FUT8 (fucosyltransferase 8) adds core fucose to the innermost N-acetylglucosamine of N-glycans on surface receptors, affecting ligand binding and downstream signaling in various cellular contexts. Here, we examine the role of FUT8-catalyzed core fucosylation in platelet activity in vivo, and we evaluate the potential antithrombotic strategy of FUT8 inhibition. To investigate whether the extracellular domains of platelet adhesion receptors are core fucosylated, we used genetic, biochemical, glycomics, and glycoproteomics approaches. To investigate the impact of core fucosylation on platelet receptors for their ligand affinity, platelet activation, and downstream signaling, we used binding assays, platelet aggregometry, and phospho-specific effector antibodies. To investigate the biological effect of genetic and pharmacological inhibition of FUT8, we used murine thrombosis models. We identified core fucosylated N-glycans in the extracellular domains of platelet adhesion receptors, such as GPVI (glycoprotein VI) and integrin αIIbβ3. Core fucosylation at platelet GPVI or αIIbβ3 N-glycans enhanced affinity and binding to type I collagen or fibrinogen, leading to greater platelet activation and downstream signaling. In 2 murine thrombosis models, platelet-specific Fut8 deletion inhibited platelet activation and thrombus formation. Furthermore, FUT8 inhibition with FDW028 led to reduced platelet aggregation and activation, protecting mice from lethal thrombosis. This study provides genetic and pharmacological evidence that FUT8-mediated core fucosylation of platelet receptors promotes platelet activation and thrombus formation. Our results suggest that FUT8 in platelets may be a therapeutic target for thrombosis-related cardiovascular diseases.

The effect of different compounds on platelet activation. After the preparation and counting of PRP cells, the samples were activated with other compounds. The amount of ions, protein, growth factors, and cytokines present in the samples and the level of platelet activation were measured.

HSP47 inhibitor Col003 attenuates thromboinflammation after cerebral ischemia-reperfusion by suppressing GPVI-mediated CD84 shedding in platelets.

Pathological platelet activation is central to cardiovascular disorders. Glycoprotein VI (GPVI), a pivotal collagen receptor, is a promising antithrombotic target. While earlier studies focused on the downstream effects of peroxisome proliferator-activated receptor γ (PPARγ) ligands, we recently identified the proximal PPARγ-Src family kinase (SFK) interaction as a key regulatory node. KR-62980 is a novel non-thiazolidinedione (non-TZD) PPARγ modulator designed to minimize traditional TZD-associated adverse effects. Here, we investigated whether KR-62980 operates through this "proximal mechanism." We found that KR-62980 dose-dependently inhibited collagen-induced human platelet aggregation in both washed platelets and platelet-rich plasma. Notably, KR-62980 exhibited a predominant sensitivity toward the collagen-GPVI axis compared to thrombin-induced protease-activated receptor signaling. Mechanistically, KR-62980 targeted the top of the GPVI signaling hierarchy by disrupting the physical and functional association between PPARγ and SFKs (Lyn and Fyn). This blockade suppressed SFK autophosphorylation and dismantled the LAT signalosome, preventing the recruitment of Gads, SLP-76, Btk, and PLCγ2. These findings confirm that the "proximal interaction" paradigm is a universal feature of PPARγ-mediated antiplatelet action, regardless of the agonist's chemical structure. In vivo, oral administration of KR-62980 significantly prolonged thrombotic occlusion time in a mouse carotid artery thrombosis model. Importantly, at therapeutic doses, KR-62980 did not significantly affect tail bleeding time, demonstrating a favorable safety profile with a wide therapeutic window. These findings confirm that the "proximal interaction" paradigm is a universal feature of PPARγ-mediated antiplatelet action and suggest that KR-62980 is a promising candidate for safe antithrombotic therapy.

