Platelet-derived biotherapies are emerging as innovative approaches for complex neurological disorders requiring multimodal interventions. Platelet-derived products, including lysates, platelet concentrate supernatants, secretome, extracellular vesicles, and fractionated components, represent a scalable and clinically accessible biotechnology platform for precision neuromedicine. Platelets provide a reservoir of trophic factors, cytokines, chemokines, lipids, antioxidants, and noncoding RNAs with demonstrated neuroprotective, anti-inflammatory, and antiferroptotic effects in models of neurodegeneration, trauma, and aging. Preclinical and patient-derived omics and neuroimaging data can help characterize mechanisms of action, identify biomarkers, and refine platelet secretome preparations toward indication-specific formulations. Combined with virus inactivation and purification technologies adapted from plasma protein manufacturing, these advances position platelet-derived biotherapies as a rational and versatile path toward future acellular therapeutics for brain disorders.

BACKGROUND:Pathogen reduction treatment (PRT) of platelet concentrates (PC) is one of the most recent advances in improving blood safety and lowering the risk of transfusion-transmitted diseases. The characteristics of PR-treated PC differ slightly from those of untreated PC and may affect transfusion outcomes. We established how effective PRT methods, (INTERCEPT™ Blood System) PC are when transfused to cardiac surgery patients. MATERIALS AND METHODS:This study examined the influence of PRT using amotosalen and UVA light in a population of cardiac surgery patients. We analysed bleeding and platelet drop following cardiopulmonary bypass (CPB) surgery. We selected 73 patients after considering the medical exclusion criteria: 46 patients transfused with untreated platelet concentrate versus 27 patients transfused with PRT-treated platelet concentrate. RESULTS:Data analysis concerns the readout after the first platelet concentrate transfusion. The decrease in patient platelet count between pre-operative and H0 [Intensive Care Unit (ICU) admission], and pre-operative and H6 post-surgery did not differ significantly with or without PRT. The volume of postoperative bleeding after CPB surgery did not differ significantly regardless of whether the patient was transfused with PRT-PC or untreated PC. No difference was documented between the groups in terms of postoperative pulmonary infection rate. Regardless of the use of platelet PRT, among the factors associated with bleeding, only Fg level was independently and significantly associated. A 1mg/L increase in fibrinogen (pre-operative) is associated with a 159mL decrease in bleeding 24hours post-surgery. DISCUSSION:In postoperative cardiac surgery, the use of platelets treated with amotosalen/UVA for pathogen reduction does not appear to affect transfusion effectiveness and postoperative bleeding.

BACKGROUND:Granulocyte transfusion remains a therapeutic option for patients with severe neutropenia or granulocyte dysfunction, though its clinical benefit is still debated. Traditional pooled granulocyte concentrates (PGC) are produced by donor stimulation and apheresis, procedures that are costly and ethically restrictive. To overcome these limitations, PGC derived from buffy coat layers (BC) have emerged as a simpler and safer alternative, yet little is known about their platelet composition and activation profile. STUDY DESIGN /METHODS:Whole blood donations (n = 256) were processed into BC, pooled (20 BC per batch), and reconstituted to form PGC20 units. Hematologic parameters and platelet activation markers (CD41, CD62P, CD63) were analyzed by automated counting and flow cytometry and compared with standard apheresis (APC) and buffy coat-derived platelet concentrates (BC-PC). RESULTS:PGC show a high platelet concentration comparable to BC-PC, with an increased mean platelet volume. The elevated expression of CD62P and CD63 confirms marked platelet activation, while the slight decrease in CD41 suggests membrane alteration during processing, indicating a mixed platelet-granulocyte product with immunomodulatory potential that requires optimization for safe transfusional use. CONCLUSIONS:PGC derived from buffy coat pools combines high granulocyte yield with an activated platelet population. This bioactive platelet component may enhance immune interactions but warrants further optimization to ensure transfusion safety and product standardization.

