Neutrophil-derived migrasomes are an essential part of the coagulation system.

Migrasomes are organelles that are generated by migrating cells. Here we report the key role of neutrophil-derived migrasomes in haemostasis. We found that a large number of neutrophil-derived migrasomes exist in the blood of mice and humans. Compared with neutrophil cell bodies and platelets, these migrasomes adsorb and enrich coagulation factors on the surface. Moreover, they are highly enriched with adhesion molecules, which enable them to preferentially accumulate at sites of injury, where they trigger platelet activation and clot formation. Depletion of neutrophils, or genetic reduction of the number of these migrasomes, significantly decreases platelet plug formation and impairs coagulation. These defects can be rescued by intravenous injection of purified neutrophil-derived migrasomes. Our study reveals neutrophil-derived migrasomes as a previously unrecognized essential component of the haemostasis system, which may shed light on the cause of various coagulation disorders and open therapeutic possibilities.

CryoET reveals actin filaments within platelet microtubules.

Crosstalk between the actin and microtubule cytoskeletons is important for many cellular processes. Recent studies have shown that microtubules and F-actin can assemble to form a composite structure where F-actin occupies the microtubule lumen. Whether these cytoskeletal hybrids exist in physiological settings and how they are formed is unclear. Here, we show that the short-crossover Class I actin filament previously identified inside microtubules in human HAP1 cells is cofilin-bound F-actin. Lumenal F-actin can be reconstituted in vitro, but cofilin is not essential. Moreover, actin filaments with both cofilin-bound and canonical morphologies reside within human platelet microtubules under physiological conditions. We propose that stress placed upon the microtubule network during motor-driven microtubule looping and sliding may facilitate the incorporation of actin into microtubules.

Immune interactions and regulation with CD39+ extracellular vesicles from platelet concentrates.

Introduction: CD39 plays an important role in the immunoregulation and inhibition of effector cells. It is expressed on immune cells, including Tregs, and on extracellular vesicles (EVs) budding from the plasma membrane. Platelet transfusion may induce alloimmunization against HLA-I antigens, leading to refractoriness to platelet transfusion with severe consequences for patients. Tregs may play a key role in determining whether alloimmunization occurs in patients with hematologic disorders. We hypothesized that CD39+ EVs might play an immunoregulatory role, particularly in the context of platelet transfusions in patients with hematologic disorders. Such alloimmunization leads to the production of alloantibodies and is sensitive to the regulatory action of CD39. Methods: We characterized CD39+ EVs in platelet concentrates by flow cytometry. The absolute numbers and cellular origins of CD39+ EVs were evaluated. We also performed functional tests to evaluate interactions with immune cells and their functions. Results: We found that CD39+ EVs from platelet concentrates had an inhibitory phenotype that could be transferred to the immune cells with which they interacted: CD4+ and CD8+ T lymphocytes (TLs), dendritic cells, monocytes, and B lymphocytes (BLs). Moreover, the concentration of CD39+ EVs in platelet concentrates varied and was very high in 10% of concentrates. The number of these EVs present was determinant for EV-cell interactions. Finally, functional interactions were observed with BLs, CD4+ TLs and CD39+ EVs for immunoglobulin production and lymphoproliferation, with potential implications for the immunological management of patients.

Prognostic Significance of Thrombocytopenia and Mean Platelet Volume in COPD Patients with Acute Exacerbations in ICU Settings.

