Platelets最新文献

Background and aims: Transgender men (female sex assigned at birth, male gender identity) who use testosterone have a higher cardiovascular risk compared to women and men from the general population, which cannot be fully attributed to traditional cardiovascular risk factors. Platelet activation and (endothelial) inflammation are interconnected mechanisms in the process of primary hemostasis, and thus the development of cardiovascular disease, but the impact of testosterone on these mechanisms is largely unexplored. Hence, we aimed to investigate the effect of testosterone on platelet activation and inflammation in vivo.

Methods: In this prospective cohort study 18 transgender men were included. Blood samples were taken at baseline and at 6, 12 and 52 weeks after testosterone initiation. We measured seven platelet activation markers (plasma thromboxane B2, Closure Time measured in two ways, CD63, CD62p, platelet-leukocyte complexes, immature platelet fraction), and twelve inflammation markers (high sensitivity CRP and 11 cytokines). Percentage changes relative to baseline were calculated at each time point using linear mixed model analyses.

Results: Platelet activation markers CD63, CD62p, and platelet-leukocyte complexes exhibited an initial tendency to increase at week 6, then slightly decreased at week 12, and again increased at week 52. Closure Time and immature platelet fraction remained stable throughout the study period. The collective of inflammation markers exhibited an overall tendency toward increase throughout the study period, which was most pronounced at week 52.

Conclusion: The results suggest that testosterone administration may increase platelet activation and inflammation. This may contribute to the higher cardiovascular risk in transgender men.

Study registration: EudraCT #2017-003072-31.

Objectives: To compare the effect of ticagrelor and clopidogrel on net clinical outcomes in patients with acute coronary syndrome (ACS) and assess the CRUSADE score's utility in guiding the selection of P2Y12 inhibitors.

Design: Nationwide observational cohort study using data from the CCC-ACS registry.

Setting: About 159 tertiary hospitals and 82 secondary hospitals across China.

Participants: About 70,319 patients with ACS who were prescribed dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor within 24 h of the first medical contact. Inclusion criteria were based on ACS diagnosis, and exclusion criteria included coronary artery bypass grafting, thrombolysis, use of oral anticoagulants, atrial fibrillation, or incomplete data.

Main outcome measures: Primary endpoint was in-hospital net adverse clinical events (NACE) defined as the composite of all-cause mortality, major ischemic events (recurrent myocardial infarction, stent thrombosis, ischemic stroke), and major bleeding (BARC types 3b, 3c, 5). Secondary endpoints included all-cause mortality, major ischemic events, major bleeding, intracranial bleeding, and major adverse cardiovascular events (MACE).

Results: After propensity score matching, no significant difference was found in NACE (1.6% in both groups; OR 0.97, 95% CI 0.82 to 1.16, p = .74) or all-cause mortality (0.7% in both groups; OR 0.92, 95% CI 0.71 to 1.20, p = .55) between ticagrelor and clopidogrel. However, ticagrelor was associated with significantly lower risks of MACE (1.0% vs. 1.2%; OR 0.80, 95% CI 0.65 to 0.99, p = .04) and major ischemic events (0.4% vs. 0.5%; OR 0.70, 95% CI 0.51 to 0.96, p = .03), but higher risks of major bleeding (1.6% vs. 1.1%; OR 1.50, 95% CI 1.24 to 1.81, p < .001), intracranial bleeding (0.3% vs. 0.1%; OR 2.24, 95% CI 1.35 to 3.72, p = .002), and gastrointestinal bleeding (0.9% vs. 0.5%; OR 1.74, 95% CI 1.33 to 2.28, p < .001). The CRUSADE score significantly interacted with the impact of P2Y12 inhibitor choice on clinical outcomes. In those with a CRUSADE score >40, ticagrelor was linked to higher risks of NACE (p = .03) and all-cause mortality (p = .04), while lower CRUSADE scores (<30) favored the use of ticagrelor.

Conclusions: In this observational study of in-hospital outcomes, ticagrelor was associated with reduced ischemic events but increased bleeding risks compared to clopidogrel in ACS patients. The CRUSADE score could be used to identify patients who may benefit from either clopidogrel or ticagrelor. Personalized treatment strategies using clinical risk scores may help optimize outcomes and minimize bleeding complications in ACS management.

Trial registration: ClinicalTrials.gov (NCT02306616).

