Platelets最新文献

The platelet integrin receptor, αIIbβ3, binds fibrinogen to mediate platelet-platelet contacts, regulate hemostasis, and modulate inflammation. The Triggering Receptor Expressed in Myeloid (TREM) - Like (TLT)-1 is an enigmatic 34kD receptor found on platelets that affects their hemostatic and inflammatory functions. Similar to αIIbβ3, TLT-1's ligand is also fibrinogen; however, TLT-1's direct role in platelet function remains unknown. We created a tamoxifen-inducible conditional αIIb deficient (^cItga2b^-/-) mouse to better understand TLT-1's role in platelet function, specifically TLT-1's binding to fibrinogen and its role in hemostasis and inflammation. We first characterized our ^cItga2b^-/- null mouse and subsequently crossed this mouse with a Treml1^-/- mouse, creating a conditional double knockout (^cDKO). While the floxed ^cItga2b /Treml1^-/- mouse shows significant differences compared to control mice, deleting Treml1 from the ^cItga2b^-/- mouse results in only minor differences from the ^cItga2b^-/- strain in bleeding, aggregation, fibrinogen deposition and platelet spreading assays. Our data suggest that while TLT-1 plays a visible role in hemostasis, it primarily supports aggregation but may not function as an adhesive component.

Inherited macrothrombocytopenia (IMT) is characterized by increased platelet volume. Using platelet parameters, including platelet count, mean platelet volume (MPV), platelet-large cell ratio (P-LCR), and platelet distribution width, to differentiate IMT from acquired thrombocytopenia (AT) in the Chinese population is unclear. This study aimed to evaluate these parameters and determine optimal thresholds for early IMT identification. This single-center, retrospective case-control study included IMT patients from 1 January 2022 to 31 January 2024. Age- and sex-matched AT patients and healthy individuals were selected (1:3 ratio). Platelet parameters were compared using a one-way analysis of variance and the Kruskal-Wallis test. The ability of platelet parameters to identify IMT was assessed using the receiver operating characteristic curve, with the optimal threshold determined using the Youden index. This study included 13 IMT patients, 39 AT patients, and 39 controls. The MPV and P-LCR were significantly higher in IMT than in AT patients (P < 0.05) and strongly differentiated between groups. The area under the curve (95% confidence interval) for MPV and P-LCR were 0.865 (0.724-1.000) and 0.860 (0.719-1.000), respectively. The optimal MPV and P-LCR thresholds for IMT were 14.55 fL and 58%, respectively. The MPV was most important for distinguishing IMT from patients with thrombocytopenia.

SARS-CoV-2 infection is associated with platelet hyperreactivity and increased rates of arterial and venous thrombosis. SARS-CoV-2 mutations have resulted in several variants with differences in transmissibility, infectivity, and patient outcomes. This study investigates the effects of the ancestral strain of SARS-CoV-2 (WA1) and two variants of concern, Delta and Omicron, on the human megakaryocyte (MK) phenotype and transcriptome. Human CD34⁺-derived MKs were incubated with WA1, Delta or Omicron SARS-CoV-2 variants for 24 hours. MK activation markers were measured under resting and thrombin-stimulated conditions. RNA-seq and cytokine release in response to the viruses were assessed. Plasma cytokines were measured in hospitalized COVID-19 patients. Treatment of MKs with WA1, Delta or Omicron variants of SARS-CoV-2 resulted in similar increases in classical activation markers. However, SARS-CoV-2 variants mediated distinct transcriptomic changes. Across variants, 60 genes overlapped, including CXCL8. Consistent with transcriptomic changes, SARS-CoV-2-incubated MKs secreted significantly elevated levels of IL-8. Among hospitalized COVID-19 patients, plasma IL-8 levels were highest in COVID-19 patients who subsequently experienced thrombotic events or died. In conclusion, WA1, Delta, and Omicron similarly induce classical MK activation responses while mediating distinct transcriptomic changes. Increased IL-8 levels may serve as a biomarker to inform platelet hyperreactivity and thrombotic events associated with COVID-19.