BACKGROUND Platelets have important modulatory effects on inflammatory and immune-mediated pathways. Thrombocytopenia is a critical condition that is frequently encountered in the intensive care unit (ICU) and increases mortality. This retrospective study of 472 patients admitted to the ICU with acute exacerbation of chronic obstructive pulmonary disease (COPD) aimed to evaluate thrombocytopenia and mean platelet volume (MPV) with prognosis and patient mortality. MATERIAL AND METHODS A total of 472 patients diagnosed with COPD according to GOLD criteria and hospitalized in the tertiary ICU between 1 April 2018 and 11 May 2021 were included in the study. Platelets were calculated by the impetance method and MPV was simultaneously calculated based on the platelet histogram. Patients with platelet count ≤100×109/L and >100×109/L and patients with MPV values <7 fl, 7-11 fl, and >11fl were compared in terms of mortality and prognosis. RESULTS The mortality rate in COPD patients with thrombocytopenia was high, at 61.5%. Thrombocytopenia (P=.002), high MPV (P=.006) Acute Physiology and Chronic Health Evaluation-2 (APACHE-II) score (P=.025), length of stay (LOS) in the ICU (P=.009), mechanical ventilation duration (P<.001), leukocytosis (P<.001), high Sequential Organ Failure Assessment (SOFA) score (P<.001), LOS in the hospital (P=.035), and hypoalbuminemia (P<.001) were significantly associated with mortality. CONCLUSIONS Thrombocytopenia, high MPV, high APACHE-II and SOFA scores, LOS in the ICU and hospital, duration of mechanical ventilation, leukocytosis, and hypoalbuminemia predict mortality in COPD patients. Since infection-sepsis, hypoalbuminemia, and hypoxia can worsen this situation, ensuring early infection control, providing albumin support, and preventing hypoxia contribute significantly to reducing thrombocytopenia and mortality.

Human platelet lysate supports SH-SY5Y neuroblastoma cell proliferation and differentiation into a dopaminergic-like neuronal phenotype under xenogeneic-free culture conditions.

SH-SY5Y is a human neuroblastoma cell line that can be differentiated into several neuronal phenotypes, depending on culture conditions. For this reason, this cell line has been widely used as an in vitro model of neurodegenerative conditions, such as Parkinson's disease (PD). However, most studies published to date used fetal bovine serum (FBS) as culture medium supplement for SH-SY5Y cell differentiation. We report on the testing of human platelet lysate (hPL) as a culture medium supplement to support SH-SY5Y cell culture. Both standard hPL and a fibrinogen-depleted hPL (FD-hPL) formulation, which does not require the addition of anticoagulants to culture media, promoted an increase in SH-SY5Y cell proliferation in comparison to FBS, without compromising metabolic activity. SH-SY5Y cells cultured in hPL or FD-hPL also displayed a higher number of neurite extensions and stained positive for MAP2 and synaptophysin, in the absence of differentiation stimuli; reducing hPL or FD-hPL concentration to 1% v/v did not affect cell proliferation or metabolic activity. Furthermore, following treatment with retinoic acid (RA) and further stimulation with brain-derived neurotrophic factor (BDNF) and nerve growth factor beta (NGF-ß), the percentage of SH-SY5Y cells stained positive for dopaminergic neuronal differentiation markers (tyrosine hydroxylase [TH] and Dopamine Transporter [DAT]) was higher in hPL or FD-hPL than in FBS, and gene expression of dopaminergic markers TH, DAT, and DR2 was also detected. Overall, the data herein presented supports the use of hPL to differentiate SH-SY5Y cells into a neuronal phenotype with dopaminergic features, and the adoption of FD-hPL as a fully xenogeneic free alternative to FBS to support the use of SH-SY5Y cells as a neurodegeneration model.

Immunoregulatory role of platelet derivatives in the macrophage-mediated immune response.

Background: Macrophages are innate immune cells that display remarkable phenotypic heterogeneity and functional plasticity. Due to their involvement in the pathogenesis of several human conditions, macrophages are considered to be an attractive therapeutic target. In line with this, platelet derivatives have been successfully applied in many medical fields and as active participants in innate immunity, cooperation between platelets and macrophages is essential. In this context, the aim of this review is to compile the current evidence regarding the effects of platelet derivatives on the phenotype and functions of macrophages to identify the advantages and shortcomings for feasible future clinical applications. Methods: A total of 669 articles were identified during the systematic literature search performed in PubMed and Web of Science databases. Results: A total of 27 articles met the inclusion criteria. Based on published findings, platelet derivatives may play an important role in inducing a dynamic M1/M2 balance and promoting a timely M1-M2 shift. However, the differences in procedures regarding platelet derivatives and macrophages polarization and the occasional lack of information, makes reproducibility and comparison of results extremely challenging. Furthermore, understanding the differences between human macrophages and those derived from animal models, and taking into account the peculiarities of tissue resident macrophages and their ontogeny seem essential for the design of new therapeutic strategies. Conclusion: Research on the combination of macrophages and platelet derivatives provides relevant information on the function and mechanisms of the immune response.

