Platelet Depletion Research Articles

Self-assembling Gn head ferritin nanoparticle vaccine provides full protection from lethal challenge of Dabie bandavirus in aged ferrets.

Dabie bandavirus (DBV) is an emerging tick-borne virus that causes severe fever with thrombocytopenia syndrome (SFTS) in infected patients. Human SFTS symptoms progress from fever, fatigue, and muscle pain to the depletion of white blood cells and platelets with fatality rates up to 30%. The recent spread of its vector tick to over 20 states in the United States increases the potential for outbreaks of the SFTS beyond the East Asia. Thus, the development of vaccine to control this rapidly emerging virus is a high priority. In this study, we applied self-assembling ferritin (FT) nanoparticle to enhance the immunogenicity of DBV Gn head domain (GnH) as a vaccine target. Mice immunized with the GnH-FT nanoparticle vaccine induced potent antibody responses and cellular immunity. Immunized aged ferrets were fully protected from the lethal challenge of DBV. Our study describes the GnH-FT nanoparticle vaccine candidate that provides protective immunity against the emerging DBV infection.

Dynamic actin/septin network in megakaryocytes coordinates proplatelet elaboration.

Megakaryocytes (MK) undergo extensive cytoskeletal rearrangements as they give rise to platelets. While cortical microtubule sliding has been implicated in proplatelet formation, the role of the actin cytoskeleton in proplatelet elongation is less understood. It is assumed that actin filament reorganization is important for platelet generation given that mouse models with mutations in actin-associated proteins exhibit thrombocytopenia. However, due to the essential role of the actin network during MK development, a differential understanding of the contribution of the actin cytoskeleton on proplatelet release is lacking. Here, we reveal that inhibition of actin polymerization impairs the formation of elaborate proplatelets by hampering proplatelet extension and bead formation along the proplatelet shaft, which was mostly independent of changes in cortical microtubule sliding. We identify Cdc42 and its downstream effectors, septins, as critical regulators of intracellular actin dynamics in MK, inhibition of which, similarly to inhibition of actin polymerization, impairs proplatelet movement and beading. Super-resolution microscopy revealed a differential association of distinctive septins with the actin and microtubule cytoskeleton, respectively, which was disrupted upon septin inhibition and diminished intracellular filamentous actin dynamics. In vivo, septins, similarly to F-actin, were subject to changes in expression upon enforcing proplatelet formation through prior platelet depletion. In summary, we demonstrate that a Cdc42/septin axis is not only important for MK maturation and polarization, but is further required for intracellular actin dynamics during proplatelet formation.

Platelet‐derived lipids promote insulin secretion of pancreatic β cells

Hyperreactive platelets are commonly observed in diabetic patients indicating a potential link between glucose homeostasis and platelet reactivity. This raises the possibility that platelets may play a role in the regulation of metabolism. Pancreatic β cells are the central regulators of systemic glucose homeostasis. Here, we show that factor(s) derived from β cells stimulate platelet activity and platelets selectively localize to the vascular endothelium of pancreatic islets. Both depletion of platelets and ablation of major platelet adhesion or activation pathways consistently resulted in impaired glucose tolerance and decreased circulating insulin levels. Furthermore, we found platelet‐derived lipid classes to promote insulin secretion and identified 20‐Hydroxyeicosatetraenoic acid (20‐HETE) as the main factor promoting β cells function. Finally, we demonstrate that the levels of platelet‐derived 20‐HETE decline with age and that this parallels with reduced impact of platelets on β cell function. Our findings identify an unexpected function of platelets in the regulation of insulin secretion and glucose metabolism, which promotes metabolic fitness in young individuals.

Platelets exacerbate cardiovascular inflammation in a murine model of Kawasaki disease vasculitis.