Cardiometabolic risk factors, obesity, diabetes and hyperlipidemia contribute to cardiovascular disease (CVD). While platelets are involved in CVD pathogenesis, the relationship between risk factor burden on platelet indices and the platelet transcriptome remains uncertain. Blood was collected from CVD-free adults, measuring platelet count, mean platelet volume (MPV), immature platelet fraction (IPF), and absolute immature platelet fraction (AIPF) by hemogram. Platelets were isolated and analyzed via RNA sequencing. Participants were stratified by number of cardiometabolic risk factors (diabetes, obesity, hyperlipidemia). We calculated median (IQR) values of platelet indices and p-for-trend via linear regression across risk factor burden. To evaluate the association between risk factor burden and platelet transcripts, we performed multivariable linear regression adjusting for age, sex, and race/ethnicity. Among 141 participants, (50.5 ± 14.8 years, 42% male, 26% Black) risk factor burden was associated with increasing platelet size, IPF, and AIPF but not platelet count. Platelet RNA sequencing identified 100 differentially expressed transcripts (p < .01; 66 upregulated, 34 downregulated). Gene ontology enrichment analysis demonstrated upregulated pathways of secondary metabolic processes (NES = 1.96, p < .01), and hematopoietic stem cell proliferation (NES = 1.95, p < .01). Greater cardiometabolic risk factor burden is associated with increased platelet size and immaturity and suggesting novel platelet-mediated mechanisms linking risk factor burden with CVD.

Xanthone, a naturally occurring oxygenated heterocyclic compound from the Garcinia family with known anti-cancer, antimicrobial, antioxidant, anti-inflammatory, and antiviral properties, has an unclear role in platelet function. This study investigated its effects by incubating human platelets with xanthone at doses of 0, 5, 10, and 20 μM for 1 hour to analyze platelet aggregation, granule release, activation, receptor expression, spreading, and clot retraction, while also administering xanthone (10 mg/kg) to mice to evaluate its impact on hemostasis, arterial, and venous thrombosis. Our findings demonstrated that xanthone dose-dependently reduced platelet aggregation and granule release induced by collagen-related peptide (CRP) or thrombin without altering the surface expression of receptors αIIbβ3, GPIbα, and GPVI; it also significantly inhibited platelet spreading on collagen or fibrinogen, thrombin-mediated clot retraction, and decreased phosphorylation of c-Src and PLCγ2 in treated platelets. In vivo, xanthone-administered mice exhibited prolonged tail bleeding time and impaired arterial and venous thrombosis. Mechanistically, xanthone inhibited NF-κB activation, phosphorylation of ERK1/2 and p38, calcium mobilization, and platelet procoagulant activity. These findings indicate that xanthone impairs platelet activation and both arterial and venous thrombus formation, suggesting its potential as a novel agent for treating thrombotic or cardiovascular diseases.

Inherited delta storage pool deficiencies are likely underdiagnosed due to limitations in available diagnostic tools. Achieving accurate diagnosis is thus challenging for clinical laboratories highlighting the need for improved methods. Our aim was to explore thiazole orange (TO) as a flow cytometric marker for dense granules and compare it with mepacrine, reported to have low positive predictive value, after optimization of both protocols. TO, typically used for reticulocyte marking, binds dense granules at high concentrations producing a strong signal in resting platelets. Upon activation, the signal substantially decreased due to degranulation, which was less pronounced for mepacrine. Gradual dense granule release could only be followed with TO indicating that solely TO can distinguish quantitative defects from release defects. In a small pilot study TO staining was compared to light aggregometry and flow cytometric CD63 exposure in patients with suspected inherited platelet disorders. Of 15 samples, five showed abnormal TO results; in three, the other methods agreed with granule defects, but solely TO differentiates quantitative defects from release defects. Of note, two samples showed slightly decreased TO staining, despite normal aggregometry and CD63 exposure. TO is a promising diagnostic tool for dense granule defects and may be a valuable complement in the diagnostic workup for inherited platelet disorders.

Background: Clopidogrel and aspirin are widely used antiplatelet agents. Although clopidogrel resistance is more prevalent in Asian populations, a Korean study suggested that clopidogrel was superior to aspirin in patients who completed standard dual antiplatelet therapy following percutaneous coronary intervention. However, the comparative effectiveness of clopidogrel versus aspirin in populations with lower levels of clopidogrel resistance remains to be further investigated.

Methods: This study included 1,007 participants from NHANES 1999-2018 who were receiving aspirin or clopidogrel monotherapy. Cox proportional hazards regression and Kaplan-Meier survival analyses were used to compare the risks of mortality between the two groups. Sensitivity analyses were conducted by excluding individuals who died within the first 6 months of follow-up.

