Thrombosis and haemostasis最新文献

Thrombotic risk stratification in coronary artery disease (CAD) patients is an unmet need. CAD patients show increased platelet activation, but its prognostic relevance remains unexplored. We aimed to assess the prognostic value of platelet-activation markers on mortality in CAD patients.Surface expression of platelet-associated activated GPIIbIIIa, P-selectin, tissue factor (TF), and platelet-leukocyte aggregate was analyzed in 527 CAD patients (acute coronary syndromes [ACS, n = 149] and chronic coronary syndrome [CCS, n = 378]) by whole-blood flow-cytometry and plasma F1 + 2 by ELISA. With COX regression model 5-year survival analysis from all-cause (AC) and cardiovascular (CV) mortality was performed. Cross-validated cut-off of TF^pos platelets was calculated by Euclidean distance method.AC and CV mortality rates were 9.7 and 6.5%, respectively. Among the biomarkers evaluated, only TF independently predicted AC mortality (hazard ratio [HR] =2.02, p = 0.042) also after adjustment for CAD presentation. ACS and CCS patients with TF^pos platelets >4% (the best cut-off value for all-cause mortality prediction) had the highest levels of F1 + 2 and a worse prognosis for AC and CV mortality (HR = 1.91; p = 0.018 and HR = 2.51; p = 0.005; respectively) than those with <4% TF^pos platelets. Interestingly, patients on dual antiplatelet therapy (n = 246, 46.8%) responder to P2Y₁₂ inhibitors with TF^pos platelets >4% had the highest risk for AC mortality (HR = 4.11; p = 0.0215) and CV mortality (HR = 6.88; p = 0.0408). In these patients, TF^pos platelet levels outperformed a clinical model in CV mortality prediction (net reclassification improvement = 0.436, p < 0.001). Platelet TF predicted AC (HR = 3.03; p = 0.012) and CV mortality (HR = 3.56; p = 0.008) in aspirin-only treated patients also (n = 239, 45.3%).The percentage of circulating TF^pos platelets may serve as an independent predictor of AC and CV mortality in CAD patients on antiplatelet therapy.

The Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) and atrial fibrillation (AF) share a common proinflammatory and prothrombotic phenotype. Despite this overlap, patients with coexisting MPNs and AF remain undertreated and poorly characterized, with no specific antithrombotic guidelines addressing this dual pathology. Emerging evidence identifies the nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome as a central and common mediator of vascular diseases. This review explores the pathophysiologic convergence between MPNs and AF, with a focus on the NLRP3 inflammasome and its downstream cytokines (IL-1β, IL-18), as well as neutrophil extracellular traps (NETs), as unifying drivers of thrombosis, atrial remodeling, and clonal propagation. In MPNs, NLRP3 is activated by JAK2-driven inflammation and sterile danger signals, sustaining a cytokine milieu that promotes pyroptosis, fibrosis, and platelet-leukocyte-endothelial interactions. In AF, inflammasome overactivation in cardiomyocytes and fibroblasts contributes to ectopic activity, electrical remodeling, and fibrosis. NETs, which are enhanced by NLRP3, amplify thrombosis and may link the hematologic and cardiovascular components of the association between MPNs and AF. We critically evaluate the translational potential of inflammasome-derived biomarkers and identify NLRP3 inhibition as a promising adjunctive strategy in MPN patients with AF. The review calls for prospective studies to redefine antithrombotic management in this overlooked population, incorporating molecular, inflammatory, and arrhythmogenic risk dimensions.

