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The utility of a methods section of a research paper is often tempered by the brevity demanded by manuscript word limitations. Whilst word limits help streamline a paper, a Methods section often bears the brunt of the editorial scalpel, resulting in only brief sketches of experimental protocols and consignment of methodology to online supplementary information files. To retain a place for important detailed methodology, and to encapsulate and highlight new and existing important techniques for platelet and megakaryocyte biology, the Platelets Journal Editorial board now accept Methods manuscripts.

Background: Determining the required daily number of platelet units in hospitals is a challenging task due to the high uncertainty in daily usage and short shelf life of platelets., Study Design and Methods: We developed a linear prediction model to guide the daily ordering quantity of platelet units at a hospital that orders the required units from a central supplier. The predictive model relies on historical demand data and other information from the hospital's information system. The ordering strategy is to place an order at the end of each day to bring the platelet inventory to the predicted demand for the next day. Unlike typical prediction models, the quality of the predictions is measured with respect to the resulting inventory costs of wastage and shortage. We used data from two hospitals in Hamilton, Ontario from 2015 to 2016 to train our model and evaluated its performance based on the resulting wastage and shortage rates in 2017., Results: In 2017, respectively 1915 and 4305 platelet units were transfused at the two hospitals, with daily average (SD) usage of 5.2 (3.7) and 11.8 (4.4). The expiry (estimated shortage) rates were 8.67% (13.86%), and 2.28% (8.48%) at the two hospitals, respectively. Our baseline model would have reduced the expiry (shortage) rates to 2.54% (4.01%) and 0.05% (0.44%) for the two hospitals, respectively., Discussion: Guiding daily ordering decisions for platelets using our proposed model could lead to a significant reduction of wastage and shortage rates at hospitals., (© 2022 AABB.)

Hemostasis is a proteolytically regulated process that requires activation of platelets and the blood coagulation cascade upon vascular injury. Activated platelets create a thrombogenic environment and amplify the coagulation process. Plant latex proteases (PLPs) have been used as therapeutic components to treat various ailments by folk healers. One of the main applications of plant latices is to stop bleeding from minor injuries and to enhance wound healing activity. Although many studies have reported the pro-coagulant activities of PLPs, an in-depth investigation is required to understand the mechanism of action of PLPs on platelets. Here, the effect of PLPs on platelet aggregation was studied systematically to validate the observed pharmacological effect by folk healers. Among 29 latices from the Ficus genus tested, Ficus drupacea exhibited potent pro-coagulant and thrombin-like activity. Drupin, a thrombin-like cysteine protease responsible for platelet aggregation was purified from F. drupacea latex. Drupin exhibits pro-coagulant activity and reduces the bleeding time in mice tail. It induces platelet aggregation by activating mitogen-activated protein kinases and the nuclear factor-κB and PI3K/Akt signalling cascade, which, in turn, phosphorylats, cytosolic phospholipase A 2  leading to the release of thromboxane A 2 from the granules to activate the nearby platelets to aggregate. Furthermore, we investigated the involvement of protease-activated receptors in drupin-induced platelet aggregation using specific protease activated receptor 1 (PAR1) and PAR4 receptor antagonists. The results confirmed that the drupin-induced platelet aggregation was mediated by both PAR1 and PAR4, synergistically. Overall, drupin reduces the bleeding time by exerting pro-coagulant activity and induces platelet aggregation by activating the intracellular signalling cascade., (© 2021 Wiley Periodicals LLC.)

This article is a commentary celebrating the 50th anniversary of Seminars in Thrombosis and Hemostasis (STH), a journal that first published in 1974. The commentary focuses on the historical significance of a paper titled "Description of an in vitro platelet function analyzer–PFA-100," which was published in a supplementary issue of STH in 1995 and is one of the most highly cited papers in the journal's history. The paper describes the PFA-100, an instrument that has since evolved into the PFA-200 and has been widely used for various purposes in the field of hemostasis. The commentary also mentions the impact of the PFA-100 on research and its potential applications in different areas, such as screening for von Willebrand disease and monitoring platelet function in animals. The article concludes by acknowledging the 30th anniversary of the PFA-100 in 2024 and its significant contributions to the hemostasis community. [Extracted from the article]

Plain language summary: What is it?: Fetal neonatal alloimmune thrombocytopenia (FNAIT), also known as neonatal alloimmune thrombocytopenia (NAIT) or fetomaternal alloimmune thrombocytopenia (FMAIT), is a rare condition which affects a baby's platelets. This can put them at risk of problems with bleeding, particularly into the brain. One baby per week in the UK may be seriously affected and milder forms can affect one in every 1000 births. How is it caused?: Platelets are blood cells that are very important in helping blood to clot. All platelets have natural proteins on their surface called human platelet antigens (HPAs). In babies, half of these antigens are inherited from the mother and half from the father. During pregnancy, some of the baby's platelets can cross into the mother's bloodstream. In most cases, this does not cause a problem. But in cases of FNAIT, the mother's immune system does not recognise the baby's HPAs that were inherited from the father and develops antibodies, which can cross the placenta and attack the baby's platelets. These antibodies are called anti‐HPAs, and the commonest antibody implicated is anti‐HPA‐1a, but there are other rarer antibody types. If this happens, the baby's platelets may be destroyed causing their platelet count to fall dangerously low. If the platelet count is very low there is a risk to the baby of bleeding into their brain before they are born. This is very rare but if it happens it can have serious effects on the baby's health. How is it inherited?: A baby inherits half of their HPAs from its mother and half from its father. Consequently, a baby may have different HPAs from its mother. As the condition is very rare, and even if the baby is at risk of the condition we have no way of knowing how severely they will be affected, routine screening is not currently recommended. What can be done?: FNAIT is usually diagnosed if a previous baby has had a low platelet count. The parents are offered blood tests and the condition can be confirmed or ruled out. There are many other causes of low platelets in babies, which may also need to be tested for. As the condition is so rare, expertise is limited to specialist centres and normally a haematologist and fetal medicine doctor will perform and interpret the tests together. Fortunately, there is an effective treatment for the vast majority of cases called immunoglobulin, or IVIg. This 'blood product' is given intravenously through a drip every week to women at risk of the condition. It may be started from as early as 16 weeks in the next pregnancy, until birth, which would be offered at around 36–37 weeks. Less common treatments that may be considered depending on individual circumstances include steroid tablets or injections, or giving platelet transfusions to the baby. What does this paper tell you?: This paper considers the latest evidence in relation to treatment options in the management of pregnancies at risk of FNAIT. Specifically, we discuss the role of screening, when IVIg should be started, what dose should be used, and what evidence there is for maternal steroids. We also consider in very rare selected cases, the use of fetal blood sampling and giving platelet transfusions to the baby before birth. Finally, we consider the approaches to blood testing mothers to tell if babies are at risk, which is offered in some countries, and development of new treatments to reduce the risk of FNAIT. [ABSTRACT FROM AUTHOR]

Introduction: Alzheimer Disease (AD) is a neurodegenerative disorder characterized by the progressive loss of memory and other cognitive functions. Protein Kinase Cε (PKCε) is an isoform that most effectively suppresses Amyloid Beta (Aβ) production and synaptic loss. Methods: In this study, spatial learning and memory for treated rats were evaluated by the Morris water maze test. The activity (total PKC), mRNA expression, and protein level of PKCε in the platelet and hippocampal tissue were evaluated using immunosorbent assay, real-time qPCR, and western blotting analysis, respectively. Results: The traveled distance was significantly prolonged, and escape latency significantly increased in Aβ-treated groups. PKC activity assay showed that there was a remarkable difference between the Aβ-treated and sham-operated groups on days 10 and 30 in the hippocampus and also day 30 in platelet after the injection of Aβ. A significant effect in PKC activity was observed between days 0 and 10, days 0 and 30, as well as days 5 and 30. Aβ significantly downregulated the PKCε mRNA expression in the hippocampus of rats on day 30; however, no significant difference was observed in platelet. Western blot analysis demonstrated that Aβ significantly reduced PKCε protein expression in the hippocampus of treated groups on day 30. Conclusion: The expression level of PKCε was downregulated following the injection of Aβ in the hippocampus, but no significant difference was observed between the AD and sham groups in platelet that may be due to the low concentration of PKCε or duration of Aβ exposure in the rat brain. [ABSTRACT FROM AUTHOR]

Platelet flow cytometry is widely used in cardiovascular medicine as the platelet surface is rich in clinical biomarkers. Surface profiling is critical in disease management, but current assays can abet clinical errors as they are suboptimal and prone to bias. Accordingly, the technical and analytical advances that can be used to create high quality assays with minimal error and maximal sensitivity were reviewed. Specifically, the best practices for instrument setup, quality control, panel design, titration, gating, and compensation were described. Adherence to these practices will enhance the validity and reliability of platelet flow cytometry in clinical/research settings. © 2019 International Clinical Cytometry Society., (© 2019 International Clinical Cytometry Society.)