Transfusions of platelets are often used as prophylaxis in patients with hematologic malignancies and as treatment for active bleeding. However, platelets are in short supply due to the fact that they could only be kept for 5-7 days in vitro and they lose some of their functionality as a result of platelet storage lesions. To address this issue, refrigeration, cryopreservation and platelet additive solutions have been researched to determine their abilities to extend platelet storage duration. However, refrigerated platelets are quickly cleared after transfusion, while platelets in platelet additive solutions still present issues such as platelets quality and the risk of allergic reactions. Recent studies showed that changes in lipid metabolites during platelet storage and inadequate of fatty acid metabolism may also limit platelet shelf life and function. In this review, we address the principles of lipid metabolism during platelet storage and discuss the strategies for effective platelet storage systems. The findings of this review highlight the role of lipid metabolism during platelet storage, providing insights into future research focused on extending the preservation period and function of platelet.

Platelets are increasingly recognized as key players not only in hemostasis, but also in immunity and inflammation. However, the mechanisms and markers underlying their activation remain incompletely understood. This study aimed to decipher how platelets respond to different stimuli and to identify specific molecular signatures using computational approaches. Platelets from 10 healthy donors were stimulated under seven conditions, including TRAP (PAR-1), AYPGKF (PAR-4), ADP, collagen, sCD40L, fibrinogen, and a control. A total of 47 markers-encompassing membrane proteins, soluble mediators, and intracellular signals-were analyzed. Statistical and machine learning methods, including hierarchical clustering and random forest algorithms, were used to classify and interpret the data. Distinct activation profiles emerged for each agonist. A reduced panel of six markers (AKT, CD40L, CD62P, PKC, RANTES, and TSLP) enabled identification of the stimulus with 86.8% accuracy. Machine learning further improved classification (87.9% multiclass accuracy). Differences were also observed across donors, highlighting inter-individual variability. This work supports a new paradigm in which platelets act as "biological sensors," fine-tuning their responses to environmental cues. The identified biomarker panel provides a basis for further investigation into the characterization of platelet activation profiles, with potential relevance for future diagnostic and therapeutic applications in thromboinflammatory and immune-mediated conditions.

Coronary artery bypass grafting (CABG) triggers oxidative stress and platelet activation. High acetylsalicylic acid (ASA) dose might mitigate the transient proinflammatory state. We compared the effect of three ASA dosages on post-CABG platelet reactivity, oxidative stress, and serum CD39 and CD73 levels. Thirty-six consecutive patients undergoing elective off-pump CABG, pre-treated with ASA 1 × 75 mg for ≥7 days, were randomized to continue the prior treatment regimen, switch to ASA 1 × 150 mg, or ASA 2 × 75 mg. Blood was collected on admission, 7 days, 1 month, and 3 months after CABG. Platelet reactivity was assessed using impedance aggregometry. Platelet oxidative stress was measured as platelet mitochondria extracellular oxygen consumption rate and oxidatively damaged whole-blood DNA cleavage. Serum CD39 and CD73 levels were determined using ELISA. Platelet reactivity and oxidative stress parameters were comparable in all groups. Patients treated with ASA 2 × 75 mg had higher CD39 levels at 7 days and 1 month (p = .049, p = .033), compared to the control group. ASA 2 × 75 mg was associated a beneficial effect on serum CD39 levels after off-pump CABG, without a significant effect on oxidative stress parameters.

Immune-checkpoint blockades (ICBs) are now used in early-stage diseases like triple-negative breast cancer (TNBC). While effective, they can cause severe toxicities. We report the first case of life-threatening immune thrombocytopenia (ITP) induced by pembrolizumab during neoadjuvant chemo-immunotherapy for early TNBC. A 42-year-old woman with early-stage TNBC developed grade 4 thrombocytopenia, diagnosed as ITP, after 107 days of pembrolizumab treatment. She required intensive care unit (ICU) admission and high-dose steroids, and intravenous immunoglobulin therapy, leading to a rapid recovery. ITP is a rare but potentially fatal complication of immunotherapy, with an incidence of less than 1% and a mortality rate of up to 20% in affected patients. Immediate recognition and steroid therapy are critical, as platelet transfusion is usually ineffective. Diagnosis is often delayed due to its similarity to chemotherapy-induced marrow toxicity. Immunotherapy-induced ITP generally contraindicates further use of the treatment. ITP, although uncommon, is a serious complication of immunotherapy requiring immediate intervention. The growing use of immunotherapy necessitates increased awareness of its potential toxicities among healthcare providers.