Lipidomic analysis enables the detailed characterization of platelet concentrates from donors of different ages, offering valuable insights into the role of lipid mediators in aging and transfusion-related adverse reactions (AR). In this study, we analyzed lipidomic profiles from a cohort of single-donor apheresis platelet concentrates, classified into three age groups: 20-44, 45-59, and 60-70 years. Total levels of LPC, LPA, S1P, and eicosanoids did not exhibit significant age-related changes. However, LPA 18:1, LPC 18:1, and S1P levels decreased with advancing age. When examining the relationship between different age groups and their association with AR, we found that LPA, LPC, and eicosanoids are associated with AR in an age-dependent manner. Based on these findings, we investigated the effect of age-related levels of LPA, LPC, and S1P on platelet and endothelial cell biology. These lipid mediators were found to modulate platelet activation, as demonstrated by increased expression of P-selectin, phosphatidylserine, platelet aggregation, as well as endothelial activation, marked by elevated expression of ICAM-1, VCAM-1, and CD40. Our findings present a comprehensive lipidomic profile of single-donor apheresis platelet concentrates across various age groups, highlighting several lipid mediators that may be implicated in aging and AR.

Background Low-titer group O whole blood (LTOWB) is increasingly used for hemorrhagic resuscitation in trauma and critical care, but the phenotype of platelets maintained within refrigerated LTOWB remains incompletely characterized. Because platelet activation may influence not only hemostatic competence but also transfusion-related inflammatory and pulmonary responses in critically ill patients, we assessed platelet surface markers in LTOWB in comparison with standard platelet concentrates and examined their evolution during 8 days of cold storage.Methods LTOWB units prepared from qualified group O donors were stored under refrigerated conditions and studied at day 0 and day 8. Platelet phenotype was assessed by flow cytometry using CD41, CD62P, and CD63 under basal conditions and after thrombin receptor-activating peptide (TRAP) stimulation. LTOWB was compared with apheresis platelet concentrates (APC) and buffy coat-derived platelet concentrates (BC-PC).Results Compared with APC and BC-PC, LTOWB showed a broader distribution of CD41-positive events and a modestly lower median CD41 signal. Basal CD62P in LTOWB was lower than in APC but higher than in BC-PC, whereas basal CD63 in LTOWB was higher than in both comparator products. Between day 0 and day 8, basal CD62P and CD63 increased in LTOWB. TRAP induced marked upregulation of CD62P and CD63 at both time points; stimulated CD63 was lower at day 8 than at day 0, whereas stimulated CD62P remained high.Conclusion Cold-stored LTOWB displays a distinct platelet activation phenotype characterized by progressive basal activation during refrigerated storage together with persistent agonist-inducible responses through day 8. These findings justify further functional and translational studies integrating platelet, endothelial, and lung-injury readouts to determine whether this storage-associated phenotype has consequences for microvascular hemostasis, immunothrombosis, or transfusion-associated pulmonary complications after hemorrhagic resuscitation.

Platelet transfusions are essential in the management of thrombocytopenia, bleeding disorders, and hematologic malignancies. With cannabis use rising worldwide, its impact on donor platelet quality and transfusion efficacy remains poorly understood. This study investigated the effects of cannabis joint extracts (CJE) on platelet activation, pro-coagulant phenotype, mitochondrial function, and cytokine/chemokine release, with implications for transfusion safety. Human platelets were exposed in vitro to increasing concentrations of two CJE with distinct cannabinoid profiles: Orchid (O-CJE, THC 10.4%, CBD 14.7%) and QCGold (G-CJE, THC 25.5%, CBD 0.04%). Platelet activation (CD62P, Annexin V), mitochondrial depolarization, ATP levels, aggregation responses, and cytokine secretion (CCL3, PF4) were assessed. RBC lysate experiments were performed to assess the role of hemolysis. The involvement of CB1 and CB2 receptors was tested using specific antagonists, and activation of p38 MAPK and NF-κB pathways was evaluated. Functional effects of platelet supernatants were examined on EA.hy926 endothelial cells. CJE exposure induced dose-dependent platelet activation, characterized by increased CD62P expression, Annexin V binding, mitochondrial depolarization, and ATP depletion, consistent with metabolic stress. Platelet aggregation in response to ADP, collagen, and arachidonic acid was impaired, suggesting a pre-activated or refractory phenotype. RBC lysate did not reproduce the observed effects, indicating hemolysis is unlikely to be the underlying mechanism. CBR1 and CBR2 antagonists did not attenuate platelet activation, while signaling analysis revealed activation of p38 MAPK and NF-κB pathways. Exploratory proteomics indicated modulation of proteins involved in angiogenesis, cytoskeletal organization, and stress responses. Elevated plasma levels of CCL3 and PF4 and endothelial activation (IL-6 secretion, CD54, CD62P, CD62E expression) further suggested a pro-inflammatory environment. Cannabis exposure can alter platelet phenotype and signaling under in vitro conditions, potentially affecting platelet function and interactions with the vascular endothelium. However, these findings require confirmation in vivo to determine their clinical relevance. Future studies should aim to establish exposure thresholds and clarify whether cannabis use has implications for transfusion safety, given potential risks of reduced efficacy or increased thrombotic complications in recipients.