Trauma patients have reduced ex vivo flow-dependent platelet hemostatic capacity in a microfluidic model of vessel injury.

Trauma is the leading cause of death in individuals up to 45 years of age. Alterations in platelet function are a critical component of trauma-induced coagulopathy (TIC), yet these changes and the potential resulting dysfunction is incompletely understood. The lack of clinical assays available to explore platelet function in this patient population has hindered detailed understanding of the role of platelets in TIC. The objective of this study was to assess trauma patient ex vivo flow-dependent platelet hemostatic capacity in a microfluidic model. We hypothesized that trauma patients would have flow-regime dependent alterations in platelet function. Blood was collected from trauma patients with level I activations (N = 34) within 60 min of hospital arrival, as well as healthy volunteer controls (N = 10). Samples were perfused through a microfluidic model of injury at venous and arterial shear rates, and a subset of experiments were performed after incubation with fluorescent anti-CD41 to quantify platelets. Complete blood counts were performed as well as plasma-based assays to quantify coagulation times, fibrinogen, and von Willebrand factor (VWF). Exploratory correlation analyses were employed to identify relationships with microfluidic hemostatic parameters. Trauma patients had increased microfluidic bleeding times compared to healthy controls. While trauma patient samples were able to deposit a substantial amount of clot in the model injury site, the platelet contribution to microfluidic hemostasis was attenuated. Trauma patients had largely normal hematology and plasma-based coagulation times, yet had elevated D-Dimer and VWF. Venous microfluidic bleeding time negatively correlated with VWF, D-Dimer, and mean platelet volume (MPV), while arterial microfluidic bleeding time positively correlated with oxygenation. Arterial clot growth rate negatively correlated with red cell count, and positively with mean corpuscular volume (MCV). We observed changes in clot composition in trauma patient samples reflected by significantly diminished platelet contribution, which resulted in reduced hemostatic function in a microfluidic model of vessel injury. We observed a reduction in platelet clot contribution under both venous and arterial flow ex vivo in trauma patient samples. While our population was heterogenous and had relatively mild injury severity, microfluidic hemostatic parameters correlated with different patient-specific data depending on the flow setting, indicating potentially differential mechanistic pathways contributing to platelet hemostatic capacity in the context of TIC. These data were generated with the goal of identifying key features of platelet dysfunction in bleeding trauma patients under conditions of flow and to determine if these features correlate with clinically available metrics, thus providing preliminary surrogate markers of physiological platelet dysfunction to be further studied across larger cohorts. Future studies will continue to explore those relationships and further define mechanisms of TIC and their relationship with patient outcomes.

Stent coating containing a charged silane coupling agent that regulates protein adsorption to confer antithrombotic and cell-adhesion properties.

The evolution of endovascular therapies, particularly in the field of intracranial aneurysm treatment, has been truly remarkable and is characterized by the development of various stents. However, ischemic complications related to thrombosis or downstream emboli pose a challenge for the broader clinical application of such stents. Despite advancements in surface modification technologies, an ideal coating that fulfills all the desired requirements, including anti-thrombogenicity and swift endothelialization, has not been available. To address these issues, we investigated a new coating comprising 3-aminopropyltriethoxysilane (APTES) with both anti-thrombogenic and cell-adhesion properties. We assessed the anti-thrombogenic property of the coating using an in vitro blood loop model by evaluating the platelet count and the level of the thrombin-antithrombin (TAT) complex, and investigating thrombus formation on the surface using scanning electron microscopy (SEM). We then assessed endothelial cell adhesion on the metal surfaces. In vitro blood tests revealed that, compared to a bare stent, the coating significantly inhibited platelet reduction and thrombus formation; more human serum albumin spontaneously adhered to the coated surface to block thrombogenic activation in the blood. Cell adhesion tests also indicated a significant increase in the number of cells adhering to the APTES-coated surfaces compared to the numbers adhering to either the bare stent or the stent coated with an anti-fouling phospholipid polymer. Finally, we performed an in vivo safety test by implanting coated stents into the internal thoracic arteries and ascending pharyngeal arteries of minipigs, and subsequently assessing the health status and vessel patency of the arteries by angiography over the course of 1 week. We found that there were no adverse effects on the pigs and the vascular lumens of their vessels were well maintained in the group with APTES-coated stents. Therefore, our new coating exhibited both high anti-thrombogenicity and cell-adhesion properties, which fulfill the requirements of an implantable stent.

