Thrombosis and haemostasis最新文献

Patients with atrial fibrillation (AF) often have clinical complexity phenotypes. Latent class analysis (LCA) is based on the concept of modeling of both observed and unobserved (latent) variables. We hypothesized that LCA can help in identification of AF patient groups with different risk profiles and identify patients who benefit most from the Atrial fibrillation Better Care (ABC) pathway.We studied non-valvular AF patients in the prospective multicenter COOL-AF registry. The outcomes were all-cause death, ischemic stroke/systemic embolism (SSE), major bleeding, and heart failure. Components of CHA₂DS₂-VASc score, HAS-BLED score, and ABC pathway were recorded.A total of 3,405 patients were studied. We identified 3 LCA groups from 42 variables: LCA class 1 (n = 1,238), LCA class 2 (n = 1,790), and LCA class 3 (n = 377). Overall, the incidence rates of composite outcomes, death, SSE, major bleeding, and heart failure were 8.69, 4.21, 1.51, 2.27, and 2.84 per 100 person-years, respectively. When compared to LCA class 1, hazard ratios (HR) of composite outcome of LCA classes 3 and 2 were 3.86 (3.06-4.86) and 2.31 (1.91-2.79), respectively. ABC pathway compliance was associated with better outcomes in LCA classes 2 and 3 with the HR of 0.63 (0.51-0.76) and 0.57 (0.39-0.84), but not in LCA class 1.LCA can identify patients who are at risk of developing adverse clinical outcomes. The implementation of holistic management based on the ABC pathway was associated with a reduction in the composite outcomes as well as the individual outcomes.

Atrial fibrillation (AF) is prevalent in dialysis-dependent patients, who face higher risks of thromboembolism and bleeding. Although vitamin K antagonists (VKAs) are commonly used for anticoagulation, the benefits of factor Xa (FXa) inhibitors over VKAs in this population are unclear. This systematic review aims to compare the efficacy and safety of VKAs and FXa inhibitors based on randomized controlled trials (RCTs). We conducted a systematic search of PubMed and Embase for RCTs comparing FXa inhibitors and VKAs up to November 2024. The primary safety outcome was major bleeding, and the primary efficacy outcome was stroke or systemic embolism (SSE). Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using random-effects models. This meta-analysis included 486 dialysis-dependent AF patients from 4 RCTs, with a median follow-up of 26 weeks to 1.88 years. FXa inhibitors were associated with a reduced risk of major bleeding compared to VKAs (RR = 0.64, 95% CI = 0.42-0.99; p = 0.04), but no significant difference in SSE (RR = 0.46, 95% CI = 0.20-1.02; p = 0.06). FXa inhibitors also showed a significantly lower risk of intracranial bleeding (RR = 0.40, 95% CI = 0.17-0.96; p = 0.04), but no differences in other outcomes, including gastrointestinal bleeding, hemorrhagic stroke, ischemic stroke, acute coronary syndrome, and mortality. This systematic review and meta-analysis suggest that FXa inhibitors may offer a safer alternative to VKAs for AF patients on dialysis, with a lower risk of bleeding and similar risks of stroke and mortality.

Various reactions are involved in the phases of activation and further propagation of coagulation in space. The effects of different anticoagulants on these phases are unknown. Our aim was to study how different anticoagulants affect the activation and propagation phases of coagulation.Coagulation in the presence of low-molecular-weight heparin (nadroparin), and direct oral thrombin or factor Xa inhibitors (dabigatran and rivaroxaban, respectively) was studied in vitro and ex vivo via a global blood coagulation assay (Thrombodynamics-4D), which allows simultaneous analysis of thrombin activity in space and the clot growth rate. The ex vivo measurements were carried out in dynamics (8-9 days). The presence of asymptomatic thrombosis after 7 to 8 days of treatment was determined for each group of patients via ultrasound of the lower extremities.All the tested anticoagulants inhibited thrombin generation but resulted in different patterns of thrombin spatial distribution and clot growth. The reversible inhibitors-dabigatran and rivaroxaban-inhibited the initiation phase of coagulation, while further clot growth was altered moderately. Irreversible nadroparin weakly affected the initiation phase of thrombin generation, but unlike dabigatran and rivaroxaban, it could completely suppress spatial thrombin propagation. Asymptomatic thrombosis was observed in 0%, 11%, and 29% of the patients in the nadroparin, dabigatran, and rivaroxaban groups, respectively.Antithrombin-dependent and independent inhibitors act differently on different phases of coagulation. High concentrations of dabigatran or rivaroxaban are insufficient to completely prevent fibrin clot growth, but even small amounts of heparin completely suppress this growth, due to factor IXa inhibition.

