Journal of Thrombosis and Thrombolysis最新文献

Reactive oxygen species (ROS) play a pivotal role in myocardial infarction (MI), contributing to oxidative stress, inflammation, and tissue remodeling. However, ROS-related gene signatures with diagnostic and mechanistic relevance in MI remain insufficiently defined. Transcriptomic data from six MI cohorts were integrated, with GSE66360 as the training set and five datasets as external validation. Batch correction was performed using ComBat. ROS pathway activity was assessed by single-sample gene set enrichment analysis (ssGSEA). Differentially expressed genes (DEGs) shared across datasets were intersected with ROS-related genes to construct an elastic net logistic regression model. Model performance was evaluated using ROC, calibration, and decision curve analysis. SHAP analysis was conducted for interpretability. Upstream transcription factor and miRNA interactions were predicted, and single-gene GSEA was used to explore biological pathways. Immune infiltration and checkpoint expression were analyzed using multiple deconvolution algorithms. Human AC16 cardiomyocytes were used to explore the functions of ADAM9 in MI. To validate our findings in vivo, we established the mice MI model and performed histology, immunostaining, and qRT-PCR to examine the six signature genes. ROS pathway activity was consistently elevated in MI samples across all cohorts. A six-gene signature (MMP9, ADAM9, BST1, TLR4, CLEC7A, CYP1B1) showed strong diagnostic performance. SHAP analysis identified MMP9 as the top contributor. Regulatory network analysis highlighted NFKB1, STAT1, and miR-21-5p as upstream regulators. Functional enrichment revealed an association with inflammatory and immune pathways. Software algorithm predictions from patient blood cell samples showed that the MI sample exhibited increased infiltration of macrophages, dendritic cells, and fibroblasts, along with upregulation of immune and inflammatory genes. Several model genes correlated positively with endothelial cell infiltration. Function studies in human AC16 cardiomyocytes suggested that ADAM9 inhibited cardiomyocyte survival and enhanced oxidative stress. Experimental validation confirmed that all six genes were significantly upregulated at both mRNA and protein levels in infarcted mouse hearts. We identified a ROS-related six-gene diagnostic signature for MI, with strong performance and mechanistic links to immune activation and vascular remodeling. This model may aid early diagnosis and provide insight into redox-immune interplay in MI.

The optimal postaortic valve replacement (AVR) anticoagulation strategy remains poorly defined, particularly when comparing nonvitamin K antagonist oral anticoagulants (NOACs) versus warfarin. This systematic review and meta-analysis aimed to evaluate the safety and efficacy of NOACs compared with warfarin in these patients. Our study was registered on PROSPERO (ID CRD420251028998). A search of the PubMed, EMBASE, and Cochrane databases was conducted on April 9, 2025, for studies published between 2015 and 2025 that compared NOACs to warfarin after aortic bioprosthetic valve replacement. Inclusion criteria included randomized controlled trials (RCTs) and observational studies reporting thromboembolic events, major bleeding, and mortality with at least 6 months of follow-up. Studies on mechanical valves, case reports, and publications that could not be translated into English were excluded. Data extraction was conducted based on study design, patient demographics, clinical outcomes, and effect sizes, expressed as hazard ratios (HRs) with 95% confidence intervals (CIs) using a random effects model. Risk of bias was assessed using the ROBINS-I tool. Seventeen studies (n = 93,510 participants) were included. NOACs were associated with an HR of 0.91 for thromboembolic events (95% CI: 0.76-1.09) and a pooled HR of 1.22 for major bleeding (95% CI: 0.88-1.68). Several studies have suggested a trend toward lower all-cause mortality and major bleeding with NOACs, particularly in patients with lower bleeding risk. In patients undergoing aortic bioprosthetic valve replacement, NOACs show similar efficacy and safety to warfarin for preventing thromboembolic events and major bleeding. However, anticoagulation decisions should be individualized, and larger RCTs are needed to determine the optimal approach.

Deep vein thrombosis (DVT) is a prevalent thrombotic condition affecting a wide range of patients, including post-partum women, immobilized individuals, and those who have undergone surgery, suffered heavy trauma, or had malignancies. Given the high incidence of the disease, identifying molecular and genetic tools that can predict, indicate prognosis, and serve as therapeutic targets would be a significant advancement in clinical practice for a broad spectrum of patients. However, traditional treatments often face challenges, leading to post-thrombotic syndrome (PTS) development in complex cases. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), have demonstrated essential regulatory roles in cellular pathways and have been found to be dysregulated in DVT patients and animal models. This knowledge provides new insights into the pathophysiology of DVT and paves the way for utilizing ncRNAs as diagnostic, predictive, and prognostic indicators, as well as therapeutic targets. Recent advancements have led to significant recanalization of thrombosed veins in animal models. In this review, we delve into the current literature on ncRNAs in DVT to highlight their potential for understanding disease mechanisms and improving patient outcomes.