The polygenic implication of clopidogrel responsiveness: Insights from platelet reactivity analysis and next-generation sequencing.

Clopidogrel is widely used worldwide as an antiplatelet therapy in patients with acute coronary disease. Genetic factors influence interindividual variability in response. Some studies have explored the polygenic contributions in the drug response, generating pharmacogenomic risk scores (PgxPRS). Importantly, these factors are less explored in underrepresented populations, such as Latin-American countries. Identifying patients at risk of high-on-treatment platelet reactivity (HTPR) is highly valuable in translational medicine. In this study we used a custom next-generation sequencing (NGS) panel composed of 91 single nucleotide polymorphisms (SNPs) and 28 genes related to clopidogrel metabolism, to analyze 70 patients with platelet reactivity values, assessed through closure time (CT). Our results demonstrated the association of SNPs with HTPR and non-HTPR, revealing the strongest associations with rs2286823 (OR: 5,0; 95% CI: 1,02-24,48; p: 0,03), rs2032582 (OR: 4,41; 95% CI: 1,20-16,12; p: 0,019), and rs1045642 (OR: 3,38; 95% CI: 0,96-11,9; p: 0,05). Bivariate regression analysis demonstrated the significant association of several SNPs with the CT value, a "surrogate" biomarker of clopidogrel response. Exploratory results from the LASSO regression model showed a high discriminatory capacity between HTPR and non-HTPR patients (AUC: 0,955), and the generated PgxPRS demonstrated a significant negative association between the risk score, CT value, and the condition of HTPR and non-HTPR. To our knowledge, our study addresses for the first time the analysis of the polygenic contribution in platelet reactivity using NGS and establishes PgxPRS derived from the LASSO model. Our results demonstrate the polygenic implication of clopidogrel response and offer insights applicable to the translational medicine of antiplatelet therapy in an understudied population.

Protein Kinase A Regulates Platelet Phosphodiesterase 3A through an A-Kinase Anchoring Protein Dependent Manner.

Platelet activation is critical for haemostasis, but if unregulated can lead to pathological thrombosis. Endogenous platelet inhibitory mechanisms are mediated by prostacyclin (PGI2)-stimulated cAMP signalling, which is regulated by phosphodiesterase 3A (PDE3A). However, spatiotemporal regulation of PDE3A activity in platelets is unknown. Here, we report that platelets possess multiple PDE3A isoforms with seemingly identical molecular weights (100 kDa). One isoform contained a unique N-terminal sequence that corresponded to PDE3A1 in nucleated cells but with negligible contribution to overall PDE3A activity. The predominant cytosolic PDE3A isoform did not possess the unique N-terminal sequence and accounted for >99% of basal PDE3A activity. PGI2 treatment induced a dose and time-dependent increase in PDE3A phosphorylation which was PKA-dependent and associated with an increase in phosphodiesterase enzymatic activity. The effects of PGI2 on PDE3A were modulated by A-kinase anchoring protein (AKAP) disruptor peptides, suggesting an AKAP-mediated PDE3A signalosome. We identified AKAP7, AKAP9, AKAP12, AKAP13, and moesin expressed in platelets but focussed on AKAP7 as a potential PDE3A binding partner. Using a combination of immunoprecipitation, proximity ligation techniques, and activity assays, we identified a novel PDE3A/PKA RII/AKAP7 signalosome in platelets that integrates propagation and termination of cAMP signalling through coupling of PKA and PDE3A.