Major bleeding and recurrent venous thromboembolism (VTE) both lead to a poor prognosis among patients with VTE. Low body weight (BW) may be a risk factor for bleeding; however, data on its impact remain limited in the direct oral anticoagulant (DOAC) era.We investigated the relationship between low BW and long-term outcomes among VTE patients in the DOAC era.From the COMMAND VTE Registry-2 in Japan between January 2015 and August 2020, we analyzed 4,959 patients with symptomatic VTE, who were divided into low BW (≤60 kg) (N = 2,897) and non-low BW (>60 kg) (N = 2,062) groups. The primary outcome was major bleeding.The low BW group was older (71.3 vs. 62.5 years, P < 0.001), included a higher percentage of female (75% vs. 36%, P < 0.001), and received initial intensive DOAC therapy less often (64% vs. 75%, P < 0.001) and reduced maintenance DOAC doses more frequently (51% vs. 15%, P < 0.001) than the non-low BW group. The risks of major bleeding (16.7% vs. 10.8% at 5 years; adjusted HR 1.43, 95%CI 1.15-1.77, P = 0.001) and all-cause death (38.9% vs. 23.2%; HR 1.59, 95%CI 1.39-1.81, P < 0.001) were higher in the low BW group than in the non-low BW group, while the risk of recurrent VTE was similar (9.4% vs. 9.7%; HR 0.98, 95%CI 0.75-1.29, P = 0.90).Low BW correlated with higher risks of major bleeding and all-cause death, but not recurrent VTE in the DOAC era.

Platelets are primarily known for their roles in hemostasis and thrombosis; however, accumulating evidence highlights their significant contribution to endothelial dysfunction and the development of atherosclerosis. Upon adhering to the endothelium, platelets engage in reciprocal activation through a variety of membrane receptors and adhesion molecules, initiating inflammatory and immune responses that drive early atherogenic processes. Several studies have shown that platelet receptors traditionally associated with hemostasis also mediate adhesion to endothelial cells. In addition, recent research has uncovered novel molecular players and mechanisms involved in platelet tethering to the endothelium. This review explores the mechanisms underlying endothelial-platelet interactions during the early stages of atherosclerosis. We examine how platelet adhesion to endothelial cells contributes to the formation of atherosclerotic plaques and discuss potential therapeutic strategies aimed at disrupting these pro-atherogenic interactions. In particular, we discuss emerging anti-platelet agents that selectively target receptors involved in platelet-endothelial cell interactions, offering promising translational approaches to prevent or slow the onset of atherosclerosis.

The use of low-molecular-weight heparin (LMWH) and aspirin during pregnancy is increasing, yet robust clinical trial evidence supporting their efficacy remains limited.In a multicenter prospectively enrolled cohort study, we evaluated the prescription patterns and associated maternal-fetal outcomes of antithrombotic therapy in 2,622 women admitted for delivery across three Italian obstetric centers between January 2022 and November 2023. Data were collected on conception methods, administration details (timing, dose, indication) of LMWH and low-dose aspirin (LDA), and maternal-fetal outcomes from admission to postpartum discharge. Data on prescription of antithrombotic drugs were available for 1,898 women.Among 1,898 women with available data, 157 (8.3%) received LDA (100 mg/day) and 746 (39.3%) received LMWH (49 during pregnancy and 697 in the postpartum period). Predictors of LMWH use included prior cesarean (OR 3.1, 95% CI 1.7-5.8), preterm delivery (OR 3.8, 95% CI 1.7-8.9), pregnancy loss (OR 2.7, 95% CI 1.5-4.9), and assisted conception (OR 14.6, 95% CI 2.8-76.5). LDA use was associated with pregnancy loss (OR 2.1, 95% CI 1.4-3.0), ART (OR 4.7, 95% CI 2.2-10.2), and LMWH co-administration (OR 2.5, 95% CI 1.1-5.5). Postpartum LMWH use was primarily associated with cesarean delivery. Postpartum hemorrhage occurred in 2.4% of cases, with no significant difference in those receiving LDA or LMWH.These findings reflect current real-world prescribing practices and highlight key maternal characteristics influencing antithrombotic therapy decisions. The study underscores the importance of evidence-based approaches in the use of LMWH and LDA during pregnancy, particularly in high-risk populations, to improve maternal-fetal outcomes while minimizing unnecessary exposure to therapies with uncertain benefit.