Red blood cell (RBC) exchanges (RCE) are particularly efficient to treat and prevent complications in patients with sickle cell anemia (SCA). However, the low weight of young children is a barrier to their use. Spectra Optia is a therapeutic apheresis platform that enables automatic priming to prevent hemodynamic complications in low-weight children. The easiest method is to use albumin for priming, which is allowed by the software. We conducted a retrospective monocenter analysis of the feasibility, safety, and efficacy of albumin priming during RCE (RCE/Alb-primed) in 19 children weighing 12 to 23 kg for a total of 153 sessions. They were treated either on an emergency basis (8 children, 8 sessions), before surgery (2 children, 4 sessions) or as part of a RCE program (9 children, 141 sessions). Indications of RCE/Alb-primed sessions included: (i) an extracorporeal volume of the kit equal to 15% of the child's total blood volume, (ii) a weight of less than 20 kg, or (iii) a weight between 20 and 25 kg with a hematocrit (Hct) of 20% or less. We monitored Grade 2 adverse events (AEs) during the sessions, in extenso decreased blood pressure, increased heart rate and fatigue. Post-apheresis hematocrit and the fraction of cell remaining (FCR) values after RCE were compared to the expected ones. A low incidence of complications was observed in the 153 RCE/Alb-primed sessions with only 1 episodes of transient Grade 2 AEs. Post-apheresis Hct and FCR reached expected values with the RCE/Alb-primed method. In conclusion, RCE/Alb-primed seems to be safe and efficient in young SCA children and should be proposed systematically for curative RCE or prophylactic programs.

Background: Platelets are crucial mediators at the crossroads of hemostasis, immunity, and inflammation, adapting their responses to diverse stimuli. Despite their recognized role, the precise pathways and markers associated with platelet activation remain poorly understood. This study aimed to unravel these mechanisms by evaluating platelet responses to various agonists, employing biomathematical models to map activation patterns and identify key biomarkers. Methods: Using samples from ten healthy donors, platelets were exposed to seven stimulation conditions: unstimulated, PAR-1 agonist TRAP, PAR-4 agonist AYPGKF, ADP, collagen, sCD40L, and fibrinogen. A comprehensive analysis of 47 biological markers - covering membrane activation, soluble mediators, and signaling pathways - was conducted. Statistical and machine learning models, including hierarchical clustering and random forests, were applied to classify and interpret platelet activation signatures. Results: Distinct activation profiles were observed for each agonist. A streamlined panel of six markers - AKT, CD40 ligand, CD62P (mean fluorescence intensity and percentage), PKC, RANTES, and TSLP - achieved 86.8% accuracy in identifying the activating stimulus. The study highlighted significant variations, influenced by both the stimulus and donor-specific factors. Machine learning approaches further refined classification, achieving a multiclass accuracy of 87.9%. Hierarchical clustering demonstrated clear distinctions, particularly between PAR-1/PAR-4 responses and other agonists. Conclusion: This innovative research redefines platelets as dynamic "biological sensors" capable of decoding complex danger signals. By integrating biomathematical modeling and artificial intelligence, it identifies a precise biomarker panel with transformative potential for diagnostics and therapies in inflammation and immune disorders. This work positions platelets not just as key players in hemostasis but as programmable agents for precision medicine, heralding a new era in adaptive, AI-driven healthcare solutions. ### Competing Interest Statement The authors have declared no competing interest.