New Findings Regarding the Effects of Selected Blue Food Colorants (Genipin, Patent Blue V, and Brilliant Blue FCF) on the Hemostatic Properties of Blood Components In Vitro.

Natural and synthetic colorants present in food can modulate hemostasis, which includes the coagulation process and blood platelet activation. Some colorants have cardioprotective activity as well. However, the effect of genipin (a natural blue colorant) and synthetic blue colorants (including patent blue V and brilliant blue FCF) on hemostasis is not clear. In this study, we aimed to investigate the effects of three blue colorants-genipin, patent blue V, and brilliant blue FCF-on selected parameters of hemostasis in vitro. The anti- or pro-coagulant potential was assessed in human plasma by measuring the following coagulation times: thrombin time (TT), prothrombin time (PT), and activated partial thromboplastin time (APTT). Moreover, we used the Total Thrombus formation Analysis System (T-TAS, PL-chip) to evaluate the anti-platelet potential of the colorants in whole blood. We also measured their effect on the adhesion of washed blood platelets to fibrinogen and collagen. Lastly, the cytotoxicity of the colorants against blood platelets was assessed based on the activity of extracellular lactate dehydrogenase (LDH). We observed that genipin (at all concentrations (1-200 µM)) did not have a significant effect on the coagulation times (PT, APTT, and TT). However, genipin at the highest concentration (200 µM) and patent blue V at the concentrations of 1 and 10 µM significantly prolonged the time of occlusion measured using the T-TAS, which demonstrated their anti-platelet activity. We also observed that genipin decreased the adhesion of platelets to fibrinogen and collagen. Only patent blue V and brilliant blue FCF significantly shortened the APTT (at the concentration of 10 µM) and TT (at concentrations of 1 and 10 µM), demonstrating pro-coagulant activity. These synthetic blue colorants also modulated the process of human blood platelet adhesion, stimulating the adhesion to fibrinogen and inhibiting the adhesion to collagen. The results demonstrate that genipin is not toxic. In addition, because of its ability to reduce blood platelet activation, genipin holds promise as a novel and valuable agent that improves the health of the cardiovascular system and reduces the risk of cardiovascular diseases. However, the mechanism of its anti-platelet activity remains unclear and requires further studies. Its in vivo activity and interaction with various anti-coagulant and anti-thrombotic drugs, including aspirin and its derivatives, should be examined as well.

Antithrombotic Effect of Oil from the Pulp of Bocaiúva-Acrocomia aculeata (Jacq.) Lodd. ex Mart. (Arecaceae).

The study aimed to evaluate the antithrombotic action of Acrocomia aculeata pulp oil (AAPO) in natura, in an in vitro experimental model. AAPO was obtained by solvent extraction, and its chemical characterization was performed by gas chromatography coupled to a mass spectrometer (GC-MS). In vitro toxicity was evaluated with the Trypan Blue exclusion test and in vivo by the Galleria mellonella model. ADP/epinephrine-induced platelet aggregation after treatment with AAPO (50, 100, 200, 400, and 800 µg/mL) was evaluated by turbidimetry, and coagulation was determined by prothrombin activity time (PT) and activated partial thromboplastin time (aPTT). Platelet activation was measured by expression of P-selectin on the platelet surface by flow cytometry and intraplatelet content of reactive oxygen species (ROS) by fluorimetry. The results showed that AAPO has as major components such as oleic acid, palmitic acid, lauric acid, caprylic acid, and squalene. AAPO showed no toxicity in vitro or in vivo. Platelet aggregation decreased against agonists using treatment with different concentrations of AAPO. Oil did not interfere in PT and aPTT. Moreover, it expressively decreased ROS-induced platelet activation and P-selectin expression. Therefore, AAPO showed antiplatelet action since it decreased platelet activation verified by the decrease in P-selectin expression as well as in ROS production.

tRF-His-GTG-1 enhances NETs formation and interferon-α production in lupus by extracellular vesicle.