Background: Data on the interplay between sexual hormones balance, platelet function and clinical outcomes of adults with ischemic heart disease (IHD) are still lacking., Objective: To assess the association between the Testosterone (T)-to-Estradiol (E2) Ratio (T/E2) and platelet activation biomarkers in IHD and its predictive value on adverse outcomes., Methods: The EVA study is a prospective observational study of consecutive hospitalized adults with IHD undergoing coronary angiography and/or percutaneous coronary interventions. Serum T/E2 ratios E2, levels of thromboxane B 2 (TxB 2 ) and nitrates (NO), were measured at admission and major adverse events, including all-cause mortality, were collected during a long-term follow-up., Results: Among 509 adults with IHD (mean age 67 ± 11 years, 30% females), males were older with a more adverse cluster of cardiovascular risk factors than females. Acute coronary syndrome and non-obstructive coronary artery disease were more prevalent in females versus males. The lower sex-specific T/E2 ratios identified adults with the highest level of serum TxB 2 and the lowest NO levels. During a median follow-up of 23.7 months, the lower sex-specific T/E2 was associated with higher all-cause mortality (HR 3.49; 95% CI 1.24-9.80; p = 0.018). In in vitro, platelets incubated with T/E2 ratios comparable to those measured in vivo in the lowest quartile showed increased platelet activation as indicated by higher levels of aggregation and TxB 2 production., Conclusion: Among adults with IHD, higher T/E2 ratio was associated with a lower long-term risk of fatal events. The effect of sex hormones on the platelet thromboxane release may partially explain such finding., (© 2022. The Author(s).)

Background and Purpose: Overweight or obese patients exhibit poorer platelet responses to clopidogrel. However, the mechanisms behind this phenotype remain to be elucidated. Here, we sought to discover whether and why obesity could affect the metabolic activation of and/or platelet response to clopidogrel in obese patients and high-fat diet-induced obese mice., Experimental Approach: A post hoc stratified analysis of an observational clinical study was performed to investigate changes in residual platelet reactivity with increasing body weight in patients taking clopidogrel. Furthermore, high-fat diet-induced obese mice were used to reveal alterations in systemic exposure of clopidogrel thiol active metabolite H4, ADP-induced platelet activation and aggregation, the expression of genes involved in the metabolic activation of clopidogrel, count of circulating reticulated and mature platelets, and proliferation profiles of megakaryocytes in bone marrow. The relevant genes and potential signalling pathways were predicted and enriched according to the GEO datasets available from obese patients., Key Results: Obese patients exhibited significantly attenuated antiplatelet effects of clopidogrel. In diet-induced obese mice, systemic exposure of clopidogrel active metabolite H4 was reduced but that of its hydrolytic metabolite was increased due to down-regulation of certain P450s but up-regulation of carboxylesterase-1 in the liver. Moreover, enhanced proliferation of megakaryocytes and elevated platelet count also contributed., Conclusion and Implications: Obesity attenuated metabolic activation of clopidogrel and increased counts of circulating reticulated and mature platelets, leading to impaired platelet responsiveness to the drug in mice, suggesting that clopidogrel dosage may need to be adjusted adequately in overweight or obese patients., (© 2021 The British Pharmacological Society.)

Background and Purpose: P2Y 12 receptor antagonists reduce platelet aggregation and the incidence of arterial thrombosis. Adenosine signalling in platelets directly affects cyclic nucleotide tone, which we have shown to have a synergistic relationship with P2Y 12 inhibition. Several studies suggest that ticagrelor inhibits erythrocyte uptake of adenosine and that this could also contribute to its antiplatelet effects. We therefore examined the effects on platelet activation of adenosine signalling activators in combination with the P2Y 12 receptor antagonists ticagrelor and prasugrel., Experimental Approach: Human washed platelets, platelet-rich plasma and whole blood were used to test the interactions between ticagrelor or prasugrel and adenosine or 5'-N-ethylcarboxamidoadenosine (NECA). Platelet reactivity to thrombin, protease-activated receptor 1 (PAR-1) activation or collagen was assessed by a combination of 96-well plate aggregometry, light transmission aggregometry, whole blood aggregometry, ATP release assay and levels of cAMP., Key Results: The inhibitory effects of ticagrelor and prasugrel on platelet aggregation and ATP release were enhanced in the presence of adenosine or NECA. Isobolographic analysis indicated a powerful synergy between P2Y 12 receptor inhibition and adenosine signalling activators. Increased levels of cAMP in platelets were also observed. In all cases, ticagrelor showed similar synergistic effects on platelet inhibition as prasugrel in the presence of adenosine or NECA., Conclusion and Implications: These results indicate that P2Y 12 antagonists have a synergistic relationship with adenosine signalling and that their efficacy may depend partly upon the presence of endogenous adenosine. This effect was common for prasugrel and ticagrelor despite reports of differences in their effects upon adenosine reuptake., (© 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Pathogen reduction (PR) technology will be implemented in pooled platelets in Canada. It is anticipated that PR platelets will be licensed in Canada for a maximum shelf life of 5 days, while non-treated apheresis platelet products will continue to be licensed for 7 days., Study Design and Methods: This study evaluates the impact on inventory, wastage, and shortages of implementing PR platelets. A custom-built simulation model was used to represent a regional distribution network. Experiments with the model were used to estimate product wastage and shortages when a 5-day PR pooled platelet product is introduced alongside a 7-day apheresis platelet product., Results: Pooled platelet waste and shortages both increase as pooled shelf life decreases. Apheresis platelets, however, show a different response: While shortages of apheresis platelets increase as the shelf life of pooled units decreases, apheresis waste declines as pooled shelf life decreases., Conclusion: Additional platelet collections will be necessary to accommodate the shorter PR platelet shelf life and to cover increased patient transfusion needs due to a lower platelet yield in PR units. Increases of 9% for pooled units and 6% for apheresis units beyond expected demand, were found to be sufficient to ensure a non-inferior level of customer service while minimizing waste., (© 2021 AABB.)

Abstract: Although recent studies described platelet reactivity (PR) changes in days after transcatheter aortic valve implantation (TAVI), precise time course and duration of these changes have not been fully investigated. The aim of this study was to investigate PR pattern during and after TAVI in multiple time points. Study included 40 consecutive patients undergoing TAVI. All patients underwent the procedure on dual antiplatelet therapy. PR was measured in 7 time points: before induction of anesthesia (T1), after heparin administration (T2), 10 minutes after initial valve implantation (T3), at the end of procedure (T4), and on 3rd, 6th, and 30th postoperative day (T5-T7). PR was measured using impedance aggregometer using 3 different platelet aggregation agonists (arachidonic acid in ASPItest, adenosine diphosphate in ADPtest and thrombin receptor activating peptide 6 in TRAPtest). All patients underwent successful TAVI procedure. Mean PR on T1 was 22.9 ± 23.0 U for ASPItest, 40.5 ± 23.7 U for ADPtest and 91.7 ± 32.5 U for TRAPtest. There was no significant difference in PR on T2. On T3, significant reduction of PR in all 3 tests was observed [ASPI 10.4 ± 11.6 U (P = 0.001), ADP 24.2 ± 14.1 U (P < 0.001) and TRAP 69.3 ± 26.6 U (P < 0.001)]. PR nadir for all tests was reached on T5, with subsequent PR incline. PR values in all tests returned to baseline levels on T7. Our results show that successful TAVI procedure induces transient decrease in PR regardless of the platelet activation pathway., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction and aim. In the literature, blood is described as a body fluid that circulates in a closed vascular system that makes up about 10% of the body weight. The morphotic elements of blood are suspended in this fluid, which is why we can define blood as liquid tissue. Blood in the organization helped to play a role, performing a transport, hemodynamic and protective-defensive function. Its main components are red blood cells, white blood cells and platelets. Erythrocytes due to the ability to connect to the source, participate in the delivery from the lungs to the source. Leukocytes include a group of blood cells that include monocytes, lymphocytes and granulocytes that participate in the body's reactions. Platelets are referred to in the literature as thrombocytes, as non-nucleated blood components. The main component of blood samples is participation in hemostatic processes in the composition. They play one key role in the blood clotting process. At some point, when the continuity of the straight line is interrupted, platelets pass to the subendothelial matrix, the formation of a platelet plug, a clot is formed. Until the beginning of the twentieth, blood functions are provided only for hemostatic activities. Recent scientific research that blood cells are involved in non-hemostatic processes. Including the immune system. Collecting information on the role of blood in an independent team, enabling review work. Material and methods. Literature search from 1989 up to 2022 has been conducted on PubMed, Google Scholar databases and the Practical Medicine for Physicians. For the final analysis, 10 research papers and 9 review papers were used. Following keywords were used to search articles: platelets, in- flammation, immune system, hemostasis. The articles were from the years 1989-2022. Results. Platelets are one of the main morphotic elements of blood, when it comes to size, they are the smallest of all components of peripheral blood, but they are very reactive. They participate in the processes of coagulation and maintaining hemostasis in the body. The characteristic properties of platelets are the presence of dense granules δ and α, their compactness during hemostasis or inflammation are released into the body. Platelets, in addition to active participation in hemostasis processes, take part in immune processes. Platelets have been shown to be regulators of immune processes through the presence of TLRs that trigger the initiation of an immune system response. In addition to the regulatory properties, platelets are involved in the innate immunity and inflammation of the body. Platelets with the participation of endothelial cells lead to the recruitment of leukocytes to the site of inflammation. Platelets participate in the recognition of a foreign pathogen that is in the body, the mechanisms that lead to this are presented in the paper. In addition to the function of platelets in the immune system, the topic of autoimmune diseases, where platelets play a role, is discussed. The work deals with the subject of the influence of platelets on the immune system and their role in immune processes. Through the progress of scientific research, platelets have been shown to play a significant role in immune mechanisms. The work is a review of literature dealing with topics related to the immune system and platelets and aims to explain the mechanisms that lead to the active participation of platelets in the immune system. Conclusion. Platelets are involved in the immune system, it has been shown at the same time that platelets perform regulatory functions in the immune system through the CD154 molecule and additionally participate in inflammation. Where are the first cells that are responsible for fighting in the body's non-specific immune response. In addition, TLR receptors that are found on the surface of platelets play a key role in recognizing a threat and initiating an immune response. Through these receptors, platelets recognize pathogens in the body. Scientists continue to study the non-haemostatic functions of platelets and discover their significant role in the body, which is not only based on blood coagulation processes, but to a large extent in the body's immune defense. [ABSTRACT FROM AUTHOR]