We aimed to investigate the effects of Xuebijing (XBJ) combined with levosimendan on the immune function and coagulation function in patients with sepsis complicated by myocardial injury. This double-blind, randomized controlled trial involved 88 sepsis patients with myocardial injury, split into control (n = 44, levosimendan plus conventional therapy) and combination (n = 44, control group's treatment plus XBJ injection) groups. Primary outcomes: coagulation parameters [prothrombin time (PT), activated partial thromboplastin time (APTT), platelet count (PLT), fibrinogen (Fib), and D-dimer (D-D)], immune function indicators (peripheral blood T lymphocyte subsets: CD4+, CD8+, and the CD4+/CD8+ ratio). Secondary outcomes: inflammatory markers [procalcitonin (PCT), C-reactive protein (CRP), and tumor necrosis factor (TNF-α)], vascular endothelial function markers [endothelin-1 (ET-1), nitric oxide (NO), vascular endothelial growth factor (VEGF), von Willebrand factor (vWF), and soluble thrombomodulin (sTM)], myocardial function biomarkers [cardiac troponin I (cTnI), creatine kinase isoenzyme (CK-MB), and B-type brain natriuretic peptide (BNP)], and hemodynamic parameter [heart rate (HR), mean arterial pressure (MAP), and central venous pressure (CVP)]. Post-treatment, serum levels of PCT, CRP, TNF-α, ET-1, vWF, sTM, PT, APTT, D-D, CD8+, cTnI, CK-MB, BNP, and HR were lower in both groups, with further reductions in the combination group. Levels of NO, VEGF, PLT, Fib, CD4+, CD4+/CD8+ ratio, MAP and CVP were higher in the combination group than in the control group (all P < 0.05). The combination of XBJ and levosimendan improves coagulation function, regulates immune function, enhances vascular endothelial function and hemodynamics, reduces inflammation, and alleviates myocardial injury.

Endovascular thrombectomy (EVT) is the standard of care in acute ischemic stroke (AIS), yet functional outcomes remain suboptimal. Normobaric hyperoxia (NBHO) is a potential neuroprotective strategy. This study is the first systematic review and meta-analysis to assess NBHO as a potential neuroprotective adjunctive to improve outcomes in EVT-treated patients. A comprehensive search of electronic databases, including PubMed, Scopus, Cochrane, and Web of Science, was performed in February 2025. The inclusion criteria targeted randomized controlled trials (RCTs) comparing NBHO and EVT to EVT alone or with sham oxygen therapy. Statistical analyses were performed using RevMan software. Four RCTs comprising 648 patients with AIS due to large vessel occlusion in the anterior circulation were included in the study. For the primary efficacy endpoint of excellent functional outcome, defined as the number of patients who had a Modified Rankin Scale (mRS) score of ≤ 1 at 90 days, the overall odds ratio with a subgroup based on the oxygen delivery duration at 2, 4, and 6 h was in favor of the NBHO group compared to the control (OR = 1.66, 95% CI [1.13, 2.45], P = 0.01, I2 = 0%). The subgroup of 4-hour oxygen delivery duration was the only significant subgroup (OR = 1.6, 95% CI [1.01, 2.51], P = 0.04). Safety outcomes showed no significant differences between the NBHO group and the control group across all reported measures. NBHO as an adjunct to EVT appears to be effective and safe. A 4-hour duration was found to be the most effective. Further RCTs are needed to confirm our results and establish the optimal treatment protocol.

Platelet activation is a hallmark feature of coronary artery disease (CAD), characterized by a proaggregatory and proinflammatory state. However, the proadhesive phenotype, mediated by the collagen receptors GPVI and integrin α₂β₁, seems to be critically essential in the pathogenesis of disease yet underexplored in advanced CAD patients. Given the limited insight into this area, we aimed, for the first time, to comprehensively assess the expression of adhesion receptors, as well as the collagen-dependent adhesion of platelets, in CAD patients candidates for CABG (Advanced CAD) compared to healthy controls. Twenty CAD patients scheduled for CABG surgery, selected using strict exclusion criteria, and healthy controls were analyzed for expression of GPVI, integrin α₂β₁, and P-selectin via flow cytometry. Collagen-dependent platelet adhesion and spreading under static conditions were evaluated by immunofluorescence microscopy, which was correlated with GPVI expression and platelet indices. CAD patients exhibited higher levels of GPVI and P-selectin expression, but not α2β1, along with increased platelet adhesion and spreading on a collagen matrix. Platelet functional activity was strongly linked to GPVI expression and platelet indices, including MPV and PDW. The study presented here for the first time exhibited the higher proadhesive function in advanced CAD, which significantly correlates with platelet indices. These findings indicate that a sustained proadhesive state may increase the risk of prothrombotic complications before CABG, while the indices themselves may serve as indirect surrogate markers of platelet adhesive potential. Moreover, ROC curve analysis confirmed the high sensitivity and specificity of the adhesion profile in discriminating CAD patients from healthy controls.