BACKGROUND: Hyperactive neutrophil extracellular traps (NETs) formation plays a crucial role in active severe systemic lupus erythematosus (SLE). However, what triggers the imbalance in dysregulated NETs formation in SLE is elusive. Transfer RNA-derived small RNAs (tsRNAs) are novel non-coding RNAs, which participate in various cellular processes. We explore the role of tsRNAs on NETs formation in SLE. METHODS: We analyzed the levels of NETs DNA and platelet-derived extracellular vesicles (pEVs) from 50 SLE patients and 20 healthy control subjects. The effects of pEVs on NETs formation were evaluated by using immunofluorescence assay and myeloperoxidase-DNA PicoGreen assay. The regulatory mechanism of pEVs on NETs formation and inflammatory cytokines production were investigated using an in vitro cell-based assay. RESULTS: Increased circulating NETs DNA and pEVs were shown in SLE patients and were associated with disease activity (P < 0.005). We demonstrated that SLE patient-derived immune complexes (ICs) induced platelet activation, followed by pEVs release. ICs-triggered NETs formation was significantly enhanced in the presence of pEVs through Toll-like receptor (TLR) 8 activation. Increased levels of tRF-His-GTG-1 in pEVs and neutrophils of SLE patients were associated with disease activity. tRF-His-GTG-1 interacted with TLR8 to prime p47phox phosphorylation in neutrophils, resulting in reactive oxygen species production and NETs formation. Additionally, tRF-His-GTG-1 modulated NF-κB and IRF7 activation in neutrophils upon TLR8 engagement, resulting IL-1ß, IL-8, and interferon-α upregulation, respectively. CONCLUSIONS: The level of tRF-His-GTG-1 was positively correlated with NETs formation in SLE patients; tRF-His-GTG-1 inhibitor could efficiently suppress ICs-triggered NETs formation/hyperactivation, which may become a potential therapeutic target.

Neutrophils and platelets are key members in the immunopathogenesis of SLE. EVs play a key role in intercellular communication. Abnormal NETs formation promotes vascular complications and organ damage in SLE patients. tsRNA is a novel regulatory small non-coding RNA and participates in diverse pathological processes. Herein, we showed that SLE patient-derived ICs activates platelets directly, followed by intracellular tRF-His-GTG-1 upregulation, which is loaded into pEVs. The pEV-carried tRF-His-GTG-1 could interact with TLR8 in neutrophils, followed by activation of the downstream signaling pathway, including p47phox-NOX2-ROS, which causes NETs enhancement, while IRF7 promotes the expression of IFN-α. The tRF-His-GTG-1 inhibitor could suppress efficiently SLE ICs-induced NETs formation and pEVs primed NETs enhancement. This study offers new molecular machinery to explain the association between the platelets-derived tsRNAs, pEVs, and hyperactive NETs formation in lupus. tRF-His-GTG-1 may serve as a potential therapeutic target and help to advance our understanding of tsRNAs in SLE pathogenesis.

The role of platelet desialylation as a biomarker in primary immune thrombocytopenia: mechanisms and therapeutic perspectives.

Primary immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by the destruction of platelets. Although it was long believed that the critical role of autoantibodies in platelet destruction, primarily through the Fc-dependent platelet clearance pathway, recent findings indicate that the significance of the Fc-independent platelet clearance pathway mediated by hepatocytes, thus shedding light on a previously obscure aspect of ITP pathogenesis. Within this context, the desialylation of platelets has emerged as a pivotal biochemical marker. Consequently, targeting platelet desialylation emerges as a novel therapeutic strategy in the pathogenesis of ITP. Notably, prevailing research has largely focused on antiplatelet antibodies and the glycosylation-associated mechanisms of platelet clearance, while comprehensive analysis of platelet desialylation remains scant. In response, we retrospectively discuss the historical progression, inducing factors, generation process, and molecular regulatory mechanisms underlying platelet desialylation in ITP pathogenesis. By systematically evaluating the most recent research findings, we contribute to a comprehensive understanding of the intricate processes involved. Moreover, our manuscript delves into the potential application of desialylation regulatory strategies in ITP therapy, heralding novel therapeutic avenues. In conclusion, this manuscript not only fills a critical void in existing literature but also paves the way for future research by establishing a systematic theoretical framework. By inspiring new research ideas and offering insights into the development of new therapeutic strategies and targeted drugs, our study is poised to significantly advance the clinical management of ITP.