Rapid and accurate clinical assessment of hemostasis is essential for managing patients who undergo invasive procedures, experience hemorrhages, or receive antithrombotic therapies. Hemostasis encompasses an ensemble of interactions between the cellular and non-cellular blood components, but current devices assess only partial aspects of this complex process. In this work, we describe the development of a new approach to simultaneously evaluate coagulation function, platelet count or function, and hematocrit using a carbon nanotube-paper composite (CPC) capacitance sensor. CPC capacitance response to blood clotting at 1.3 MHz provided three sensing parameters with distinctive sensitivities towards multiple clotting elements. Whole blood-based hemostasis assessments were conducted to demonstrate the potential utility of the developed sensor for various hemostatic conditions, including pathological conditions, such as hemophilia and thrombocytopenia. Results showed good agreements when compared to a conventional thromboelastography. Overall, the presented CPC capacitance sensor is a promising new biomedical device for convenient non-contact whole-blood based comprehensive hemostasis evaluation. • Capacitance based non-contact multiparameter hemostasis assessment is realized for the first time. • Multiple key clotting biomarkers were evaluated simultaneously with high sensitivity & accuracy. • Sensor showed good agreements with commercial thromboelastography. • Rapid screening for pathological conditions was demonstrated using the sensor. • Sensor has potential applications as inexpensive POC blood analyzer. [ABSTRACT FROM AUTHOR]

Dual antiplatelet therapy (DAPT) is standard in acute coronary syndrome but confers a bleeding risk. To compare effects of clopidogrel single antiplatelet therapy (SAPT) with clopidogrel-based DAPT on hemostatic system activation we conducted a randomized clinical trial in 44 volunteers (clopidogrel (d1: 600 mg, d2-6: 150 mg) ± aspirin (100 mg)). Multiple electrode aggregometry-adenosine diphosphate (MEA-ADP) and MEA-arachidonic acid (MEA-AA) triggered aggregometry, vasodilator-stimulated phosphoprotein (VASP), beta thromboglobulin, p-selectin, thromboxane B 2 , d-Dimer, prothrombin fragment 1.2 (f1.2), and a phospholipid-dependent clotting time were measured in venous blood. Changes are described by mean differences (Δmean (95% confidence interval (CI)) or geometric mean ratios (95% CI)). DAPT and SAPT comparably and significantly decreased MEA-ADP at 2 hours (-60% vs. -63%; P = 0.35, Δmean -4.9, 95% CI -15.4 to 5.5). At 24 hours (-59% vs. -47%, P = 0.04, Δmean -11.1, 95% CI -21.7 to -0.4]) and 8 days (-61% vs. -53%, P = 0.04, Δmean -11.3, 95% CI -22.0 to -0.6). Both treatments significantly reduced VASP and MEA-AA after 2 hours and 8 days. DAPT inhibited MEA-AA significantly stronger at 2 hours (-77% vs. -30%; P < 0.0001, Δmean -39.6, 95% CI -54.2 to -25.0), at 24 hours (-80% vs. -27%, P < 0.0001, Δmean -47.8, 95% CI -62.3 to -33.3), and 8 days (-79% vs. -27%, P < 0.0001, Δmean -48.9, 95% CI -62.5 to -35.4). Neither treatment significantly influenced beta thromboglobulin or p-selectin. DAPT abolished and SAPT reduced thromboxane B 2 after 24 hours and 8 days. The d-Dimer was reduced by DAPT (0.94, 95% CI 0.89-1.00, P = 0.04) at 2 hours but not after 24 hours and 8 days. SAPT did not decrease d-Dimer. Neither treatment affected f1.2. DAPT and SAPT comparably affect platelet and coagulation activation in venous blood., (© 2020 The Authors Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics.)

Abstract: Acute physiology and chronic health evaluation II (APACHE-II) scoring system is used to classify disease severity of patients in the intensive care unit. However, several limitations render the scoring system inadequate in identifying risk factors associated with outcomes. Little is known about the association of platelet count patterns, and the timing of platelet count and other hematologic parameters in predicting mortality in patients with sepsis.This retrospective observational study included 205 septic shock patients, with an overall mortality of 47.8%, enrolled at a tertiary care hospital in Riyadh, Kingdom of Saudi Arabia between 2018 and 2020. Bivariate and multivariate regression analyses were used to identify hematologic risk factors associated with mortality. We used the bivariate Pearson Correlation test to determine correlations between the tested variables and APACHE-II score.Two platelet count patterns emerged: patients with a decline in platelet count after admission (group A pattern, 93.7%) and those with their lowest platelet count at admission (group B pattern, 6.3%). The lowest mean platelet count was significantly lower in nonsurvivors (105.62 ± 10.67 × 103/μL) than in survivors (185.52 ± 10.81 × 103/μL), P < .001. Bivariate Pearson correlation revealed that the lowest platelet count and platelet count decline were significantly correlated with APACHE-II score (r = -0.250, P < .01), (r = 0.326, P < .001), respectively. In multiple logistic regression analysis, the independent mortality risk factors were degree of platelet count decline in group A (odds ratio, 1.028 [95% confidence interval: 1.012-1.045], P = .001) and platelet pattern in group B (odds ratio, 6.901 [95% confidence interval: 1.446-32.932], P = .015). The patterns, values, subsets, and ratios of white blood cell count were not significantly associated with mortality.Nadir platelet count and timing, and degree of platelet count decline are useful markers to predict mortality in early septic shock. Therefore, platelet count patterns might enhance the performance of severity scoring systems in the intensive care unit., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Abstract: The mechanisms of aspirin antithrombotic actions have not been fully elucidated. We re-analyzed the data from the project Aspirin Resistance in Patients with Ischemic Atherothrombotic Diseases from April 2008 to June 2010. A total of 530 subjects were classified into 3 groups, including 40 patients without aspirin use, 24 patients taking 25-50 mg/d aspirin, and 466 patients taking 75-100 mg/d aspirin over 1 month. By 1:1:1 propensity score matching adjusting 15 primary clinical covariates, 51 patients (n = 17 per group) comprised the final sample. Hemostasis-related parameters and high platelet reactivity as measured by arachidonic acid-induced and adenosine diphosphate-induced light transmission aggregometry were compared in the 3 groups. A dose-dependent relationship was observed between aspirin and decreased high platelet reactivity incidence (PAA < 0.001, PADP < 0.01, respectively), decreased monocyte ratio (P = 0.052), increased antithrombin activity (P < 0.001), and increased platelet distribution width (P < 0.05). Aspirin at 25-50 mg/d is related to the lowest red blood cell (RBC) count, whereas 75-100 mg/d aspirin showed the highest RBC count among the 3 groups (4.52 ± 0.35 × 1012/L vs. 4.35 ± 0.57 × 1012/L vs. 4.80 ± 0.59 × 1012/L, P = 0.046). Our finding demonstrated that aspirin exerts its antithrombotic effects at least by antiplatelet function, enhancing antithrombin activity and suppressing monocytes in vivo. In addition, 3 blood cell types, namely RBCs, monocytes, and platelets, are involved in the aspirin antithrombotic mechanism. The cellular response to aspirin partially enhances the antithrombotic effects while partially inhibiting the effects., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Cryopreservation of platelets with dimethylsulfoxide (DMSO) at -80°C increases their shelf life from days to years. Once thawed, platelets are stored at room temperature (RT), and the shelf life is limited to 4-6 hours. However, refrigeration (cold storage) may facilitate a prolongation of the shelf life of thawed platelets., Study Design and Methods: ABO-matched buffy coat-derived platelets (30% plasma/70% SSP+) were cryopreserved at -80°C in 5%-6% DMSO. Paired cryopreserved platelet components were thawed, resuspended in 30% plasma/70% SSP+, and then stored at either 20°C-24°C with agitation (RT) or at 2°C-6°C (cold). In vitro platelet quality was assessed over 10 days of postthaw storage., Results: During postthaw storage, the platelet concentration of RT-stored components decreased significantly more than components in cold storage (Day 10 RT 58 ± 10 × 10 9 /unit vs Day 10 cold 142 ± 16 × 10 9 /unit; P < .0001). Cold storage reduced the metabolic rate of thawed platelets. During storage, the surface glycoprotein ([GP] Ibα, GPVI, GPIIb, GPIIIa) and activation marker (P-selectin and phosphatidylserine) profile of cold platelets was closer to freshly thawed platelets (Day 0) than those stored at RT. Thromboelastography (reaction time) demonstrated that the procoagulant nature of cryopreserved platelets was preserved during 10 days of cold storage, while RT-stored thawed platelets displayed a gradual prolongation of the time taken to initiate clot formation., Conclusion: Cold storage of thawed platelets preserves the platelet phenotype and function for up to 10 days, compared to thawed platelets stored at RT. Thus, cold storage of thawed platelets may represent a simple approach to extend the postthaw shelf life., (© 2020 AABB.)