Kawasaki disease (KD) is the leading cause of acquired heart disease among children. Increased platelet counts and activation are observed during the course of KD, and elevated platelet counts are associated with higher risks of developing intravenous immunoglobulin resistance and coronary artery aneurysms. However, the role of platelets in KD pathogenesis remains unclear. Here, we analyzed transcriptomics data generated from the whole blood of patients with KD and discovered changes in the expression of platelet-related genes during acute KD. In the Lactobacillus casei cell wall extract (LCWE) murine model of KD vasculitis, LCWE injection increased platelet counts and the formation of monocyte-platelet aggregates (MPAs), upregulated the concentration of soluble P-selectin, and increased circulating thrombopoietin and interleukin 6 (IL-6). Furthermore, platelet counts correlated with the severity of cardiovascular inflammation. Genetic depletion of platelets (Mpl-/- mice) or treatment with an anti-CD42b antibody significantly reduced LCWE-induced cardiovascular lesions. Furthermore, in the mouse model, platelets promoted vascular inflammation via the formation of MPAs, which likely amplified IL-1B production. Altogether, our results indicate that platelet activation exacerbates the development of cardiovascular lesions in a murine model of KD vasculitis. These findings enhance our understanding of KD vasculitis pathogenesis and highlight MPAs, which are known to enhance IL-1B production, as a potential therapeutic target for this disorder.

IN VITRO PROPAGATION OF PLATELETS FROM EMBRYONIC STEM CELLS WITH C. PAPAYA LEAF EXTRACT

Objective: The depletion of platelets in patients under different clinical conditions like thrombocytopenia is often associated with a significant mortality factor. Alternative modes of platelet propagation from other resources, including stem cells, are evaluated under in vitro conditions. Embryonic stem (ES) cells can proliferate and differentiate into various cell types. This study evaluated the generation of functional platelets from embryonic stem cells with C. papaya leaf extract through a controlled sequential pathway to meet the clinical demand.
 Methods: In vitro culture of embryonic stem cells was carried out with the help of growth factors and a suitable medium. The differentiated megakaryocytes and platelets were analyzed by staining, flow cytometer and functional studies. The normal megakaryocytes were compared with the megakaryocytes differentiated from Embryonic Stem cells.
 Results: The platelets derived from embryonic stem cells are morphologically identical to normal platelets isolated from peripheral blood, and the number of viable cells was analyzed by flow cytometer. The distinctive two waves of platelet production represented normal primitive and definitive hematopoiesis.
 Conclusion: This study is a preliminary milestone in platelet propagation from embryonic stem cells with C. papaya leaf extract. The differentiation of ESCs into megakaryocyte-mediated platelets with C. papaya leaf extract has shown valuable information on the positive effects that embryonic stem cells can be used for large-scale platelet production.

Mixed IgG Fc immune complexes exhibit blended binding profiles and refine FcR affinity estimates

Immunoglobulin G (IgG) antibodies coordinate immune effector responses by interacting with effector cells via fragment crystallizable γ (Fcγ) receptors. The IgG Fc domain directs effector responses through subclass and glycosylation variation. Although each Fc variant has been extensively characterized in isolation, during immune responses, IgG is almost always produced in Fc mixtures. How this influences effector responses has not been examined. Here, we measure Fcγ receptor binding to mixed Fc immune complexes. Binding of these mixtures falls along a continuum between pure cases and quantitatively matches a mechanistic model, except for several low-affinity interactions mostly involving IgG2. We find that the binding model provides refined estimates of their affinities. Finally, we demonstrate that the model predicts effector cell-elicited platelet depletion in humanized mice. Contrary to previous views, IgG2 exhibits appreciable binding through avidity, though it is insufficient to induce effector responses. Overall, this work demonstrates a quantitative framework for modeling mixed IgG Fc-effector cell regulation.

Panhematopoietic RNA barcoding enables kinetic measurements of nucleate and anucleate lineages and the activation of myeloid clones following acute platelet depletion

BackgroundPlatelets and erythrocytes constitute over 95% of all hematopoietic stem cell output. However, the clonal dynamics of HSC contribution to these lineages remains largely unexplored.ResultsWe use lentiviral genetic labeling of mouse hematopoietic stem cells to quantify output from all lineages, nucleate, and anucleate, simultaneously linking these with stem and progenitor cell transcriptomic phenotypes using single-cell RNA-sequencing. We observe dynamic shifts of clonal behaviors through time in same-animal peripheral blood and demonstrate that acute platelet depletion shifts the output of multipotent hematopoietic stem cells to the exclusive production of platelets. Additionally, we observe the emergence of new myeloid-biased clones, which support short- and long-term production of blood cells.ConclusionsOur approach enables kinetic studies of multi-lineage output in the peripheral blood and transcriptional heterogeneity of individual hematopoietic stem cells. Our results give a unique insight into hematopoietic stem cell reactivation upon platelet depletion and of clonal dynamics in both steady state and under stress.