Nomogram development for predicting ovarian tumor malignancy using inflammatory biomarker and CA-125.

Global challenges in ovarian cancer underscore the need for cost-effective screening. This study aims to assess the role of pretreatment Neutrophil-to-Lymphocyte Ratio (NLR), Lymphocyte-to-Monocyte-Ratio (LMR), Platelet-to-Lymphocyte Ratio (PLR), and CA-125 in distinguishing benign and malignant ovarian tumors, while also constructing nomogram models for distinguish benign and malignant ovarian tumor using inflammatory biomarkers and CA-125. This is a retrospective study of 206 ovarian tumor patients. We conducted bivariate analysis to compare mean values of CA-125, LMR, NLR, and PLR with histopathology results. Multiple regression logistic analysis was then employed to establish predictive models for malignancy. NLR, PLR, and CA-125 exhibited statistically higher levels in malignant ovarian tumors compared to benign ones (5.56 ± 4.8 vs. 2.9 ± 2.58, 278.12 ± 165.2 vs. 180.64 ± 89.95, 537.2 ± 1621.47 vs. 110.08 ± 393.05, respectively), while lower LMR was associated with malignant tumors compared to benign (3.2 ± 1.6 vs. 4.24 ± 1.78, p = 0.0001). Multiple logistic regression analysis revealed that both PLR and CA125 emerged as independent risk factors for malignancy in ovarian tumors (P(z) 0.03 and 0.01, respectively). Utilizing the outcomes of multiple regression logistic analysis, a nomogram was constructed to enhance malignancy prediction in ovarian tumors. In conclusion, our study emphasizes the significance of NLR, PLR, CA-125, and LMR in diagnosing ovarian tumors. PLR and CA-125 emerged as independent risk factors for distinguishing between benign and malignant tumors. The nomogram model offers a practical way to enhance diagnostic precision.

Association of the hemoglobin, albumin, lymphocyte, and platelet score with the risk of Erectile dysfunction: a cross-sectional study.

Erectile dysfunction (ED) is related to nutritional and inflammatory factors. The hemoglobin, albumin, lymphocyte, and platelet score (HALP), a new index reflecting the nutritional and inflammatory status, has been associated with a higher risk of diabetic retinopathy, particularly at lower values (≤ 42.9). However, studies focusing on the relationship between HALP and ED risk are scarce. Hence, this study aimed to investigate the association between HALP and ED. Data were extracted from the National Health and Nutrition Examination Survey (NHANES) conducted between 2001 and 2004. Based on self-reported data, participants were classified into either the ED group or the non-ED group. Next, the HALP score was categorized into four quartiles (Q1-4). Weighted multivariate regression analysis was performed to assess the relationship between categorical HALP and ED risk. Additionally, restricted cubic spline (RCS) analysis was conducted to examine the association between continuous HALP scores and ED risk. Furthermore, subgroup analyses were conducted to examine the association between categorical HALP and the risk of ED based on age, as well as the status of hypertension, diabetes and cardiovascular disease. Finally, a mediation analysis was carried out to investigate the mediating effect of HALP and related parameters on the association between urinary cobalt levels and ED. Initially, the data of 21,161 participants were collected. After implementing the inclusion and exclusion criteria, 3406 participants were included in the final analyses. Weighted multivariate regression analysis demonstrated that the Q4 HALP group was associated with a lower risk of ED (OR 0.96, 95% confidence intervals 0.92-1.00, P = 0.037). Meanwhile, RCS analysis showed that HALP was nonlinearly associated with the risk of ED. In addition, subgroup analyses demonstrated that participants in the Q3/4 HALP group had a significantly lower ED risk than those in the Q1 group among patients aged ≥ 50 years, as well as those with hypertension and diabetes. Lastly, mediation analysis revealed that HALP and its associated parameters had a marginal average causal mediation effect on the relationship between urinary cobalt levels and ED risk (P > 0.05). In US adults, high HALP scores were correlated with a lower risk of ED. The relationship was more pronounced in participants aged ≥ 50 years with hypertension and diabetes. Furthermore, HALP and its parameters may not mediate the association between urinary cobalt levels and ED risk.

