incriminated as a causative factor for oxidative stress, leading to a pro-thrombotic phenotype. Alterations in the vascular architecture, impaired vascular relaxation through decreased bioavailability of NO, accumulation of Nε-homocysteinylated proteins, ER stress, and endothelial cells’ apoptosis are among the pro-oxidant mechanisms of homocysteine. This review article focuses on describing key concepts on the oxidant-based molecular pathways that contribute to thrombotic episodes, with emphasis on the endogenous compound, homocysteine, aiming to promote further molecular, clinical, and pharmacological research in this field. Full article

Calafate berry, an ancient perennial shrub of South America (Chile and Argentina), produces a high antioxidant capacity berry with a high polyphenol (1344.2–6553 mg GAE/100 g d.w.) and anthocyanin (26.5–80 mg C-3-G/100 g d.w.) content. The beneficial effects of calafate berries on human health are related to the anti-inflammatory, hypoglycemic, anticancer, and antioxidant properties that the berries possess, which have been confirmed through evidence to date, primarily from in vitro, ex vivo, and animal studies. Several investigations have shown a relationship between the consumption of calafate and a reduction in the risk of contracting cardiovascular diseases (CVD). This was evident in changes in plasma level biomarkers related to CVD, such as thrombomodulin (−24%), adiponectin (+68%), sE-selectin (−34%), sICAM-1 (−24%) and proMMP-9 (−31%), and changes in the production of OH radicals in plasma (−17%) after calafate intake. Calafate may have an antithrombotic role that supports cardiovascular health by lowering the Atherogenic and Cardiovascular Risk Indices. Various authors indicate delphinidin-3-glucoside (384–386 mg/100 g) as the primary bioactive compound responsible for the beneficial properties of Calafate. Although some studies report calafate’s health benefits, scientific evidence, especially in humans, remains limited. Meanwhile, Chile is working to domesticate and cultivate calafate, aiming to turn it from a wild native berry into a sustainable crop for use in the antioxidants and nutraceuticals industry. The lack of human clinical trials emphasizes the need for future research to validate calafate’s health benefits berry. Full article

Clinical trials of drugs specifically targeting the sepsis response have frequently produced negative or inconclusive results. This has largely been due to the broad heterogeneity of enrolled patient populations, particularly when inclusion was based on the presence of the non-specific systemic inflammatory response syndrome (SIRS) criteria. The heterogeneity may have diluted any possible treatment effect: while some patients may have benefited from the intervention under investigation, others will have been harmed, resulting in an overall null-effect. Furthermore, an underlying infection is not always required for immune-modulating interventions to be effective; for example, patients with severe acute pancreatitis, but no infection, may still benefit from such therapies. There is therefore a need for better patient stratification or subphenotyping to identify those most likely to benefit from a particular therapy. Several trials have already adopted this approach using prognostic and/or predictive enrichment strategies. For example, measurements of triggering receptor expressed on myeloid cells (TREM) could be used to identify candidates most likely to respond to anti-TREM therapies, or patients with coagulopathy or specific inflammatory patterns could be selected for treatments like thrombomodulin or activated protein C. However, challenges remain, including the need for more rapid tools that can be used at the bedside to inform real-time treatment decisions given the rapidly evolving nature of the sepsis response. Nevertheless, the era of broad-spectrum “sepsis drugs” is now giving way to more selective, personalized interventions tailored to individual biological profiles, offering a more promising pathway for future therapeutic development—even in the absence of infection. Full article

Chimeric antigen receptor-T (CAR-T) cell immunotherapy constitutes a cornerstone in the management of patients with relapsed/refractory B-cell lineage lymphoid malignancies. Toxicities such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and hematotoxicity (ICAHT) have been recognized in the post-infusion period. The initial interplay between CAR-T cells and tumor cells, followed by cytokine release and the bystander activation of the innate immunity cells, result in endothelial cell injury. In the current review, the ongoing research regarding endothelial injury in CAR-T cell recipients is summarized. Various markers of endothelial injury have been investigated in CAR-T cell recipients, including markers of complement activation, such as soluble C5b-9, endothelial dysfunction (angiopoietin-2, VCAM1, ICAM-1), inflammation, and thrombosis (von Willebrand antigen, ADAMTS13, thrombomodulin). The expression level of these endothelial injury markers has been identified as impaired in CAR-T cell recipients, not only when compared with healthy controls but also among patients with severe CRS/ICANS and those with mild toxicities or without toxicities. Furthermore, the Endothelial Activation and Stress Index (EASIX) and modified versions of this score, calculated in the pre- and early post-infusion period, seem to predict development of severe toxicities, ICAHT, and, thus, poor overall survival in CAR-T cell patients. More data concerning the role of these endothelial injury markers and clinical outcomes in CAR-T cell settings are essential. Full article