Blood pumps generate non-physiological shear stress (NPSS) that activates platelets and disrupts haemostasis. Ticagrelor is used in antiplatelet therapy for mechanical circulatory support, yet its effects under NPSS remain unclear. This study investigated how ticagrelor and NPSS interact to modulate platelet haemostatic function. Citrated bovine blood was circulated in a Rotaflow loop (500 ml, 5.0 l·min-1, ΔP of 0, 100 and 350 mmHg) for up to 3 h. Ticagrelor (20 μM) was administered either before circulation or after shear stress exposure. Flow cytometry and aggregometry quantified platelet activation, P2Y12 receptor surface expression, adhesion and aggregation. Proteomics compared signalling across treatment sequences, and thromboelastography (TEG) assessed clot kinetics. NPSS increased P-selectin, GPIIb/IIIa expression and fibrinogen adhesion and reduced P2Y₁2 receptor surface expression. Ticagrelor suppressed adenosine diphosphate (ADP)-induced aggregation and attenuated shear-driven platelet activation and also mitigates shear-induced loss of platelet P2Y₁2 surface expression. Proteomics showed lower Gi-coupled signalling and relative preservation of cAMP-PKA-related proteins, with the post-ticagrelor group showing the strongest suppression of activation signalling. As the ΔP of loop increases, the drug's ability to inhibit activation decreases. TEG showed faster clot initiation and growth after shear exposure, and these changes were most effectively moderated when ticagrelor was administered after shear exposure. NPSS activates platelets through pathways linked to Gi signalling. Ticagrelor reduced shear-induced activation, with the greatest reduction when used after shear. These findings support timing as a controllable variable during blood pump support.

The development of highly efficient hemostatic materials is of great significance for trauma treatment. Hemostasis occurs through the synchronous interaction of the following three mechanisms: vasoconstriction, platelet aggregation and blood coagulation. During the blood coagulation phase, the coagulation cascade converts fibrinogen into fibrin, forming a stable blood clot. This process involves the interaction of various plasma proteins, clotting factors, calcium ions (Ca2+), and platelets. To synergistically enhance vascular compression, platelet activation, and acceleration of the coagulation cascade, researchers have employed material compositing or modification to improve the functionality of hemostatic dressings. However, the isotropic hybrid materials struggle to perform their respective functions without interference. Janus materials, with their distinct chemical compartmentalization, can independently perform distinct functions on each side. Herein, we first provide a concise overview of the hemostatic process and mechanisms to establish the theoretical foundation for developing Janus hemostatic dressings and then focus on the latest research advances and development prospects of Janus-structured materials in the field of hemostatic management. Additionally, it discusses the future opportunities and challenges associated with Janus hemostatic dressing.

Thrombi are not uniform structures, and neither are the red blood cells (RBCs) that populate them. Most models of thrombosis, however, implicitly treat erythrocytes as mechanically and biologically uniform, obscuring a key determinant of clot architecture: RBC heterogeneity. Circulating RBCs vary widely in size, shape, deformability, membrane composition, and biochemical state, generating subpopulations that behave differently under flow and within forming thrombi. These differences actively govern how RBCs marginate, where they localize during thrombus growth, how they interact with fibrin and platelets, and how they resist or accommodate platelet-driven contraction. The outcome is not merely variable RBC content but spatially organized thrombi with region-specific mechanics, permeability, and fibrinolytic susceptibility. Experimental models and analyses of patient-derived thrombi demonstrate that RBCs are unevenly distributed within clots. This spatial variability shapes local fibrin architecture, platelet activity, and clot mechanics in ways that cannot be inferred from total RBC content or average erythrocyte properties, highlighting RBC heterogeneity as a critical, yet underrecognized, determinant of thrombus formation. In this review, we present a conceptual framework of thrombus heterogeneity along three coupled axes, namely, mechanical, structural, and biochemical, illustrating how erythrocyte subpopulations influence clot formation and function. We synthesize emerging evidence, discuss approaches for identifying RBC subpopulations, and explore implications for thrombosis modeling, thrombolysis, thrombectomy, and clinical outcomes.