The bile acid receptor TGR5 inhibits platelet activation and thrombus formation.

Liver failure and cirrhosis are characterized by abnormal hemostasis with aberrant platelet activation. In particular, the consequences of cholestatic liver disease and molecular mechanisms, including the role of bile acids leading to impaired platelet responses, are not well understood. Here, we demonstrate that bile acids inhibit human and murine platelet activation, adhesion and spreading, leading to reduced thrombus formation under flow conditions. We identified the G-protein coupled receptor TGR5 in platelets and provide support for its role as mediator of bile acid-induced impairment of platelet activation. In the liver, TGR5 couples to Gαs proteins, activates the adenylate cyclase to induce a transient cAMP rise and stimulates the MAPK signaling pathway to regulate cholangiocyte proliferation, hepatocyte survival and inflammation. In this report, we demonstrate that the genetic deficiency of TGR5 in mice led to enhanced platelet activation and thrombus formation, suggesting that TGR5 plays an important role in hemostasis. Mechanistically, platelet inhibition is achieved by TGR5 mediated PKA activation and modulation of AKT and ERK1/2 phosphorylation. Thus, this report provides evidence for the ability of TGR5 ligands to reduce platelet activation and identifies TGR5 agonism as a new target for the prevention of cardiovascular diseases.

What is the context? Liver failure or cirrhosis are related to impaired hemostasis and a role of bile acids in impaired platelet responses is known but only less understood.Platelets express the bile acid receptor FXR. Ligand binding to the FXR on platelets causes a shift in platelet reactivity and is atheroprotective suggesting that the FXR is a potential target for the prevention of atherothrombotic diseases.What is new? Treatment of murine and human blood with bile acids in low molecular quantity led to reduced platelet activation, adhesion and thrombus formation.The bile acid receptor TGR5 was identified on human and murine platelets.TGR5 plays an important role in hemostasis because TGR5 deficient mice showed elevated platelet reactivity and enhanced thrombus formation.Loss of TGR5 led to enhanced PKA activation and modulated the phosphorylation of MAPK such as AKT and ERK1/2.What is the impact? Impairment of platelet activation by bile acids is mediated by TGR5 via the protein kinase A signaling pathway.Our findings provide evidence for the modulation of TGR5 activation as a potential new target of both, anti-platelet therapy in cardiovascular diseases and the restoration of hemostasis upon liver injury.

Eff ect of platelet-rich autoplasma on endometrial thickness and receptor sensitivity to estrogen and progesterone.

AIM: The effect of platelet-rich autoplasma on endometrial thickness and receptor sensitivity to estrogen and progesterone. MATERIALS AND METHODS: This prospective clinical study included 200 patients. The participants in the study were divided into two groups. The first control group received hormone replacement therapy (HRT). The second study group received an intrauterine infusion of platelet-rich autoplasma (PRP group). On the 19th day of the menstrual cycle, an ultrasound examination was performed to assess endometrial thickness, as well as an immunohistochemical analysis to determine receptor sensitivity to estrogen and progesterone. RESULTS: In the course of the study, we found that the use of platelet-rich autoplasma increased the thickness of the endometrium by 0.85 mm; the average thickness of the endometrium in the group who received PRP therapy was 8.25 (8.25-8.61)  mm; and in the group of patients who only received HRT, it was 7.40 (7.34-7.65)  mm. The sensitivity of receptors to estrogen in the experimental group increased by 3.5, in the experimental group it was 75.00 (71.43-74.22), and in the control group it was 71.50 (67.05-70.85). The sensitivity of receptors to progesterone also increased by 9.0, in the experimental group it was 95.0 (91.4-93.8), and in the control group it was 86.0 (83.47-86.27). CONCLUSION: Due to the action of platelet factors, PRP therapy has a positive effect on the endometrium, increasing its thickness and improving its receptivity. Therefore, it can be concluded that this method can find great practical application to improve the outcomes of assisted reproductive technology programs.