Platelet-derived chemokines promote skeletal muscle regeneration by guiding neutrophil recruitment to injured muscles

Skeletal muscle regeneration involves coordinated interactions between different cell types. Injection of platelet-rich plasma is circumstantially considered an aid to muscle repair but whether platelets promote regeneration beyond their role in hemostasis remains unexplored. Here, we find that signaling via platelet-released chemokines is an early event necessary for muscle repair in mice. Platelet depletion reduces the levels of the platelet-secreted neutrophil chemoattractants CXCL5 and CXCL7/PPBP. Consequently, early-phase neutrophil infiltration to injured muscles is impaired whereas later inflammation is exacerbated. Consistent with this model, neutrophil infiltration to injured muscles is compromised in male mice with Cxcl7-knockout platelets. Moreover, neo-angiogenesis and the re-establishment of myofiber size and muscle strength occurs optimally in control mice post-injury but not in Cxcl7ko mice and in neutrophil-depleted mice. Altogether, these findings indicate that platelet-secreted CXCL7 promotes regeneration by recruiting neutrophils to injured muscles, and that this signaling axis could be utilized therapeutically to boost muscle regeneration.

Abstract 156: Role of Platelets in Maintaining Hemostasis and Coagulation Activation in Viral-induced Acute Respiratory Distress Syndrome (ards) in Mice

Platelets are crucial players during viral infections, as bridge hemostasis, inflammation, and immune response. RNA viruses like IAV are associated with pathologic platelet activation and thrombosis. We are currently investigating how platelet depletion before or post initial IAV infection can affect disease outcome. WT mice were infected with IAV (0.02HAU, intranasally) for 7 days to induce viral ARDS. Mice were injected with platelet depletion antibody R300 or control IgG at day 0 (prior) and day 3 (after infection). Mice treated with R300/control IgG were subjected to dsRNA mimetic poly IC intranasally for 3 days to induce virus-like ARDS. Global lung function was recorded, plasma and BALF were collected 7 or 3 dpi or final poly IC treatment, respectively. BALF cellularity and blood cellular composition was analyzed. Markers of lung injury and cytokines were measured. We observed that IAV infection leads to local lung inflammation, coagulation activation and ARDS-like lung dysfunction. Mice treated with R300 showed severe thrombocytopenia in blood. We observed more impaired alveolar hemostasis and increased hemorrhages into the airspace when platelet depletion was initiated 3 dpi compared to mice where platelets were depleted prior to infection. In addition, in dsRNA-induced ARDS model, platelet depletion resulted in increased signs of lung dysfunction, increased lung injury and local inflammation compared to mice with normal platelet levels. In conclusion, depletion of platelets after IAV infection resulted in increased alveolar hemorrhage and was associated with more pronounced lung inflammation, injury, and lung dysfunction. Our study suggests that interfering with platelet before viral infection can be beneficial as it limits the role of platelets as potential multiplicator of an initial pathologic immune reaction subsequently reducing collateral damage and organ dysfunction/failure. However, at later stages of viral infection, platelet activation is beneficial to facilitate tissue hemostasis as their absence later can result in increased hemorrhagic risk and more pronounced lung dysfunction. We aim to address the mechanism by which platelet contribute later to pathologic immune processes in dsRNA-induced or viral ARDS

Proinflammatory microenvironment promotes lymphoma progression in mice with high megakaryocyte and TPO levels.