Initial thrombin (FIIa) generation is a critical trigger for the amplification and propagation phases of coagulation, driven by two distinct pathways: the tissue factor (TF)-driven and the FVIIIa/FIXa-dependent pathways. However, the clinical utility of measuring initial thrombin generation (ITG) as a marker of thrombogenicity or as a tool to monitor the efficacy of oral anti-FXa therapy remains uncertain.ITG driven by TF and the FVIIIa/FIXa complex was first measured in plasma samples from healthy adults (n = 40). This was followed by an analysis of ITG profiles in 771 consecutive patients with cardiovascular diseases to evaluate the effects of anticoagulant therapy and clinical characteristics.Of the 771 patients studied, 169 were receiving direct oral anticoagulants (DOACs). DOAC treatment significantly suppressed thrombin generation via both TF-driven and FVIIIa/FIXa-dependent pathways. Receiver operating characteristic (ROC) analysis confirmed the strong discriminatory power of both pathways for detecting DOAC use (FVIIIa/FIXa: AUC 0.863, 95% CI: 0.826-0.900; TF: AUC 0.887, 95% CI: 0.856-0.917; both p values < 0.0001). Among patients not on anticoagulants, logistic regression revealed that dialysis was associated with reduced thrombin generation through both pathways. Furthermore, chronic kidney disease and active cancer were specifically associated with diminished TF-driven thrombin generation.The ITG potentials driven by TF- and FVIIIa/FIXa-dependent pathways represent promising biomarkers for evaluating anticoagulant efficacy. Moreover, the distinct influence of pathological conditions on each pathway underscores the need to account for specific disease contexts when assessing coagulation potential.

Elevated FXI levels are associated with increased risk of venous thromboembolism, yet genetic mutations contributing to elevated FXI levels have not been reported yet.We described a patient with a history of deep venous thrombosis (DVT) who tested negative on routine laboratory screening but was found to carry a novel pathogenic FXI mutation, Gly397Ser (G397S). FXI mutant protein was expressed, and functional assays were conducted in vitro to explore the underlying thrombotic mechanism.Consistent with FXI activity (FXI:C) and antigen (FXI:Ag) determined in the patient, the FXI G397S mutant exhibited a 2-fold increase of FXI:C/FXI:Ag. FXIa hydrolysis assay demonstrated that the Km value for G397S mutant was comparable to the wild-type FXIa (186.2~281.9 μM V.S. 141.6~242.6 μM), whereas the mutant FXIa displayed approximately 3-fold increases in kcat values. FXI activation by polyanions was more pronounced in the G397S mutant. Notably, this activation was more significant when triggered by thrombin compared with FXIIa in the presence of heparin. Otherwise, the G397S FXI mutant exhibited similar hydrolytic activity of FXIa against FIX, and equivalent inhibition of FXIa by Protease nexin 2 (PN2). Clot lysis assay revealed that the lysis time was longer in G397S mutant than the wild-type and the enhanced fibrinolytic resistance was thrombin-activatable fibrinolysis inhibitor-dependent. In summary, the FXI G397S mutation exhibited higher FXIa activity mainly because of the enhanced activation of FXI, which sustained thrombin generation and manifested resistance to fibrinolysis, ultimately leading to the development of DVT.