Inherited deficiency of the antithrombin (hereditary antithrombin deficiency, AT deficiency, OMIM #613118) is a relatively rare (1:2,000-3,000) autosomal-dominant disorder with high risk of venous thromboembolism. The molecular basis of this condition has not yet fully understood, highlighting the need for further research to elucidate the underlying pathological mechanisms.This study aimed to investigate coagulation parameters and genetic phenotypes in a proband with hereditary antithrombin deficiency and her family members. Additionally, the investigation sought to provide preliminary insights for the molecular pathogenesis of this condition.Blood coagulation parameters, including plasma antithrombin activity (AT:A), antithrombin antigen (AT:Ag), protein C activity (PC:A), and protein S activity (PS:A) were measured in the peripheral blood of each family member by a Stago instrument. Peripheral blood was also extracted and sequenced to identify possible genetic mutation sites. The functional impact of variants on protein was subsequently analyzed by bioinformatics software.The proband, her mother, and brother all exhibited decreased activity and antigen of AT but normal PC and PS activity. The proband's father had normal activity and antigen levels of AT, PC, and PS. Sequencing revealed the proband's mother inherited the SERPINC1:c.661T > C,p.(Trp221Arg) heterozygous variant and her father harbored PROC:c.572_574del,p.(Lys193del) heterozygous variant while the proband as well as her brother carried both. Conservation analysis revealed that Trp221 is highly conserved across homologous species. Bioinformatics tools consistently classify the p.Trp221Arg mutation as "pathogenic" or "deleterious." Protein modeling indicated that the p.Trp221Arg variant does not alter the protein structure but may modify glycosylation sites to affect its function.The proband and family members exhibited varying degrees of decreased levels of AT and thrombosis, which were closely associated with inheritance of SERPINC1:c.661T > C,p.(Trp221Arg).

Compared with an arterial thrombus (AT) or a venous thrombus (VT), there is limited knowledge about arteriovenous thrombus (AVT). AVT develops in 69% of arteriovenous fistulae (AVF) and 50% of arteriovenous grafts (AVG) within 1 year. Thrombosis remains one of the major complications after creation of a vascular access often resulting in failure of the access.To characterize and differentiate AVT from VT or AT.An AVT model was established by a needle puncture through the aorta to the inferior vena cava (IVC) in wild type mice and different reporter mice and compared with a mouse venous thrombus (VT) model using IVC ligation. AVT was also examined under defined arteriovenous flow conditions. AVT was examined by gross view, histology, immunofluorescence, and scanning electron microscopy.AVT occurs immediately at the juxta-anastomotic area (JAA) after successful arteriovenous flow was established, with platelets being a major component of early AVT. Reduced injury to the endothelium resulted in smaller AVT, whereas local delivery of rapamycin to inhibit cell proliferation failed to decrease the volume of the AVT. Incomplete reendothelialization of the peri-fistula exit area correlated with growth of the AVT. AVT universally presents at the JAA in other arteriovenous models.We provide the first detailed histopathological characterization of AVT induced by AVF. AVT originates from the injured vessel wall and is more similar to AT than VT. This model provides a valuable tool to characterize AVT. Both this AVT model and our data have potential for clinical translation.

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.