BACKGROUND:Platelet components (PCs) with persistent aggregates are typically discarded. Few studies have characterized components with aggregates. A multicenter study was therefore conducted to determine whether PCs containing aggregates are more activated and whether donor attributes or processing methods influence aggregate formation. STUDY DESIGN AND METHODS:Seven international centers collected and tested apheresis PCs with persistent aggregates (n = 147), and controls without aggregates (n = 65). PCs were assigned a score (0-24), based on the size and number of aggregates. Platelet count, metabolism, activation markers (annexin-V, CD62P, cytokines, glycocalicin and prothrombin F1 + F2 fragments), extracellular vesicles (EVs), and function (collagen aggregation, TRAP-1, and ADP responses) were measured. A subset of PCs was filtered through a transfusion set. Donor attributes and processing methods were also assessed. Data were analyzed using a mixed model of linear regression. RESULTS:The median aggregate score in PCs with aggregates was 8. PCs with aggregates had a significantly lower glucose concentration, with significantly higher lactate levels. Platelets in PCs with aggregates were more activated, with significantly higher CD62P, annexin-V, and CD61/annexin-V-positive EVs, glycocalicin and prothrombin F1 + F2 fragments compared to controls. Although filtration removed aggregates, the activated platelet phenotype remained unchanged. PCs with aggregates came from older donors with a higher BMI, and from donors who had previously given donations with aggregates. CONCLUSIONS:Platelets in PCs with aggregates are markedly activated, and filtration does not change their phenotype. PCs containing many, large aggregates should be discarded, but those with fewer, small aggregates (aggregate score of 6 or less) could be retained.

IntroductionThe treatment of chronic viral infections can often bring viral replication under control. However, chronic immune activation persists and can lead to the development of comorbid conditions, such as cardiovascular disease and cancer. This is particularly true for people living with HIV (PLWH), who have significantly more extracellular vesicles from membrane budding, also called plasma microparticles (MPs), than healthy individuals (HDs), and a much more immunomodulatory phenotype. We hypothesized that the number and phenotypic heterogeneity of MPs can trigger a functional remodeling of immune responses in PLWH, preventing full immune restoration.MethodsWe investigated the rapid impact of three types of MPs — derived from membrane budding in platelets (CD41a+ PMPs), monocytes (CD14+ MMPs) and lymphocytes (CD3+ LMPs) in the plasma of PLWH or HDs—on four cell types (CD4+ and CD8+T lymphocytes, monocytes and DCs).ResultsThese investigations of the short multiple interactions and functions of MPs with these cells revealed an increase in the secretion of cytokines such as IFNg, IL2, IL6, IL12, IL17 and TNFa by the immune cells studied following interactions with MPs. We show that this functional remodeling of immune cells depends not only on the number, but also on the phenotype of MPs.ConclusionThese data suggest that the large numbers of MPs and their impact on functional remodeling in PLWH may be incompatible with the effective control of chronic infections, potentially leading to chronic immune activation and the onset of comorbid diseases.

Immunothrombosis is the process by which inflammatory stimuli promote coagulation and thrombus formation. Bacterial sepsis is a well established risk factor for venous thrombosis, and numerous experimental studies have shown that sepsis indeed enhances thrombotic responses. In this study, we aimed to investigate the impact of endotoxemia - induced by either lipopolysaccharides or α-toxin - on venous thrombosis development in mice. Venous thrombosis was induced using a model based on siRNA-mediated transient inhibition of the natural anticoagulants - protein C (PC) and anti-thrombin (AT). Unexpectedly, endotoxemia attenuated rather than promoted venous thrombus formation. This counterintuitive finding appears to be explained by a transient increase in circulating protein C levels following endotoxemia. As our venous thrombosis mouse model strongly depends on the level of reduced protein C activity, this endotoxemia-induced elevation interfered with the intended prothrombotic conditions and compromised comparability between experimental groups. These results highlight the context-dependent effects of bacterial sepsis on venous thrombosis and underscore the importance of rigorous model validation in (immuno)thrombosis research.