Owing to the rapid development of high-power and minimized electronic devices, the materials with ultra-flexibility and effective heat dissipation have attracted much interest. Herein, the high thermally conductive epoxidized natural rubber (ENR) papers with layered structures based on boron nitride (BN) platelets are reported. First, polyrhodanine (PRd) was coated on the surface of BN platelets via oxidative polymerization of rhodanine (Rhd), which was initiated by the absorbed (S 2 O 8)2- ions. Then, BN-PRd platelets were grafted with ENR chains using a mechanochemical method due to the presence of N–C S groups in PRd, allowing the combination of PRd and ENR chains with stable covalent bonds. Moreover, the grafted ENR chains acted as bridges between adjacent BN platelets and improved the heat transfer ability of BN-PRd/ENR thermally conductive composite papers. The as-prepared ultra-flexible 30 wt% BN-PRd/ENR thermally conductive composite papers rendered high in-plane (λ ∥) and through-plane (λ ⊥) thermal conductivity of 14.57 and 0.52 W/(mK), respectively, which were correspondingly 8094% and 289% of pure ENR paper (0.18 W/(mK)). Also, Young's modulus of the 30 wt% BN-PRd/ENR thermally conductive composite paper was 25.90 MPa. Overall, the as-fabricated BN-PRd/ENR thermally conductive composite papers demonstrated high flexibility, excellent mechanical robustness, outstanding thermal conductivity, and superior electronic illustration, indicating potential applications in areas of electronic components as thermal interface materials. [Display omitted] [ABSTRACT FROM AUTHOR]

Changes in platelet physiology are associated with simultaneous changes in microRNA concentrations, suggesting a role for microRNA in platelet regulation. Here we investigated potential associations between microRNA and platelet reactivity (PR), a marker of platelet function, in two cohorts following a non-ST elevation acute coronary syndrome (NSTE-ACS) event. First, non-targeted microRNA concentrations and PR were compared in a case (N = 77) control (N = 76) cohort within the larger TRILOGY-ACS trial. MicroRNA significant in this analysis plus CVD-associated microRNAs from the literature were then quantified by targeted rt-PCR in the complete TRILOGY-ACS cohort (N = 878) and compared with matched PR samples. Finally, microRNA significant in the non-targeted & targeted analyses were verified in an independent post NSTE-ACS cohort (N = 96). From the non-targeted analysis, 14 microRNAs were associated with PR (Fold Change: 0.91-1.27, p-value: 0.004-0.05). From the targeted analysis, five microRNAs were associated with PR (Beta: -0.09-0.22, p-value: 0.004-0.05). Of the 19 significant microRNAs, three, miR-15b-5p, miR-93 and miR-126, were consistently associated with PR in the TRILOGY-ACS and independent Singapore post-ACS cohorts, suggesting the measurement of circulating microRNA concentrations may report on dynamic changes in platelet biology following a cardiovascular ischemic event.

Platelet function is regulated by finely tuned phosphoprotein signals. Subtle aberrations in signaling can cause platelet hyperactivity and severe cardiovascular events. Mapping phosphorylation profiles in health and disease could accelerate antiplatelet discovery and enhance cardiovascular management, but traditional assays are ill-suited to clinical application as they are laborious and low throughput. Recent advances in multiplex flow cytometry (barcoding) allow the rapid acquisition of highly batched samples with standard laboratory equipment. However, many assays have not been standardized, and success is largely dependent on protocol/reagent selection. Accordingly, we review the technical steps that are key to success with an emphasis on fixation, permeabilization, staining, controls, and data visualization., (© 2019 International Clinical Cytometry Society.)

Clopidogrel is still widely used in acute coronary syndrome despite the development of more potent P2Y12 inhibitors. Previously, we conducted a trial that evaluated serial clopidogrel dose adjustment based on platelet function testing in acute coronary syndrome patients with initial high on-treatment platelet reactivity (HTPR). In this substudy, we performed post hoc analysis of the effect of ABCB1 genetic variants C3435T and G2677T/A on platelet inhibition and outcomes. There were no differences in the proportion of HTPR patients among C3435T carriers and noncarriers in both interventional and control group. G2677T carriers expressed significantly higher proportion of HTPR pattern throughout 12-month follow-up in the control group with no difference in the interventional group. There was no difference in ischemic outcomes between C3435T and G2677T carriers and noncarriers in both groups of patients. The results indicate that ABCB1 genotyping is not useful to guide clopidogrel therapy tailoring to improve high-risk patient management.

Background: Ticagrelor induces more potent platelet reactivity (PR) inhibition with reduced interindividual variability compared to clopidogrel. Although on-clopidogrel PR was shown to correlate with ischemia and bleeding events, no study has investigated the relationship between on-ticagrelor PR and outcome., Objectives: We aimed to evaluate the relationship between on-ticagrelor PR, assessed by the vasodilator-stimulated phosphoprotein index (VASP), and thrombotic and bleeding events in patients with acute coronary syndrome (ACS) treated by percutaneous coronary intervention (PCI)., Methods: We performed a prospective, multicenter observational study on patients treated with PCI for ACS. The VASP index was used to assess PR after ticagrelor loading dose (LD). The primary endpoint was the link between major adverse cardiovascular events (MACE) and PR., Results: Among the 530 patients with ACS included, 183 (34.5%) were admitted for ST elevation myocardial infarction. We observed high potency and limited interindividual variability after the ticagrelor LD (VASP 19.1% ± 16.6%). At 1 month, 21 (3.8%) MACE and 29 (5.5%) bleedings ≥ 2 according to the Bleedings Academic Research Consortium (BARC) scale were recorded. Neither MACE nor bleeding was associated with PR (P = .34 and P = .78, respectively). However, there was a strong association between PR and the occurrence of definite acute stent thrombosis (P = .03). Platelet reactivity was the only factor associated with acute definite stent thrombosis., Conclusion: In patients receiving a ticagrelor LD while undergoing PCI for ACS, PR using the VASP did not predict MACE or bleeding, but it was significantly associated with the occurrence of definite acute stent thrombosis., (© 2019 Aix-Marseille University. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc.)

