Thrombosis and haemostasis最新文献

Background:  Many platelet agonists mediate their cellular effects through G protein-coupled receptors (GPCRs) to induce platelet activation, and GPCR kinases (GRKs) have been demonstrated to have crucial roles in most GPCR functions in other cell types. Here, we investigated the functional role of GRK3 and the molecular basis for the regulation of GPCR desensitization by GRK3 in platelets.

Methods:  We used mice lacking GRK3 as well as β-arrestin2, which has been shown to be important in GPCR function in platelets.

Results:  Platelet aggregation and dense granule secretion induced by 2-MeSADP, U46619, thrombin, and AYPGKF were significantly potentiated in both GRK3 -/- and β-arrestin2 -/- platelets compared with wild-type (WT) platelets, whereas non-GPCR agonist collagen-induced platelet aggregation and secretion were not affected. We have previously shown that GRK6 is not involved in the regulation of G_q-coupled 5HT_2A and G_z-coupled α_2A adrenergic receptors. Interestingly, in contrast to GRK6, platelet aggregation induced by costimulation of serotonin and epinephrine, which activate 5-HT_2A and α_2A adrenergic receptors, respectively, was significantly potentiated in GRK3 -/- platelets, suggesting that GRK3 is involved in general GPCR regulation. In addition, platelet aggregation in response to the second challenge of adenosine diphosphate was restored in GRK3 -/- platelets, whereas restimulation of the agonist failed to induce aggregation in WT platelets, confirming that GRK3 contributes to general GPCR desensitization. Furthermore, 2-MeSADP- and AYPGKF-induced AKT and ERK phosphorylation were significantly potentiated in GRK3 -/- platelets. Finally, GRK3 -/- mice showed shorter tail bleeding times compared with WT, indicating that GRK3 -/- mice is more susceptible to hemostasis.

Conclusion:  GRK3 plays a crucial role in the regulation of platelet activation through general GPCR desensitization in platelets.

Background:  The occurrence and development of ST-segment elevation myocardial infarction (STEMI) are accompanied by coronary atherothrombosis and occlusion, and immune responses play prominent roles in their pathogeneses. However, the causes of atherothrombosis remain elusive, and a comprehensive study of T cell-mediated immune responses in coronary thrombi from STEMI patients is lacking.

Objectives:  The aim of this study was to determine the heterogeneity and clonality of CD3⁺ T lymphocytes in STEMI patients at the single-cell level.

Methods:  Paired single-cell RNA and T cell receptor (TCR) sequencing was performed on CD3⁺ T lymphocytes in the coronary thrombi and peripheral blood of STEMI patients, as well as the blood from control subjects without coronary artery disease (CAD).

Results:  Compared with those in the peripheral blood of STEMI patients, the activation, cytotoxicity, proinflammatory, and prothrombotic characteristics of CD3⁺ T lymphocytes in coronary thrombi were decreased, and the clonality of CD3⁺ T cells was increased. Compared with those from non-CAD controls, T lymphocytes from STEMI patients exhibited an upregulation of genes related to recent TCR engagement, suggesting antigen-specific stimulation in STEMI. Antigen specificity prediction using an algorithm indicated the probability of T cells from different patients binding to similar antigens for clonal expansion during STEMI.

Conclusion:  This study provides a basis for exploring the cellular heterogeneity of CD3⁺ T lymphocytes in the coronary thrombi and peripheral blood of STEMI patients. Identifying the precise adaptive immune mechanisms driving atherothrombosis may lead to innovative therapies that selectively target the aberrant immune response, resulting in more effective treatments for STEMI.

Background:  Real-world data on clinical characteristics and outcomes related to the use of different direct oral anticoagulants (DOACs) for cancer-associated venous thromboembolism (VTE) is lacking.

Methods:  The COMMAND VTE Registry-2 is a multicenter registry enrolling 5,197 consecutive patients with acute symptomatic VTE from 31 centers in Japan from January 2015 to August 2020. Our study population comprised 1,197 patients with active cancer who were divided into the edoxaban (N = 643, 54%), rivaroxaban (N = 297, 25%), and apixaban (N = 257, 22%) groups.

Results:  The cumulative 5-year incidence of recurrent VTE (9.3, 10.2, and 8.5%, respectively, p = 0.82) and all-cause death (67.5, 66.8, and 63.8%, respectively, p = 0.22) did not differ among the groups. Despite adjusting for confounders, the risks of recurrent VTE and all-cause death did not differ significantly among the groups. The cumulative 5-year incidence of major and clinically relevant bleeding was significantly lower in the rivaroxaban group than those in the other groups (22.6, 14.0, and 22.8%, p = 0.04; and 37.6, 26.8, and 38.3%, p = 0.01, respectively). After adjusting for confounders, in the rivaroxaban group, the risk for major bleeding was numerically lower (hazard ratio [HR]: 0.65, 95% confidence interval [CI]: 0.40-1.01) and that of clinically relevant all bleeding was significantly lower (HR: 0.67, 95% CI: 0.48-0.92) than those in the edoxaban group.

Conclusion:  The risks of recurrent VTE and all-cause death did not differ significantly among the different DOACs ; however, the risk of bleeding events could differ, with a potentially lower risk of bleeding with rivaroxaban.