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease characterized by chronic inflammation, extracellular matrix degradation, and smooth muscle cell apoptosis. Porphyromonas gingivalis (P. gingivalis), a key periodontal pathogen, has been implicated in the progression of cardiovascular diseases, including AAA, but the underlying mechanisms remain unclear. In this study, we investigated the role of GroEL, a bacterial heat shock protein 60 homolog derived from P. gingivalis, in AAA development. We employed a CaCl₂-induced AAA mouse model to evaluate the in vivo effects of GroEL. Mice received periaortic CaCl₂ application followed by intravenous injections of recombinant GroEL. Histological analyses were performed to assess aneurysmal dilation, elastin degradation, and inflammatory cell infiltration. Flow cytometry and immunohistochemistry were used to determine macrophage phenotypes, while cytokine profiles were quantified via ELISA. In vitro, THP-1 monocytes were treated with GroEL to evaluate its impact on macrophage polarization and cytokine expression. Our results showed that GroEL administration significantly enhanced aortic diameter expansion and elastin breakdown, accompanied by increased infiltration of M1-like macrophages and elevated levels of pro-inflammatory cytokines such as TNF-α and IL-6. In vitro findings confirmed that GroEL promotes M1 polarization and inhibits M2 marker expression in THP-1-derived macrophages. These findings suggest that P. gingivalis-derived GroEL plays a pathogenic role in AAA by modulating macrophage polarization toward a pro-inflammatory phenotype. Targeting microbial components such as GroEL may offer new therapeutic strategies for AAA management. Full article

The objective of this study was to evaluate the serum biomarkers implicated in the interaction of platelets and endothelium, as well as the efficacy of antiplatelet therapy in patients with aortic stenosis (AS) and coronary artery disease (CAD). A total of 78 adult patients with CAD on aspirin therapy participated in this study, including 49 consecutive patients with AS and 29 control subjects. The analysis included the following serum biomarkers: thrombomodulin (TM), platelet factor 4 (PF4), P-selectin, and CD40L. The efficacy of antiplatelet treatment was evaluated using the VerifyNow Aspirin test (ASPI test) and P2Y12 assay test (ADP test). Patients with AS exhibited increased serum levels of TM (7.64 ± 3.5 ng/mL vs. 6.28 ± 2.1 ng/mL, p = 0.011) and PF4 (25.16; Q1: 8.3; Q3: 29.6 μg/mL vs. 12.85; Q1: 5.7; Q3: 14.5 μg/mL, p = 0.021) compared to the control group. P-selectin and CD40L levels did not differ between groups. There were no significant differences in platelet aggregation in the ASPI (474.04 ± 66.7 ARU vs. 471.31 ± 56.2 ARU; p = 0.822) or ADP (224.88 ± 46.4 PRU vs. 216.62 ± 29.6 PRU; p = 0.394) tests. Bleeding incidence did not differ significantly between groups. The coexistence of AS in patients with CAD is associated with elevated levels of the aforementioned biomarkers, which are indicative of endothelial damage and platelet activation. However, the efficacy of antiplatelet treatment was independent of the presence of AS. Full article

Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease (SOS/VOD) is a severe complication of hematopoietic cell transplantation (HCT). Furthermore, emerging evidence suggests the potential role of complement activation and endothelial injury in SOS/VOD pathogenesis. In this study, we aimed to identify potential distinct pathogenic genetic variants between SOS/VOD and other endothelial injury syndromes following HCT, such as transplant-associated thrombotic microangiopathy (TA-TMA). For this aim, genomic DNA from 30 SOS/VOD patients and 30 controls with TA-TMA was analyzed. Using Next-Generation Sequencing (NGS), variants in complement-related genes (CFH, CFI, CFB, CFD, C3, CD55, C5, CD46, and thrombomodulin/THBD) and ADAMTS13 were examined. Out of 426 detected variants, 20 were classified as pathogenic. In SOS/VOD patients, variants were identified in ADAMTS13 (4), CFH (3), C3 (2), and CFB (1) genes. One of the variants has been recognized as the strongest genetic predictor of ADAMTS13 activity. Controls exhibited more variants in complement-related genes, particularly CFH, CFI, and C3. The genetic differences between SOS/VOD and TA-TMA highlight different pathogenic mechanisms, offering the potential for targeted risk assessment and therapy in HCT recipients. Full article

Trauma remains a leading cause of death and disability in adults, and about 20% of deaths occur due to intractable bleeding. Trauma-induced coagulopathy (TIC) is a complex hemostatic disorder characterized by an abnormal coagulation response, which can manifest as either a hypo-coagulable state, leading to excessive bleeding, or a hypercoagulable state, resulting in thromboembolic events and multiple organ failure. Early diagnosis and correction of hypocoagulability may be lifesaving. Replacement of coagulation factors using blood components as well as counteracting enhanced fibrinolysis with tranexamic acid in association with a strategy of damage control are the current practices in the management of TIC. Nevertheless, the improved comprehension of the several mechanisms involved in the development of TIC might offer space for a tailored treatment with improvement of clinical outcome. This review aims to outline the pathophysiology of TIC and evaluate both established and emerging management strategies. A thorough literature review was made with a specific emphasis on articles discussing the molecular mechanisms of trauma-induced coagulopathy. We utilized PubMed, Scopus, and Web of Science with the main search terms “trauma-induced coagulopathy”, “molecular mechanisms”, and “coagulation pathways”. Full article