The article discusses the historical significance and ongoing relevance of platelet physiology and biochemistry in the field of thrombosis and hemostasis. It highlights the early discoveries of platelets as distinct blood cells involved in clotting and describes the development of various methods to study platelet function. The article also emphasizes the recent understanding of platelets' role beyond thrombosis and hemostasis, including their involvement in immune responses, tumor promotion, and metastasis. The importance of incorporating new technologies, such as -omics approaches, for studying platelet biology is also mentioned. The article concludes by noting the continued interest in platelet physiology, as evidenced by the popularity of recent papers on the topic. [Extracted from the article]

Hyperactivation of blood platelets, one of the causes of heart attack, and other cardiovascular diseases (CVDs), is influenced by various dietary components, including phenolic compounds from vegetables, fruits, teas, wines, cocoa and its products, including chocolate. The present paper sheds new light on the effect of cocoa and its products, especially dark chocolate, on the number and function of blood platelets, and the anti-platelet activity of their constituent phenolic compounds. A review was performed of papers identified in various electronic databases, including PubMed, Science Direct, Scopus, Web of Knowledge, and Google Scholar, with the aim of determining whether their anti-platelet activity may serve as part of a sweet strategy in countering CVDs. Various studies demonstrate that cocoa consumption, especially in the form of dark chocolate, with a high flavanol concentration, has anti-platelet activity and may play a significant role in cardioprotection; they also note that cocoa consumption may be a good strategy in diminishing cardiovascular risk, including hyperactivation of blood platelets. [ABSTRACT FROM AUTHOR]

Electronic devices play an increasingly vital role in modern society, and heat accumulation is a major concern during device development, which causes strong market demand for thermal conductivity materials and components. In this paper, a novel thermal conductive material consisting of polydimethylsiloxane (PDMS) and a binary filler system of h-BN platelets and Al2O3 nanoparticles was successfully fabricated using direct ink writing (DIW) 3D printing technology. The addictive manufacturing process not only endows the DIW-printed composites with various geometries but also promotes the construction of a 3D structural thermal conductive network through the shearing force during the printing process. Moreover, the integrity of the thermal conductive network can be optimized by filling the gaps between the BN platelets with Al2O3 particles. Resultingly, the configuration of the binary fillers is arranged by the shearing force during the DIW process, fabricating the thermal conductive network of oriented fillers. The DIW-printed BN/Al2O3/PDMS with 45 wt% thermal conductive binary filler can reach a thermal conductivity of 0.98 W/(m·K), higher than the 0.62 W/(m·K) of the control sample. In this study, a novel strategy for the thermal conductive performance improvement of composites based on DIW technology is successfully verified, paving a new way for thermal management. [ABSTRACT FROM AUTHOR]