Platelet-monocyte aggregates (PMA) are modern biomarkers for the early onset of cardiovascular diseases (CVD). PMA occur in the presence of activated platelets (AP), whose incidence is higher in patients with metabolic diseases. These patients frequently benefit from anticoagulant therapy, particularly in advanced disease stages. However, the impact of these drugs on PMA occurrence is unknown.Blood samples from healthy volunteers, patients with type 1 diabetes mellitus (DMT1), type 2 diabetes mellitus (DMT2), dyslipidemia (hypercholesterolemia), and severe forms of familial hypercholesterolemia (FH) were analyzed by flow cytometry to detect both AP and PMA. Subsequently, blood samples were treated with four direct anticoagulants (rivaroxaban, apixaban, dabigatran, or argatroban, all at a final concentration of 1 µM), and PMA were again detected. Anthropological and biochemical parameters were recorded and correlated with AP and PMA.AP levels were higher solely in DMT2 patients, but PMA occurrence was significantly increased in all patient groups in comparison to that of generally healthy donors, except for FH patients. No sex-related differences were observed, but an increasing trend in AP and PMA incidence was observed with increasing age and BMI. Significant correlations of AP and PMA with anthropological and biochemical parameters were found solely in some groups of patients or in some anticoagulant-treated samples. Only argatroban and apixaban-treated samples significantly decreased PMA occurrence, and this was observed solely in the dyslipidemia patient group.These findings suggest a potential positive outcome of anticoagulant treatment for metabolic disease patients and confirm PMA as a sensitive marker in patients with metabolic diseases.

Ischemic stroke affects more than 15 million people annually, where atheroembolism from unstable atherosclerotic plaques in the carotid bifurcation contributes a significant and potentially preventable aetiology. Landmark carotid endarterectomy trials conducted decades ago proved that removing high-grade symptomatic stenoses outperforms medical therapy, yet accurately identifying unstable plaques, the true embolic source, remains elusive. Consequently, procedural efficacy is modest, and more personalized diagnostic methods are necessary for refined risk stratification and improved stroke prevention. Plaque instability and atheroembolism from rupture of the fibrous cap is driven by an enlargement of the lipid-rich necrotic core, inflammation, neovascularisation, intraplaque haemorrhage, and fibrous-cap thinning. Hypoxia-induced angiogenesis produces fragile neovessels that bleed, generating oxidative stress and further destabilisation. Biomolecules escaping into the circulation from such lesions could flag individuals at imminent risk, but imaging modalities such as magnetic resonance, computed tomography angiography, or ultrasound are necessary to identify lesions at risk. Using these methods, aligning imaging phenotypes with molecular signatures of stability or vulnerability can aid in the development of refined diagnostic methods. Integrating blood-based with quantitative imaging biomarkers and systems-biology modelling promises a personalised diagnostic pipeline to screen for circulating signals of instability to detect individuals at risk, together with noninvasive imaging to localise culprit lesions, creating the basis for tailored surgical or pharmacologic therapy. In this review, we discuss scientific advances in the development of such strategies that possess the potential to sharpen patient selection, reduce unnecessary procedures, and advance precision in stroke prevention.

Leukocyte-platelet aggregates (LPAs) play a crucial role in the pathogenesis of inflammatory diseases, linking pathological immune responses with thrombosis.The levels of LPAs, their composition, and cellular reactivity were determined in patients with distinct inflammatory conditions, namely coronavirus disease 2019 (COVID-19), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE), compared with healthy controls. Flow cytometry was used to identify cell types and measure LPA levels in the blood. The ability of platelets, neutrophils, and monocytes to form additional LPAs in response to hyperstimulation with phorbol-12-myristate-13-acetate (PMA) was assessed. Coaggregation of isolated neutrophils and platelets in vitro was visualized using scanning electron microscopy. Blood tests included coagulation, hematology, biochemistry, and immunology.LPA levels were significantly higher in all patient groups compared with controls, with variations in the composition: neutrophil-platelet aggregates predominated in the COVID-19 patients, whereas monocyte-platelet aggregates prevailed in the blood of RA and SLE patients. Platelet-to-leukocyte ratios within aggregates varied in a broad range with a substantial prevalence of platelets over leukocytes. Morphological analysis revealed coaggregation of platelets with neutrophils, including relatively large homotypic platelet aggregates associated with one or two neutrophils. In PMA-treated pathological blood samples from COVID-19, RA, and SLE patients, the ability to form additional LPAs over the patients' baseline level was reduced compared with normal blood samples, indicating impaired reactivity (exhaustion) of neutrophils and monocytes in all patient groups.This study highlights distinct changes in the number and composition of LPAs in inflammatory diseases of various etiologies associated with altered functionality of the innate immune cells.