BACKGROUND:The neurobiological basis of suicidal behaviour remains poorly understood. However, emerging evidence suggests that inflammation and vascular homeostasis factors may play a role in its pathophysiology. Childhood trauma, through immune system dysfunction and increased risk of suicidal behaviours, might influence these associations. This study examined the relationships between immune-inflammatory and vascular homeostasis-related markers and their interaction with childhood trauma in relation to a history of suicide attempts in individuals with depression. METHODS:A total of 328 patients with major depression were recruited: 166 with a history of suicide attempts and 162 without. Using multivariate binary logistic regression models adjusted for cofounders, we examined the associations between childhood trauma, levels of platelet-related immune markers (serotonin, MCP-1, TSP-1, TSP-2, PDGF-AB, PDGF-BB), and suicide attempt history. Independent associations between PDGF-BB, childhood trauma, and suicide attempts were further assessed using interaction models. Stratified sensitivity analyses based on childhood trauma history were also conducted. RESULTS:Childhood trauma consistently emerged as associated with suicide attempts across all models. Among the measured biomarkers, higher TSP-2 levels were associated with a suicide attempt history, independent of childhood trauma. Meanwhile, while PDGF-BB alone was not directly linked to suicide attempt history, the interaction analysis revealed that individuals with lower PDGF-BB levels and more severe childhood trauma were more likely to have attempted suicide. CONCLUSIONS:TSP-2 and PDGF-BB are potential biomarkers linked to suicide attempts, with distinct roles in the interplay between biological processes and early-life adversity. These insights can inform the biomarker-informed development of tailored prevention and treatment strategies.

BACKGROUND AND OBJECTIVES:High mobility group box 1 (HMGB1) is a nuclear protein expressed by various cell types and recognized as a damage-associated molecular pattern (DAMP). DAMPs play a pivotal role in driving inflammatory responses. Platelet-derived HMGB1 has been associated with severe adverse reactions following platelet concentrate transfusions, underscoring its clinical relevance. This study investigated whether HMGB1 levels in single-donor apheresis platelet concentrates (SDA-PCs) are influenced by routinely documented donor characteristics, such as age, sex and ABO blood group. MATERIALS AND METHODS:We analysed HMGB1 levels in 190 unpaired SDA-PC units. Donor characteristics, that is, age, sex and ABO blood group were obtained from routine records and examined for associations with HMGB1 levels. RESULTS:HMGB1 levels showed no significant correlation with donor age or ABO blood group. However, levels were modestly lower in SDA-PC units derived from female donors compared to male donors. CONCLUSION:These findings reveal donor-specific variability in HMGB1 levels, particularly regarding donor sex, and underscore the need to systematically document donor demographic and biological characteristics during blood donation. Such data could enhance our understanding of donor-related factors influencing transfusion outcomes.

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.

Interpersonal stress is a major precipitant of suicidal ideation (SI) and suicide attempts (SA), yet the underlying biological mechanisms remain unclear. This study examined dynamic plasma concentrations of inflammatory, platelet activation, and neurotrophic markers during acute social stress in 76 depressed women (mean age: 39.7 ± 1.39 years) with and without SA history or recent SI. Participants underwent the Trier Social Stress Test, with biomarkers measured at five time points before, during, and after the stressor. Covariate-adjusted growth curve models and area under the curve analyses were applied. SI was associated with elevated overall TNF-α levels (0.82 ± 0.05 vs. 0.61 ± 0.05, p = 0.039). Participants without SI showed cubic trajectories in TNF-α (t228 = 4.76, p < 0.001) and MIP-1β (t235 = 2.12, p = 0.035), and quadratic trajectories in platelet markers TSP-1 (t274 = -2.42, p = 0.016), PF-4 (t274 = -2.25, p = 0.025), and NAP-2 (t274 = -2.43, p = 0.016), which were absent in participants with SI. Cubic patters in inflammatory responses were also observed in participants without SA history, but not in suicide attempters (TNF-α: t228 = 3.15, p = 0.030; MIP-1β: t235 = 2.74, p = 0.007). Meanwhile, participants with SI or SA, but not those without, showed a linear BDNF increase (t275 = 2.39, p = 0.017; t275 = 2.28, p = 0.024, respectively). These findings suggest that SI and SA may be associated with impaired dynamic immune-inflammatory, platelet, and neurotrophic systems responses to acute interpersonal stress, reflecting systemic biological rigidity.