Coagulation disturbances are major contributors to COVID-19 pathogenicity, but limited data exist on the involvement of extracellular vesicles (EVs) and residual cells (RCs). Fifty hospitalized COVID-19 patients stratified by their D-dimer levels into high (>1.5 mg/L, n = 15) or low (≤1.5 mg/l, n = 35) and 10 healthy controls were assessed for medium-sized EVs (mEVs; 200-1000 nm) and large EVs/RCs (1000-4000 nm) by high sensitivity flow cytometry. EVs were analyzed for CD61, CD235a, CD45, and CD31, commonly used to detect platelets, red blood cells, leukocytes or endothelial cells, respectively, whilst phosphatidyl serine EVs/RCs were detected by lactadherin-binding implicating procoagulant catalytic surface. Small EV detection (sEVs; 50-200 nm) and CD41a (platelet integrin) colocalization with general EV markers CD9, CD63, and CD81 were performed by single particle interferometric reflectance imaging sensor. Patients with increased D-dimer exhibited the highest number of RCs and sEVs irrespective of cell origin (p < .05). Platelet activation, reflected by increased CD61+ and lactadherin+ mEV and RC levels, associated with coagulation disturbances. Patients with low D-dimer could be discriminated from controls by tetraspanin signatures of the CD41a+ sEVs, suggesting the changes in the circulating platelet sEV subpopulations may offer added prognostic value during COVID progression.

Previous studies have reported inconsistent associations between platelet count (PLT) and cancer survival. However, whether there is linear causal effect merits in-depth investigations. We conducted a cohort study using the UK Biobank and a two-sample Mendelian randomization (MR) analysis. PLT levels were measured prior to cancer diagnosis. We adopted overall survival (OS) as the primary outcome. Cox models were utilized to estimate the effects of PLTs on survival outcomes at multiple lag times for cancer diagnosis. We employed 34 genetic variants as PLT proxies for MR analysis. Linear and non-linear effects were modeled. Prognostic effects of gene expression harboring the instrumental variants were also investigated. A total of 65 471 cancer patients were included. We identified a significant association between elevated PLTs (per 100 × 10⁹/L) and inferior OS (HR: 1.07; 95% CI: 1.04-1.10; p < .001). Similar significant associations were observed for several cancer types. We further observed a U-shaped relationship between PLTs and cancer survival (p < .001). Our MR analysis found null evidence to support a causal association between PLTs and overall cancer survival (HR: 1.000; 95% CI: 0.998-1.001; p = .678), although non-linear MR analysis unveiled a potential greater detrimental effect at lower PLT range. Expression of eleven PLT-related genes were associated with cancer survival. Early detection of escalated PLTs indicated possible occult cancer development and inferior subsequent survival outcomes. The observed associations could potentially be non-linear. However, PLT is less likely to be a promising therapeutic target.

ST-segment elevation myocardial infarction (STEMI) is usually caused by a ruptured atherosclerotic plaque, with subsequent thrombus formation. Platelet inhibition and primary percutaneous coronary intervention (PCI) are essential treatments. Morphine, used to relieve pain and anxiety in STEMI patients, delays the onset of P2Y12 inhibitors. This study aimed to further explore the association between platelet activity and morphine treatment in patients with STEMI. In this sub-study of the VALIDATE-SWEDHEART trial, 89 STEMI patients treated with ticagrelor, and primary PCI were included. Platelet aggregation and biomarkers of platelet activity, coagulation, and inflammation (sP-selectin, thrombin-antithrombin complexes, prothrombin fragments 1 + 2, CD40L, CRP, beta-thromboglobulin, and pentraxin3) were assessed at three time points: before, one, and twelve hours after PCI. Of the 89 patients, 40 received morphine before hospital arrival. There were no significant differences in age, sex, medical history, or coronary disease extent. One hour after PCI, ADP-induced (36 vs 61, p < .001), arachidonic acid-induced (20 vs 36, p = .003), collagen-induced (48 vs 60, p = .03) aggregation, and the proportion of high on-treatment ADP-induced platelet reactivity (27% vs 60%, p = .001) were significantly higher in morphine-treated patients. No significant differences were found before or 12 hours after PCI. No significant differences in platelet activity biomarkers were observed. Morphine increased platelet aggregation in STEMI patients but did not affect biomarkers.