Background:  Thromboangiitis obliterans (TAO) is a vascular condition characterized by poor prognosis and an unclear etiology. This study employs Mendelian randomization (MR) to investigate the causal impact of circulating inflammatory proteins on TAO.

Methods:  In this MR analysis, summary statistics from a genome-wide association study meta-analysis of 91 inflammation-related proteins were integrated with independently sourced TAO data from the FinnGen consortium's R10 release. Methods such as inverse variance weighting, MR-Egger regression, weighted median approaches, MR-PRESSO, and multivariable MR (MVMR) analysis were utilized.

Results:  The analysis indicated an association between higher levels of C-C motif chemokine 4 and a reduced risk of TAO, with an odds ratio (OR) of 0.44 (95% confidence interval [CI]: 0.29-0.67; p = 1.4 × 10^-4; adjusted p = 0.013). Similarly, glial cell line-derived neurotrophic factor exhibited a suggestively protective effect against TAO (OR: 0.43, 95% CI: 0.22-0.81; p = 0.010; adjusted p = 0.218). Conversely, higher levels of C-C motif chemokine 23 were suggestively linked to an increased risk of TAO (OR: 1.88, 95% CI: 1.21-2.93; p = 0.005; adjusted p = 0.218). The sensitivity analysis and MVMR revealed no evidence of heterogeneity or pleiotropy.

Conclusion:  This study identifies C-C motif chemokine 4 and glial cell line-derived neurotrophic factor as potential protective biomarkers for TAO, whereas C-C motif chemokine 23 emerges as a suggestive risk marker. These findings elucidate potential causal relationships and highlight the significance of these proteins in the pathogenesis and prospective therapeutic strategies for TAO.

Background:  Deep vein thrombosis (DVT) is a common condition associated with significant mortality due to pulmonary embolism. Despite advanced prevention and anticoagulation therapy, the incidence of venous thromboembolism remains unchanged. Individuals with elevated hematocrit and/or excessively high erythropoietin (EPO) serum levels are particularly susceptible to DVT formation. We investigated the influence of short-term EPO administration compared to chronic EPO overproduction on DVT development. Additionally, we examined the role of the spleen in this context and assessed its impact on thrombus composition.

Methods:  We induced ligation of the caudal vena cava (VCC) in EPO-overproducing Tg(EPO) mice as well as wildtype mice treated with EPO for two weeks, both with and without splenectomy. The effect on platelet circulation time was evaluated through FACS analysis, and thrombus composition was analyzed using immunohistology.

Results:  We present evidence for an elevated thrombogenic phenotype resulting from chronic EPO overproduction, achieved by combining an EPO-overexpressing mouse model with experimental DVT induction. This increased thrombotic state is largely independent of traditional contributors to DVT, such as neutrophils and platelets. Notably, the pronounced prothrombotic effect of red blood cells (RBCs) only manifests during chronic EPO overproduction and is not influenced by splenic RBC clearance, as demonstrated by splenectomy. In contrast, short-term EPO treatment does not induce thrombogenesis in mice. Consequently, our findings support the existence of a differential thrombogenic effect between chronic enhanced erythropoiesis and exogenous EPO administration.

Conclusion:  Chronic EPO overproduction significantly increases the risk of DVT, while short-term EPO treatment does not. These findings underscore the importance of considering EPO-related factors in DVT risk assessment and potential therapeutic strategies.

Background:  Japanese Association for Acute Medicine (JAAM) disseminated intravascular coagulation (DIC) criteria were launched nearly 20 years ago. Following the revised conceptual definition of sepsis and subsequent omission of systemic inflammatory response syndrome (SIRS) score from the latest sepsis diagnostic criteria, we omitted the SIRS score and proposed a modified version of JAAM DIC criteria, the JAAM-2 DIC criteria.

Objectives:  To validate and compare performance between new JAAM-2 DIC criteria and conventional JAAM DIC criteria for sepsis.

Methods:  We used three datasets containing adult sepsis patients from a multicenter nationwide Japanese cohort study (J-septic DIC, FORECAST, and SPICE-ICU registries). JAAM-2 DIC criteria omitted the SIRS score and set the cutoff value at ≥3 points. Receiver operating characteristic (ROC) analyses were performed between the two DIC criteria to evaluate prognostic value. Associations between in-hospital mortality and anticoagulant therapy according to DIC status were analyzed using propensity score weighting to compare significance of the criteria in determining introduction of anticoagulants against sepsis.

Results:  Final study cohorts of the datasets included 2,154, 1,065, and 608 sepsis patients, respectively. ROC analysis revealed that curves for both JAAM and JAAM-2 DIC criteria as predictors of in-hospital mortality were almost consistent. Survival curves for the anticoagulant and control groups in the propensity score-weighted prediction model diagnosed using the two criteria were also almost entirely consistent.

Conclusion:  JAAM-2 DIC criteria were equivalent to JAAM DIC criteria regarding prognostic and diagnostic values for initiating anticoagulation. The newly proposed JAAM-2 DIC criteria could be potentially alternative criteria for sepsis management.