Ethnopharmacological Relevance: Xuefu Zhuyu Decoction (XZD), a renowned traditional Chinese medicine prescription, is widely employed for the management of conditions characterized by qi-stagnation and blood stasis. Although its anti-thrombotic effect on deep vein thrombosis (DVT) patients has been clinically observed, the underlying mechanism remains largely unexplored., Aim of the Study: Our aim was to investigate the mechanisms by which XZD exerted its effect on DVT., Materials and Methods: The ultra performance liquid chromatography (UPLC) technique was employed to evaluate quality of XZD. To examine the effect of XZD on DVT, a DVT rat model with inferior vena cava (IVC) stenosis was established. The 4D-label-free proteomics approach was then utilized to uncover the possible mechanisms of XZD against DVT. Based on proteomics, citrullinated histone H3 (CitH3), along with serum levels of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) were observed the inhibitory activity of XZD on neutrophil activation. Subsequently, the marker of platelet activation, specifically glycoprotein IIb (CD41) and glycoprotein IIIa (CD61), were assessed along with the secretion of von Willebrand factor (vWF) to investigate the inhibitory activity of XZD on platelet activation. Finally, we explored the impact of XZD on the sirtuin 1 (SIRT1)/nuclear factor kappa-B (NF-κB) pathway, which was associated with the activation of platelets and neutrophils., Results: Eight distinct components were identified for the quality control of XZD. XZD effectively reduced thrombus weight and length in DVT rats, without affecting the coagulation function or hematological parameters in the systemic circulation. Proteomics analysis revealed that XZD alleviated DVT by inhibiting the activation of platelets and neutrophils. The protein expression of CitH3, along with serum levels of TNF-α and IL-1β, were reduced in XZD-treated DVT rats. Similarly, protein expressions of CD41 and CD61, along with the release of vWF, were markedly down-regulated in XZD-treated DVT rats. Finally, treatment with XZD resulted in an up-regulation of SIRT1 protein expression and a down-regulation of both acetylated NF-κB/p65 and phosphorylated NF-κB/p65 protein expressions in endothelium., Conclusions: XZD alleviates DVT by inhibiting the activation of platelets and neutrophils at the injured endothelium via the regulation of SIRT1/NF-κB pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Platelet concentrates (PC) are used to treat patients with thrombocytopenia and hemorrhage, but there is still the demand to find the optimal strategy for temperature-dependent storage of PC. Recently, we could show that cold storage for 1 h (short-term refrigeration) is sufficient to induce enhanced platelet responsiveness. The aim of this study was to investigate effects of cold storage on collagen-dependent activating signalling pathways in platelets from apheresis-derived PC (APC). APC on day 1 or day 2 of storage, were either continuously kept at room temperature (RT, 22 °C), or for comparison, additionally kept at cold temperature (CT, 4 °C) for 1 h. CD62P expression was determined by flow cytometry. Western Blot technique was used to analyze collagen-induced phosphorylation of p38, ERK1/2 or Akt/PKB and its inhibition by prostaglandin E1 (PGE1) or nitric monoxide donor. Adhesion of platelets on collagen-coated surfaces and intracellular phosphorylation of vasodilator-stimulated phosphoprotein (VASP) was visualized by immune fluorescence microscopy. CD62P expression was increased after short-term refrigeration. CT exposition for 1 h induced an elevation of basal ERK1/2 phosphorylation and an alleviation of PGE1- or DEA/NO-suppressed ERK1/2 phosphorylation in APC on day 1 and 2 of storage. Similar, but more moderate effects were observable for p38 phosphorylation. Akt/PKB phosphorylation was increased only in APC on day 2. Refrigeration for 1 h promoted platelet adhesion and reduced basal VASP phosphorylation in adherent platelets. The attenuation of inhibitory signalling in short-term refrigerated stored platelets is associated with enhanced reactivity of activating signalling pathways, especially ERK1/2. Functionally, these processes correlate with increased adhesion of refrigerated platelets on collagen-coated surfaces. The results help to further optimize temperature-dependent strategies for platelet storage., Competing Interests: Declaration of competing interest he authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Juergen Koessler reports financial support was provided by Stiftung Transfusionsmedizin und Immunhämatologie of the Deutsche Gesellschaft für Transfusionsmedizin und Immunhämatologie (DGTI). Juergen Koessler reports a relationship with Stiftung Transfusionsmedizin und Immunhämatologie of the Deutsche Gesellschaft für Transfusionsmedizin und Immunhämatologie (DGTI) that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Previous research has revealed that platelets promote tumor metastasis by binding to circulating tumor cells (CTCs). However, the role of platelets in epithelial-mesenchymal transition (EMT) of cancer cells at the primary tumor site, the crucial initial step of tumor metastasis, remains to be elucidated. Here, we found that platelet releasate enhanced EMT and motility of hepatocellular carcinoma (HCC) cells via AMPK/mTOR-induced autophagy. RNA-seq indicated that platelet releasate altered TGF-β signaling pathway of cancer cells. Inhibiting TGFBR or deleting platelet TGF-β1 suppressed AMPK/mTOR pathway activation and autophagy induced by platelet releasate. Compared with Pf4cre - ; Tgfb1 fl/fl mice, HCC orthotopic models established on Pf4cre + ; Tgfb1 fl/fl mice showed reduced TGF-β1 in primary tumors, which corresponded with decreased cancer cell EMT, autophagy, migration ability and tumor metastasis. Inhibition of autophagy via Atg5 knockdown in cancer cells negated EMT and metastasis induced by platelet-released TGF-β1. Clinically, higher platelet count correlated with increased TGF-β1, LC3 and N-cad expression in primary tumors of HCC patients, suggesting a link between platelets and HCC progression. Our study indicates that platelets promote cancer cell EMT in the primary tumor and HCC metastasis through TGF-β1-induced HCC cell autophagy via the AMPK/mTOR pathway. These findings offer novel insights into the role of platelets in HCC metastasis and the potential therapeutic targets for HCC metastasis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Platelets endocytose many molecules from their environment. However, this process of pinocytosis in platelets is poorly understood. Key endocytic regulators such as dynamin, clathrin, CDC42 and Arf6 are expressed in platelets but their roles in pinocytosis is not known. Stimulated platelets form two subpopulations of pro-aggregatory and procoagulant platelets. The effect of stimulation on pinocytosis is also poorly understood. In this study, washed human platelets were treated with a range of endocytosis inhibitors and stimulated using different activators. The rate of pinocytosis was assessed using pHrodo green, a pH-sensitive 10 kDa dextran. In unstimulated platelets, pHrodo fluorescence increased over time and accumulated as intracellular puncta indicating constituently active pinocytosis. Stimulated platelets (both pro-aggregatory and procoagulant) had an elevated pinocytosis rate compared to unstimulated platelets. Dynamin inhibition blocked pinocytosis in unstimulated, pro-aggregatory and procoagulant platelets indicating that most platelet pinocytosis is dynamin dependent. Although pinocytosis was clathrin-independent in unstimulated and procoagulant populations, clathrin partially contributed to pinocytosis in pro-aggregatory platelets., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Matthew Harper reports financial support was provided by British Heart Foundation. Ruby Baxter reports financial support was provided by British Heart Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Sepsis is a severe inflammatory disease characterized by cytokine storm, often accompanied by disseminated intravascular coagulation (DIC). PANoptosis is a novel form of cell death triggered by cytokine storms, characterized by a cascade reaction of pyroptosis, apoptosis, and necroptosis. It exists in septic platelets and is closely associated with the onset and progression of DIC. However, there remains an unmet need for drugs targeting PANoptosis. The anti-PANoptosis effect of myricetin was predicted using network pharmacology and confirmed through molecular docking. In vitro platelet activation models demonstrated that myricetin significantly attenuated platelet particle release, integrin activation, adhesion, spreading, clot retraction, and aggregation. Moreover, in a sepsis model, myricetin reduced inflammatory infiltration in lung tissue and platelet activation while improving DIC. Additionally, whole blood sequencing samples from sepsis patients and healthy individuals were analyzed to elucidate the up-regulation of the PANoptosis targets. Our findings demonstrate the inhibitory effect of myricetin on septic platelet PANoptosis, indicating its potential as a novel anti-cellular PANoptosis candidate and therapeutic agent for septic DIC. Furthermore, our study establishes a foundation for utilizing network pharmacology in the discovery of new drugs to treat various diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: Blood clots are composed of aggregated fibrin and platelets, and thrombosis is the body's natural response to repairing injured blood vessels or stopping bleeding. However, when this process is activated abnormally, such as in a mechanical blood pump, it can lead to excessive thrombus formation. Therefore, how to avoid or reduce the probability of thrombus formation is an important indicator of the stable operation of a blood pump., Methods: In this paper, Lagrangian particle tracking trajectories are simulated to study platelet transport in a blood pump. The design of the thrombus blood pump was optimized using an orthogonal design method based on three factors: inlet angle, outlet angle, and blade number. The effect of blood pump pressure, rotational speed, impeller outlet angle, inlet angle, and number of blades on thrombus formation was analysed using Fluent software. The thrombogenic potential was derived by analyzing the trajectory and flow parameters of platelet particles in the blood pump, as well as the statistical parameters of residence time and stress accumulation thrombus in the platelet pump., Results: When the impeller inlet angle is 30°, the outlet angle is 20°, and the number of blades is 6, the probability of thrombus formation is minimized in the orthogonal design method, aligning with the requirements for blood pump performance., Conclusions: These design parameters serve as a numerical guideline for optimizing the geometry of the semi-open impeller in blood pumps and provide a theoretical foundation for subsequent in vitro experiments., (© 2024 International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Osteoarthritis (OA) is the most prevalent joint disease in the elderly population and its substantial morbidity and disability impose a heavy economic burden on patients and society. Knee osteoarthritis (KOA) is the most common subtype of OA, which is characterized by damage to progressive articular cartilage, synovitis, and subchondral bone sclerosis. Most current treatments for OA are palliative, primarily aim at symptom management, and do not prevent the progression of the disease or restore degraded cartilage. The activation of α-granules in platelets releases various growth factors that are involved in multiple stages of tissue repair, suggesting potential for disease modification. In recent years, platelet-based therapies, such as platelet-rich plasma, platelet-rich fibrin, and platelet lysates, have emerged as promising regenerative treatments for KOA, but their related effects and mechanisms are still unclear. Therefore, this review aims to summarize the biological characteristics and functions of platelets, classify the products of platelet-based therapy and related preparation methods. Moreover, we summarize the basic research of platelet-based regeneration strategies for KOA and discuss the cellular effects and molecular mechanisms. Further, we describe the general clinical application of platelet-based therapy in the treatment of KOA and the results of the meta-analysis of randomized controlled trials., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Alzheimer's disease (AD) is the most common form of dementia and characterized by extracellular amyloid-β (Aβ) plaques, intracellular neurofibrillary tau tangles and neurodegeneration. Over 80 % of AD patients also exhibit cerebral amyloid angiopathy (CAA). CAA is a cerebrovascular disease caused by deposition of Aβ in the walls of cerebral blood vessels leading to vessel damage and impairment of normal blood flow. To date, different studies suggest that platelet function, including activation, adhesion and aggregation, is altered in AD due to vascular Aβ deposition. For example, the transgenic AD model mice APP23 mice that exhibit CAA and parenchymal Aβ plaques, show pre-activated platelets in the blood circulation and increased platelet integrin activation leading to a pro-thrombotic phenotype in these mice late stages of AD. However, it is still an open question whether or not platelets exhibit changes in their activation profile before they are exposed to vascular Aβ deposits. Therefore, the present study examined platelets from middle-aged transgenic APP23 mice at the age of 8-10 months. At this age, APP23 mice show amyloid plaques in the brain parenchyma but not in the vasculature. Our analyses show that these APP23 mice have unaltered platelet numbers and size, and unaltered surface expression of glycoproteins. However, the number of dense granules in transgenic platelets was increased while the release was unaltered. Male, but not female APP23 mice, exhibited reduced platelet activation after stimulation of the thrombin receptor PAR4 and decreased thrombus stability on collagen under flow conditions ex vivo compared to control mice. In an arterial thrombosis model in vivo, male APP23 mice showed attenuated occlusion of the injured artery compared to controls. These findings provide clear evidence for early changes in platelet activation and thrombus formation in male mice before development of overt CAA. Furthermore, reduced platelet activation and thrombus formation suggest sex-specific differences in platelet physiology in AD that has to be considered in future studies of platelets and their role in AD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Leukocyte-platelet aggregates comprise a pathogenic link between hemostasis and immunity, but the prerequisites and mechanisms of their formation remain not understood., Aims: To quantify the formation, composition, and morphology of leukocyte-platelet aggregates in vitro under the influence of various cellular activators., Methods: Phorbol-12-myristate-13-acetate (PMA), lipopolysaccharide (LPS), thrombin receptor-activating peptide (TRAP-6), and adenosine diphosphate (ADP) were used as cellular activators. Flow cytometry was utilized to identify and quantify aggregates in whole human blood and platelet-rich plasma. Cell types and cellular aggregates were identified using fluorescently labeled antibodies against the appropriate cellular markers, and cell activation was assessed by the expression of appropriate surface markers. For confocal fluorescent microscopy, cell membranes and nuclei were labeled. Neutrophil-platelet aggregates were studied using scanning electron microscopy., Results: In the presence of PMA, ADP or TRAP-6, about 17-38 % of neutrophils and 61-77 % of monocytes formed aggregates with platelets in whole blood, whereas LPS did not induce platelet aggregation with either neutrophils or monocytes due the inability to activate platelets. Similar results were obtained when isolated neutrophils were added to platelet-rich plasma. All the cell types involved in the heterotypic aggregation expressed molecular markers of activation. Fluorescent and electron microscopy of the aggregates showed that the predominant platelet/leukocyte ratios were 1:1 and 2:1., Conclusions: Formation of leukocyte-platelet aggregates depends on the nature of the cellular activator and the spectrum of its cell-activating ability. An indispensable condition for formation of leukocyte-platelet aggregates is activation of all cell types including platelets, which is the restrictive step., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Hutchinson-Gilford Progeria Syndrome (HGPS) is an ultra-rare premature aging genetic disorder caused by a point mutation in the lamin A gene, LMNA. Children with HGPS display short lifespans and typically die due to myocardial infarction or ischemic stroke, both acute cardiovascular events that are tightly linked to arterial thrombosis. Despite this fact, the effect of the classic HGPS LMNA gene mutation on arterial thrombosis remains unknown., Methods: Heterozygous Lmna G609G knock-in (Lmna G609G/+ ) mice, yielding an equivalent classic mutation observed in HGPS patients (c.1824C>T; pG608G mutation in the human LMNA gene) and corresponding wild-type (WT) control littermates underwent photochemically laser-induced carotid injury to trigger thrombosis. Coagulation and fibrinolytic factors were measured. Furthermore, platelet activation and reactivity were investigated., Results: Lmna G609G/+ mice displayed accelerated arterial thrombus formation, as underlined by shortened time to occlusion compared to WT littermates. Levels of factors involved in the coagulation and fibrinolytic system were comparable between groups, while Lmna G609G/+ animals showed higher plasma levels of thrombin-antithrombin complex and lower levels of antithrombin. Bone marrow analysis showed larger megakaryocytes in progeric mice. Lastly, enhanced platelet activation upon adenosine diphosphate, collagen-related peptide, and thrombin stimulation was observed in Lmna G609G/+ animals compared to the WT group, indicating a higher platelet reactivity in progeric animals., Conclusions: LMNA mutation in HGPS mice accelerates arterial thrombus formation, which is mediated, at least in part, by enhanced platelet reactivity, which consequently augments thrombin generation. Given the wide spectrum of antiplatelet agents available clinically, further investigation is warranted to consider the most suitable antiplatelet regimen for children with HGPS to mitigate disease mortality and morbidity., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yustina M Puspitasari reports financial support was provided by Swiss Life Group. Giovanni G Camici reports financial support was provided by Swiss National Science Foundation. Luca Liberale reports a relationship with Daiichi Sankyo Inc. that includes: speaking and lecture fees. Giovanni G Camici reports a relationship with Sovida Solutions that includes: consulting or advisory. Thomas F Luescher reports a relationship with AstraZeneca Pharmaceuticals LP that includes: funding grants. Thomas F Luescher reports a relationship with Abbott that includes: funding grants. Thomas F Luescher reports a relationship with Amgen Inc. that includes: funding grants. Thomas F Luescher reports a relationship with Bayer HealthCare Pharmaceuticals Inc. that includes: funding grants. Thomas F Luescher reports a relationship with Boehringer Ingelheim GmbH that includes: funding grants. Thomas F Luescher reports a relationship with Daiichi Sankyo Inc. that includes: funding grants. Thomas F Luescher reports a relationship with Eli Lilly and Company that includes: funding grants. Thomas F Luescher reports a relationship with Novartis Pharmaceuticals Corporation that includes: funding grants. Thomas F Luescher reports a relationship with Novo Nordisk Inc. that includes: funding grants. Thomas F Luescher reports a relationship with Roche that includes: funding grants. Thomas F Luescher reports a relationship with Sanofi that includes: funding grants. Thomas F Luescher reports a relationship with Vifor Pharma Switzerland SA that includes: funding grants. Giovanni G Camici has patent #WO/2020/226993 pending to University of Zurich. Luca Liberale has patent #WO/2020/226993 pending to University of Zurich. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Disclosures LL and GGC are coinventors on the International Patent WO/2020/226993 filed in April 2020. The patent relates to the use of antibodies which specifically bind IL-1α to reduce various sequelae of ischemia-reperfusion injury to the central nervous system. GGC is a consultant to Sovida Solutions Limited. TFL has no conflicts related to this manuscript. Outside the work, he received unrestricted research and education grants from Abbott, Amgen, AstraZeneca, Bayer HealthCare, Boehringer Ingelheim, Daichi-Sankyo, Eli Lilly, Novartis, Novo Nordisk, Roche Diagnostics, Sanofi and Vifor. LL reports speaker fees outside of this work from Daichi-Sankyo. The other authors report no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Acute ST-elevation myocardial infarction (STEMI) remains a globally significant health challenge in spite of improvement in management strategy. Being aware that mitochondrial dysfunction plays a crucial role in ischaemia-reperfusion injury (IRI) modulation, empirical evidence suggests functional mitochondrial transplantation strikes as a reliable therapeutic approach for patients with acute myocardial infarction., Methods and Results: We conducted a prospective, triple-blinded, parallel-group, blocked randomised clinical trial to investigate the therapeutic effects and clinical outcomes of platelet-derived mitochondrial transplantation in 30 patients with acute STEMI, such that the 15 subjects in the control group were given standard of care treatment, whereas the subjects in the intervention group received autologous platelet-derived mitochondria through the intracoronary injection. We observed that within 40 days, the intervention group had a slightly greater improvement in the left ventricular ejection fraction (LVEF) compared to the control group and experienced a significant enhancement in the exercise capacity (p < 0.001). Moreover, major adverse cardiac events (MACE), arrhythmia, fever, and tachycardia were compared between the groups and lack of significant difference marks the safety of mitochondrial transplantation (p > 0.05). Furthermore, the two groups were not significantly distinct as regards the average length of stay for a hospitalisation (p > 0.05)., Conclusion: We suggest platelet-derived mitochondrial transplantation appears as a beneficial and highly promising therapeutic option for patients of ischaemic heart disease (IHD); however, we are aware that further in-depth studies with larger sample sizes along with longer follow-up periods are necessary for validating the clinical implications of our findings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Platelet aggregation is a dynamic process that can obstruct blood flow, leading to cardiovascular diseases. While many studies have demonstrated clear connections between shear rate and platelet aggregation, the impact of flow-derived mechanical signals on this process is not fully understood. The objective of this work is to investigate the role of flow conditions on platelet aggregation dynamics, including effects on growth, shape, density composition, and their potential correlation with binding processes that are characterised by longer (e.g., via αIIbβ3 integrin) and shorter (e.g., via VWF) initial binding times. In vitro blood perfusion experiments were conducted at wall shear rates of 800, 1600 and 4000 s -1 . Detailed analysis of two modalities of experimental images was performed to offer insights into the morphology of platelet aggregates. A consistent structural pattern was observed across all samples: a high-density core enveloped by a low-density outer shell. An image-based 3D computational blood flow model was subsequently employed to study the local flow conditions, including binding availability time and flow-derived mechanical signals via shear rate and rate of elongation. The results show substantial dependence of the aggregation dynamics on these flow parameters. We found that the different binding mechanisms that prefer different flow regimes do not have a monotonic cross-over in efficiency as the flow increases. There is a significant dip in the cumulative aggregation potential in-between the preferred regimes. The results suggest that treatments targeting the biomechanical pathways could benefit from creating conditions that exploit these low-efficiency zones of aggregation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We investigated the hemotoxic effects of three North American pit vipers in healthy human donor blood. Using experiments focusing on platelet and red blood cell activity, we found differential effects of these venoms on these cellular components. Platelet aggregation was most induced by C. adamanteus. Platelet activation was highest with C. atrox. Red blood cells had calcium expression and erythrocyte formation most induced by C. adamanteus and A. piscivorus. These results demonstrate the complex interplay of individual cellular effects with clinical presentations seen in envenomings from these species., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Samuel Francis reports financial support was provided by BTG Specialty Pharmaceuticals. Luke Welton reports a relationship with BTG Specialty Pharmaceuticals that includes: employment. Richard Straight reports a relationship with BTG Specialty Pharmaceuticals that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Understanding the mechanisms controlling platelet function is crucial for exploring potential therapeutic targets related to atherothrombotic pathologies and primary hemostasis disorders. Our research, which focuses on the role of platelet mitochondria and Ca2+ fluxes in platelet activation, the formation of the procoagulant phenotype, and thrombosis, has significant implications for the development of new therapeutic strategies. Traditionally, Ca 2+ -dependent cellular signaling has been recognized as a determinant process throughout the platelet activation, controlled primarily by store-operated Ca 2+ entry and the PLC-PKC signaling pathway. However, despite the accumulated knowledge of these regulatory mechanisms, the effectiveness of therapy based on various commonly used antiplatelet drugs (such as acetylsalicylic acid and clopidogrel, among others) has faced challenges due to bleeding risks and reduced efficacy associated with the phenomenon of high platelet reactivity. Recent evidence suggests that platelet mitochondria could play a fundamental role in these aspects through Ca 2+ -dependent mechanisms linked to apoptosis and forming a procoagulant phenotype. In this context, the present review describes the latest advances regarding the role of platelet mitochondria and Ca 2+ fluxes in platelet activation, the formation of the procoagulant phenotype, and thrombosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Fabry disease (FD) is an X-linked lysosomal storage disorder characterized by the progressive accumulation of globotriaosylceramide (Gb3) leading to systemic manifestations such as chronic kidney disease, cardiomyopathy, and stroke. There is still a need for novel markers for improved FD screening and prognosis. Moreover, the pathological mechanisms in FD, which also include systemic inflammation and fibrosis, are not yet fully understood., Methods: Plasma and platelets were obtained from 11 ERT (enzyme-replacement therapy)-treated symptomatic, 4 asymptomatic FD patients, and 13 healthy participants. A comprehensive targeted lipidomics analysis was conducted quantitating more than 550 lipid species., Results: Sphingadiene (18:2;O2)-containing sphingolipid species, including Gb3 and galabiosylceramide (Ga2), were significantly increased in FD patients. Plasma levels of lyso-dihexosylceramides, sphingoid base 1-phosphates (S1P), and GM3 ganglioside were also altered in FD patients, as well as specific plasma ceramide ratios used in cardiovascular disease risk prediction. Gb3 did not increase in patients' platelets but displayed a high inter-individual variability in patients and healthy participants. Platelets accumulated, however, lyso-Gb3, acylcarnitines, C16:0-sphingolipids, and S1P., Conclusions: This study identified lipidome changes in plasma and platelets from FD patients, a possible involvement of platelets in FD, and potential new markers for screening and monitoring of this disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Qilong capsule (QC) is developed from the traditional Chinese medicine formula Buyang Huanwu Decoction, which has been clinically used to invigorate Qi and promote blood circulation to eliminate blood stasis. Myocardial ischemia‒reperfusion injury (MIRI) can be attributed to Qi deficiency and blood stasis. However, the effects of QC on MIRI remain unclear., Aim of the Study: This study aimed to investigate the protective effect and possible mechanism of QC on platelet function in MIRI rats., Materials and Methods: The left anterior descending artery of adult Sprague‒Dawley rats was ligated for 30 min and then reperfused for 120 min with or without QC treatment. Then, the whole blood viscosity, plasma viscosity, coagulation, platelet adhesion rate, platelet aggregation, and platelet release factors were evaluated. Platelet CD36 and its downstream signaling pathway-related proteins were detected by western blotting. Furthermore, the active components of QC and the molecular mechanism by which QC regulates platelet function were assessed via molecular docking, platelet aggregation tests in vitro and BLI analysis., Results: We found that QC significantly reduced the whole blood viscosity, plasma viscosity, platelet adhesion rate, and platelet aggregation induced by ADP or AA in rats with MIRI. The inhibition of platelet activation by QC was associated with reduced levels of β-TG, PF-4, P-selectin and PAF. Mechanistically, QC effectively attenuated the expression of platelet CD36 and thus inhibited the activation of Src, ERK5, and p38. The active components of QC apparently suppressed platelet aggregation in vitro and regulated the CD36 signaling pathway., Conclusions: QC improves MIRI-induced hemorheological disorders, which might be partly attributed to the inhibition of platelet activation via CD36-mediated platelet signaling pathways., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Binding of activated factor IX (fIXa) to the phosphatidylserine-expressing procoagulant platelets is a critical step in blood coagulation, which is necessary for the membrane-dependent intrinsic tenase complex assembly and factor X activation. However, the nature and parameters of the fIXa binding sites on the procoagulant platelet surface remain unclear. We used flow cytometry to elucidate the quantitative details of the fluorescently labeled fIXa binding to gel-filtered activated platelets. FIXa bound to the procoagulant platelet subpopulation only, with the parameters (maximal number of binding sites at 58900 ± 3400, K d at 1000 ± 170 nM) similar to binding observed with phospholipid vesicles. No specific high-affinity binding sites for fIXa were detected, and binding proceeded similarly for different methods of procoagulant platelet production (thrombin, thrombin receptor activation peptide, collagen-related peptide, their combinations, or calcium ionophore A23187). Factor VIII, known to form a high affinity complex with fIXa, enhanced fIXa binding to platelets. In contrast, only competition effects were observed for factor X, which binds fIXa with much lower affinity. Unexpectedly, fIXa itself, fIX, and prothrombin also dose-dependently enhance fIXa binding at concentrations below 1000 nM, suggesting the formation of membrane-bound fIXa dimers and fIXa-prothrombin complexes on platelets. These findings provide a novel perspective on the fIXa binding site on procoagulant platelets, which does not have any major differences from pure phospholipid-based model membranes, exhibits inherently low affinity (3-5 orders of magnitude below the physiologically relevant fIXa concentration) but is significantly enhanced by its cofactor VIII, and regulated by previously unknown membrane interactions., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests Mikhail A. Panteleev reports financial support was provided by Russian Science Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Thrombosis is associated with various fatal arteriovenous syndromes including ischemic stroke, myocardial infarction, and pulmonary embolism. However, current clinical thrombolytic treatment strategies still have many problems in targeting and safety to meet the thrombolytic therapy needs. Understanding the molecular mechanism that underlies thrombosis is critical in developing effective thrombolytic strategies. It is well known that platelets play a central role in thrombosis and the binding of fibrinogen to activated platelets is a common pathway in the process of clot formation. Based on this, a concept of biomimetic thrombus-targeted thrombolytic strategy inspired from fibrinogen binding to activated platelets in thrombosis was proposed, which could selectively bind to activated platelets at a thrombus site, thus enabling targeted delivery and local release of thrombolytic agents for effective thrombolysis. In this review, we first summarized the main characteristics of platelets and fibrinogen, and then introduced the classical molecular mechanisms of thrombosis, including platelet adhesion, platelet activation and platelet aggregation through the interactions of activated platelets with fibrinogen. In addition, we highlighted the recent advances in biomimetic thrombus-targeted thrombolytic strategies which inspired from fibrinogen binding to activated platelets in thrombosis. The possible future directions and perspectives in this emerging area are briefly discussed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Drug delivery systems are becoming increasingly utilized; however, a major challenge in this field is the insufficient target of tissues or cells. Although efforts with engineered nanoparticles have shown some success, issues with targeting, toxicity and immunogenicity persist. Conversely, living cells can be used as drug-delivery vehicles because they typically have innate targeting mechanisms and minimal adverse effects. As active participants in hemostasis, inflammation, and tumors, platelets have shown great potential in drug delivery. This review highlights platelet-based drug delivery systems, including platelet membrane engineering, platelet membrane coating, platelet cytoplasmic drug loading, genetic engineering, and synthetic/artificial platelets for different applications., Competing Interests: Declaration of Competing Interest The authors declare that they have no financial interests or personal relationships that could influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background The storage time of platelet products negatively affects bacterial safety and platelet function. However, low maximum storage time increases outdating of valuable products. Thus, to quantify the effect of platelet storage time on platelet measurements after platelet transfusion, a systematic review and meta-analyses were performed. Methods Reports and meeting abstracts of randomized trials and observational studies, performed in humans, reporting platelet measurements after transfusion of platelet products of different storage times, were selected until February 2016. Meta-analyses were performed for four different storage time contrasts, each answering a different question. Random-effects models were used to account for substantial heterogeneity and the weighted mean differences calculated. Results Our search strategy yielded 4234 studies of which 46 papers satisfied the inclusion criteria. As judged by the 1-h corrected count increment, transfusions of fresher platelets compared to stored platelets showed better increment. The weighed mean difference varied from 2·11 (95% CI: 1·51-2·71) to 2·68 (95% CI: 1·92-3·45). For the 24-h corrected count increment, the weighted mean difference varied from 1·36 (95% CI: 0·12-2·60) to 1·68 (95% CI: 1·07-2·28) depending on the contrast. Recovery and survival of old platelets as percentage of fresh platelets were 81% and 73% for the original definition contrast. For the extended storage contrast, recovery and survival were 75% and 68%. Conclusions Fresh platelets were superior to old platelets for all platelet measurements and for all storage time contrasts meta-analysed. [ABSTRACT FROM AUTHOR]