Platelet G protein-coupled receptor (GPCR) signaling plays a central role in platelet activation and thrombus formation; however, much of our current understanding of GPCR regulation is derived from isolated platelets and single-receptor knockout mouse models, and it does not fully capture vascular bed-specific regulation in vivo . This review highlights recent advances in GPCR regulatory mechanisms, including GPCR kinases (GRKs) and biased signaling, and discusses the challenges posed by interspecies differences in modeling and interpreting human thrombin/PAR signaling. Recent work reveals distinct roles of platelets in arterial thrombosis versus venous thromboembolism, platelet heterogeneity within developing thrombi, and the emergence of procoagulant platelets as a functional link between coagulation and thromboinflammation. Together, these findings indicate that platelet GPCR signaling should be reconsidered in the context of vascular bed-specific cues, platelet-immune cell crosstalk, and the spatial organization of growing thrombi, highlighting its dynamic and context-dependent nature. Spatiotemporal regulation of platelet GPCR signaling provides a conceptual framework to better understand context-dependent platelet function in hemostasis and thrombosis and may inform the development of more selective antithrombotic strategies, including approaches that target specific GPCR downstream effectors or signaling bias while preserving physiological hemostasis.

Vascular consequences of antidepressant use: Balancing neuropsychiatric benefits and hemostatic risks.

Prevention of NMDA receptor sensitization by neurotoxic β-amyloid through polyphosphate coacervation.

Evaluating Four HIT Prediction Scores After Cardiac Surgery With Cardiopulmonary Bypass: A Comparative Study.

"Targeting platelets in breast cancer: Insights into pathophysiology and therapeutic strategies".

Platelets are the key cell types in haemostasis after vascular injury and crucially contribute to thrombus formation. In addition to their aggregation and clot contraction functions after stimulation by soluble agonists or extracellular matrix proteins, platelets can adopt a highly activated state known as procoagulant activation. Procoagulant platelets influence the pathophysiology underlying various cardiovascular diseases, including myocardial infarction, stroke and deep vein thrombosis. Findings described in the past decade position procoagulant platelets at the dynamic intersection between thrombosis and inflammation. In this Review, we discuss the expanding research on procoagulant platelets, describing how this platelet activation state contributes to macrovascular and microvascular clot formation in cardiovascular diseases. We summarize the key receptors and signalling pathways that control platelet procoagulant activation and that distinguish the procoagulant phenotype from other platelet activation states. Finally, we highlight the clinical significance of platelet procoagulant activation and discuss how the individual pathways involved in this activation can be targeted with the use of both readily available and novel therapeutic approaches, providing a framework for future research that might lead to new diagnostic and therapeutic applications in cardiovascular disease, septic inflammation and immune complex-mediated diseases.

Multiscale insights into thrombus growth and detachment under non-physiological blood flow.

BackgroundAcetylsalicylic acid (aspirin) is a widely used medication with antipyretic, anti-inflammatory, and antiplatelet effects. It also exhibits antitumor properties by enhancing immune responses, downregulating proinflammatory cytokines, and interfering with platelet-tumor cell interactions that promote metastatic dissemination. Identifying effective, safe interventions for brain metastases (BMs) remains a major clinical challenge.ObjectivesThis narrative review synthesizes mechanistic, preclinical, clinical, and safety evidence on aspirin's potential role in preventing or modulating brain metastasis and proposes possible preventive and adjuvant strategies for future investigation.DiscussionThe development of BMs involves tumor-derived factors, extracellular vesicles, and recruited host cells that remodel the brain microenvironment into a premetastatic niche. Platelet activation and the COX-1/TXA2 axis promote platelet-tumor cell aggregates, immune evasion, and endothelial adhesion-key steps in metastatic seeding. Aspirin may inhibit these processes by (1) irreversibly blocking platelet COX-1 (reducing TXA2 and aggregation), (2) lowering prostaglandin E2 (PGE2)-mediated immunosuppression, and (3) preserving blood-brain barrier (BBB) integrity. Preclinical and retrospective clinical studies provide supportive but heterogeneous evidence across cancer types. Combination strategies-aspirin with radiotherapy, antioxidants (e.g., ascorbic acid), or immunotherapy-are biologically plausible and supported by limited data. Major safety concerns remain, particularly bleeding risk and intracranial hemorrhage in patients with intracranial disease.ConclusionAspirin is a low-cost, biologically plausible adjunct for metastasis prevention. However, direct evidence in brain-metastasis settings is limited. Prospective trials with mechanistic biomarkers and careful safety monitoring are required to determine optimal dosing, timing, patient selection, and combination strategies.