Results: Across all Cox models, clopidogrel use was associated with significantly higher risks of all-cause mortality (Model 1, HR1.47, 95%CI 1.20-1.79, p < .01; Model 2, HR1.25, 95%CI 1.02-1.54, p = .03; Model 3, HR 1.33, 95%CI 1.08-1.64, p = .01; Model 4, HR1.31, 95%CI 1.06-1.63, p = .01), stroke and cardiac mortality (Model 1, HR1.76, 95%CI 1.27-2.43, p < .01; Model 2, HR1.41, 95%CI 1.01-1.97, p = .04; Model 3, HR 1.54, 95%CI 1.10-2.17, p = .01; Model 4, HR1.47, 95%CI 1.03-2.08, p = .03) compared with aspirin. These associations remained consistent in sensitivity analyses. Kaplan-Meier survival curves also indicated higher risks of all-cause mortality, stroke and cardiac mortality in the clopidogrel group relative to the aspirin group.

Conclusion: In this community-based population, clopidogrel monotherapy was associated with higher risks of all-cause mortality, stroke and cardiac mortality compared with aspirin.

Immune thrombocytopenia (ITP) is an autoimmune disease with isolated platelet count decrease. A subset of patients responds inferiorly to the first-line therapies including glucocorticoid and intravenous immunoglobulins (IVIG), of which the underlying mechanisms have not been fully elucidated. We first found that expression of miR-28-5p was obviously increased in complete responders, and decreased to substantially low levels in partial or non-responders. In the passive ITP model, upregulation of miR-28-5p by injecting agomir slightly improved thrombocytopenia, and obviously inhibited the Rap1b gene expression. Luciferase reporter assay demonstrated there was significant decrease of luciferase activity in 293T cells co-transfected with miR-28-5p mimics and plasmids with Rap1b wide-type sequence. Upregulation of miR-28-5p, and downregulation of Rap1b played a favorable role in reducing B cell infiltration in the marginal zone of spleen in mice. However, miR-28-5p exhibited no significant influence on megakaryocyte maturation in ITP both in vitro and in vivo studies. Finally, we confirmed that miR-28-5p upregulation was associated with superior early treatment response in ITP, and possibly functioned by targeting Rap1b gene to inhibit humoral immunity.

Platelet storage is associated with storage lesions, including platelet morphological changes and a gradual functional loss. We investigated the impact of complement C3 inhibition on complement activation and platelet storage lesions in clinical platelet concentrates. Platelet concentrates (n = 8) were prepared in PAS-E and stored for seven days at 22°C. Each concentrate was split in two, with the C3 inhibitor compstatin Cp40 added to one part, and the other serving as the control. Complement and platelet activation markers, platelet function, and metabolic measures were analyzed every second day. Cp40 significantly reduced C3bc and sC5b-9 levels, but not C4c, indicating inhibition of complement activation at the level of C3. However, Cp40 did not affect platelet-specific or metabolic measures. Surface expression of CD62P and NAP-2 release increased significantly over the storage time, whereas CD63 expression and PF4 and TSP-1 release remained stable. Platelet responses to TRAP-6 mediated PAR-1 activation and U46619 mediated TXA₂R stimulation decreased over time, recorded as CD62P and CD63 expression and release of soluble factors. No drop in platelet count was observed, and metabolic markers remained within their critical limits. While C3 inhibition effectively reduced complement activation in stored platelet concentrates, it did not mitigate platelet storage lesions.

Optimal long term antithrombotic treatment in high-risk chronic coronary syndrome (CCS) patients remains uncertain. Both ticagrelor (60 mg BID) and low-dose rivaroxaban (2.5 mg BID) in addition to low-dose aspirin resulted in significant reductions in major cardiovascular events in high-risk patients at the expense of increased bleeding risk. We aimed to compare the effects of both strategies on bleeding time, fibrin clot lysis time and inflammatory biomarkers in CCS patients with history of acute coronary syndrome. Twenty aspirin-treated patients were recruited into a randomized crossover study to receive ticagrelor 60 mg BID in 1 week and rivaroxaban 2.5 mg BID in the other with a 2-week washout period in between. Outcome measures were determined at the start and end of each treatment week. Two-way ANOVA was used to determine difference in treatment effect. Data are presented as mean ± SD. At baseline, there was no significant difference in any studied outcome measure. Bleeding time was significantly longer with ticagrelor compared to rivaroxaban (Ticagrelor: 897 ± 481secs vs. Rivaroxaban: 440 ± 184 secs; p = .0001). Fibrin clot lysis time was not impacted by ticagrelor but significantly dropped post treatment with rivaroxaban (Ticagrelor: 5743 ± 2590 secs vs. Rivaroxaban: 4309 ± 2308 secs; p = .0049). Neither treatment had an impact on levels of high-sensitivity CRP or white cell count. In conclusion, ticagrelor 60 mg BID has greater impact on bleeding time compared to rivaroxaban 2.5 mg BID. Whereas rivaroxaban, positively modulates fibrin clots, rendering them more prone to lysis.