The significant biological and functional differences between small and large platelets suggested by recent studies could have profound implications for transfusion medicine. However, investigating the relationship between platelet size and function is challenging because separating platelets by size without affecting their properties is difficult. A standard approach is centrifugation, but it inevitably leads to premature activation and aggregation of separated platelets. This paper describes the development and validation of a microfluidic device based on controlled incremental filtration (CIF) for separating platelets by size without the cell damage and usability limitations associated with centrifugation. Platelet samples derived from whole blood were used to evaluate the dependence of the CIF device separation performance on design parameters and flow rate, and to compare the properties of PLT fractions generated by the CIF device with those produced using a centrifugation protocol in a split-sample study. This was accomplished by quantifying the platelet size distribution, mean platelet volume (MPV), platelet-large cell ratio (P-LCR) and platelet activation before and after processing for all input and output samples. The 'large platelet' fractions produced by the CIF device and the centrifugation protocol were essentially equivalent (no significant difference in MPV and P-LCR). Platelets in the 'small platelet' fraction produced by the CIF device were significantly smaller than those produced by centrifugation (lower MPV and P-LCR). This was because the CIF 'small platelet' fraction was contaminated by much fewer large platelets (∼2-times lower recovery of >12 fL platelets) and retained the smallest platelets that were discarded by the centrifugation protocol. There was no significant difference in platelet activation between the two methods. However, centrifugation required a substantial amount of additional anticoagulant to prevent platelet aggregation during pelleting. Unlike centrifugation, the CIF device offered continuous, flow-through, single-step processing that did not cause platelet aggregation. Such a capability has the potential to accelerate the basic studies of the relationship between platelet size and function, and ultimately improve transfusion practice, particularly in the pediatric setting, where the need for low-volume, high-quality platelet transfusions is most urgent. [ABSTRACT FROM AUTHOR]