Warfarin dosing guided by INR fails to account for pharmacokinetic/pharmacodynamic variability, leading to suboptimal outcomes; genetic and clinical factors, such as VKORC1 polymorphism and comorbidities, could refine dosing strategies and improve anticoagulation safety.  The aim of this was to identify the main determinants of INR variability in Mexican patients under long-term anticoagulation therapy. For this purpose, patients undergoing warfarin treatment were included and a clinical data was retrieved from medical record. A bioanalytical HPLC method to quantify warfarin (CPW) and its primary metabolite, 7-OH warfarin (CP7OH), in plasma samples was standardized and validated. INR variability was assessed in relation to Charlson comorbidity index (CCI), warfarin dose, drug interactions, vitamin K intake, CPW, CP7OH, metabolic ratio, and VKORC1 1693 polymorphism using univariate and multivariate analysis. The results showed that among 22 patients (64% women) with atrial fibrillation and aortic-mitral valve replacement, warfarin dosing ranged from 8.75 to 55 mg/week (median: 22.5 mg/week). Over half (68.2%) did not achieve the therapeutic INR goal (2.0-3.5). VKORC1 1693 genotype frequencies were GG (36%), GA (50%), and AA (14%), with AA carriers requiring lower maintenance doses (p<0.01). Multivariate analysis incorporating CCI, CPW and CP7OH explained up to 70% of INR variability (p<0.01). Furthermore, currently reported dosing algorithms showed limited accuracy in predicting the appropriate warfarin dose in this cohort. Overall, INR variability depends on plasma warfarin levels, metabolite concentration, and key comorbidities. Therefore, tailored population models are essential to optimize anticoagulation therapy in Mexico. This research highlights the need for more inclusive studies incorporating genetic and clinical factors to refine warfarin dosing and improve outcomes.

Endovascular thrombectomy (EVT) is an effective treatment for acute ischemic stroke (AIS). Oral anticoagulants are used for stroke prevention in pro-embolic patients, but their impact on EVT outcomes, particularly symptomatic intracranial hemorrhage (sICH), remains uncertain. This study aims to evaluate the safety and efficacy of vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs) on EVT outcomes. We searched PubMed, Cochrane, and Embase from 2015 to August 2024 for studies comparing anticoagulated and non-anticoagulated AIS patients undergoing EVT. Safety outcomes included sICH and 90 days mortality. Efficacy outcomes included successful reperfusion rate and 90 days functional outcome. Subgroup analyses evaluated the effect of therapeutic-dose anticoagulation. Fifteen studies with 62,328 AIS patients were included; 9,977 were anticoagulated (6,879 VKA, 3,098 DOAC). VKA patients had a significantly higher rate of sICH (OR = 1.32, 95% CI [1.05, 1.66]) and 90 days mortality (OR = 1.61, 95% CI [1.25, 2.08]) compared to non-anticoagulated patients. DOACs showed no significant difference in sICH risk (OR = 0.83, 95% CI [0.48, 1.44]) or mortality (OR = 1.20, 95% CI [0.89, 1.61]). Functional outcomes at 90 days were significantly worse in both anticoagulated groups, but only VKA patients demonstrated worsened outcomes in the therapeutic-dose subgroup analysis. EVT success rates were comparable between all groups. DOACs offer a safer EVT profile than VKAs, with lower sICH risk and mortality. These findings support DOACs as the preferred anticoagulant for stroke prevention. Further research should assess long-term outcomes and distinguish procedure-related mortality from secondary causes.

Atherosclerosis is the main cause of cardiovascular diseases. These diseases can lead to mortality and morbidity worldwide. Macrophage apoptosis plays an important role in the progression of atherosclerosis. ASA-X₃ has anticancer effects by inducing significant apoptosis in gastric cancer cells. We conducted a preliminary experiment and reported that ASA-X₃ promotes macrophage apoptosis. Therefore, we hypothesize that ASA-X₃ might play a role in anti-atherosclerosis by inducing macrophage apoptosis. The effects of ASA-X₃ and ASA on RAW264.7 cells (in vitro) and mice (in vivo) were investigated. In vitro, RAW264.7 cell viability and apoptosis rates were assessed, and the levels of PARP, caspase-9, p-JNK, and p53 in cells treated with the two substances were compared. In vivo, Terminal-deoxynucleoitidyl Transferase Mediated Nick End Labeling (TUNEL) assays revealed macrophage apoptosis in mice treated with medium- or high-dose ASA-X₃ or ASA. Aortic plaques in mice treated with either drug were examined using oil red O and H&E staining. Masson and collagen staining was performed on the aortic rings of mice treated with high-dose ASA-X₃ or ASA. In vitro, unlike ASA, which had no effect, ASA-X₃ markedly reduced RAW264.7 cell viability. ASA-X₃ induced apoptosis at a rate about four times higher than ASA, with increased levels of PARP, caspase-9, phosphorylated JNK, and p53. In vivo, medium- and high-dose ASA-X₃ significantly increased macrophage apoptosis in mice compared with ASA. In addition, ASA-X₃ (at medium and high doses) reduced the number of aortic plaques, as shown by oil red O and H&E staining. Masson and collagen staining of aortic rings revealed similar results for the high-dose ASA-X₃ and ASA treatments. ASA-X₃ appeared to exhibit anti-atherosclerosis effects via a mechanism that involves the induction of macrophage apoptosis and the lowering of blood plasma lipid levels, eventually resulting in reduced aortic plaque. ASA-X₃ could, therefore, be considered a promising candidate for the treatment of this cardiovascular disease.