Structural mechanisms for self-activation of protease-activated receptor 4 by tethered ligand.

Selective degradation of platelet BTK by PROTAC NX-5948 provides antithrombotic benefits without affecting haemostasis.

Platelet-rich fibrin (PRF), a second-generation platelet concentrate, has emerged as a promising autologous biomaterial in regenerative medicine. Unlike platelet-rich plasma (PRP), PRF is prepared without anticoagulants or biochemical additives, allowing natural platelet activation and fibrin polymerization. This process generates a three-dimensional fibrin matrix containing concentrated platelets, leukocytes, cytokines, and growth factors that collectively support tissue regeneration. Owing to these regenerative properties, PRF has been increasingly applied in oral and maxillofacial surgery. Despite its widespread clinical use, the precise biological mechanisms underlying PRF-mediated bone regeneration remain incompletely understood. PRF functions not only as a reservoir for growth factors, but also as a dynamic immunomodulatory scaffold that regulates inflammation, angiogenesis, cellular migration, and osteogenic differentiation. Recent evidence further suggests that leukocytes, fibrin architecture, cytokine networks, and osteoimmunological interactions within PRF play critical roles in coordinating tissue regeneration. This scoping review aims to summarize the current understanding of the biological mechanisms and regenerative potential of PRF in bone healing and oral and maxillofacial reconstruction. Particular emphasis is placed on the interplay between growth factor release, fibrin matrix structure, immune modulation, and cellular signaling pathways involved in osteogenesis. Furthermore, recent advances, limitations, and future perspectives regarding PRF optimization and clinical applications are discussed.

Platelet activation is traditionally viewed as a signaling process initiated by receptor engagement. In this issue of The FEBS Journal, Govatati etal. identify an additional regulatory layer linking lipid metabolism to receptor trafficking. The authors show that ALOX15-derived lipid mediators promote PKCθ-NMT1-dependent myristoylation of PAR4, thereby facilitating its membrane localization and platelet activation. These findings position receptor lipidation and trafficking as active regulatory mechanisms in platelet activation and suggest new opportunities for therapeutic modulation of hemostasis.

This study aimed to use machine learning to explore Behçet's syndrome (BS) heterogeneity by integrating immunocyte subpopulations and clinical characteristics. We prospectively enrolled BS patients and recorded their demographic and clinical characteristics. Various peripheral immune cells were analysed using flow cytometry. Unsupervised machine learning was used to perform cluster analysis based on the clinical manifestations and immune cell subsets. Patients were followed up for one year to evaluate treatment response and remission rates. RNA sequencing was performed in patients with clustered BS and healthy controls. Unsupervised machine learning categorized 201 BS patients into four clusters with distinct clinical and immunological features. Cluster 1 showed isolated mucocutaneous lesions, low inflammation, and high remission, with transcriptomic enrichment in IFN-γ, IL-6, and JAK-STAT pathways. Cluster 2 featured arthritis, elevated inflammatory levels, and responded well to TNF-α inhibitors, with transcriptomic enrichment in TNF and B-cell activation pathways. Cluster 3 had cardiovascular involvement, reduced CLA+ Tregs, and also responded to TNF-α inhibitors, with transcriptomic enrichment in coagulation, platelet activation, and MAPK pathways. Cluster 4 demonstrated neurological involvement, elevated CD161⁺ Tregs, low remission, and a better response to mycophenolate mofetil, with transcriptomic enrichment in T-cell activation and NF-κB pathways. Unsupervised clustering of BS patients revealed four distinct subtypes with significant clinical and immunological heterogeneity, which may provide a foundation for mechanistic studies and personalized treatment.