Platelets have been shown to enhance the survival of lymphoma cell lines. However, it remains unclear whether they play a role in lymphoma. Here, we investigated the potential role of platelets and/or megakaryocytes in the progression of Eμ-myc lymphoma. Eμ-myc tumor cells were transplanted into recipient wild-type (WT) control, Mpl-/-, or TpoTg mice, which exhibited normal, low, and high platelet and megakaryocyte counts, respectively. TpoTg mice that underwent transplantation exhibited enhanced lymphoma progression with increased white blood cell (WBC) counts, spleen and lymph node weights, and enhanced liver infiltration when compared with WT mice. Conversely, tumor-bearing Mpl-/- mice had reduced WBC counts, lymph node weights, and less liver infiltration than WT mice. Using an Mpl-deficient thrombocytopenic immunocompromised mouse model, our results were confirmed using the human non-Hodgkin lymphoma GRANTA cell line. Although we found that platelets and platelet-released molecules supported Eμ-myc tumor cell survival invitro, pharmacological inhibition of platelet function or anticoagulation in WT mice transplanted with Eμ-myc did not improve disease outcome. Furthermore, transient platelet depletion or sustained Bcl-xL-dependent thrombocytopenia did not alter lymphoma progression. Cytokine analysis of the bone marrow fluid microenvironment revealed increased levels of the proinflammatory molecule interleukin 1 in TpoTg mice, whereas these levels were lower in Mpl-/- mice. Moreover, RNA sequencing of blood-resident Eμ-myc lymphoma cells from TpoTg and WT mice after tumor transplantation revealed the upregulation of hallmark gene sets associated with an inflammatory response in TpoTg mice. We propose that the proinflammatory microenvironment in TpoTg mice promotes lymphoma progression.

Investigating and imaging platelets in inflammation.

Blood platelets are best known for their roles in hemostasis and thrombosis, but platelets also make important contributions to inflammation, immunity, and inflammatory resolution. Experiments involving depletion, genetic modification, and live imaging of platelets in animal models have increased our mechanistic understanding of platelet contributions to inflammation. In this minireview, we provide a critical overview of experimental techniques for manipulating and imaging platelets in inflammation models. We then highlight studies using innovative approaches to elucidate molecular mechanisms through which platelet subsets, platelet Fc gamma receptors, and pro-resolution platelet functions influence inflammatory responses. We also propose future technologies and research directions which might move us closer to harnessing of platelet functions for improved therapeutic modulation of inflammatory diseases.

336 Prognostic Significance of Plasma Insulin Level for Deep Venous Thrombosis in Patients with Severe Traumatic Brain Injury in Critical Care

INTRODUCTION: Whether insulin resistance is underlying the deep venous thrombosis (DVT) development in patients with traumatic brain injury (TBI) is elusive. METHODS: A prospective observational study of 73 severe TBI patients who had measurements of plasma insulin, glucose, glucagon-like peptide 1 (GLP-1), inflammatory factors, and hematological profile within 4 preset time periods during 2 weeks after TBI. Ultrasonic surveillance of DVT was tracked weekly. Two-way ANOVA analysis was applied to determine whether the factors could discriminate between patients with and without DVT. Partial correlations of insulin level with other variables were carried out in patients with or without DVT. Factors associated with DVT were analyzed by multivariable logistic regression. Neurological outcome 6 months after TBI was assessed for Glasgow Outcome Scale (GOS). RESULTS: Among patients with an average (SD) age of 53 ± 16 years, DVT developed in 20 patients (27%). The 14-day plasma insulin levels were higher in patients with DVT (P = 0.01). Platelet profile discriminated significantly between patients with and without DVT. None of other factors differed between the two groups. Patients with insulin therapy had significant higher insulin (P = 0.006), glucose (P < 0.001) and GLP-1 (P = 0.01) levels, and were more likely to develop DVT (60% vs. 15%, P < 0.001) with concomitant platelet depletion. Insulin levels correlated with glucose, GLP-1 levels, and platelet exclusively in patients without DVT. Conversely, in patients with DVT, insulin correlated negatively with GLP-1 level (r = -0.297, P = 0.016). Age (P = 0.01) and elevated insulin level at day 4-7 (P = 0.04) were independently associated with DVT. Patients with insulin therapy also showed worse GOS (P = 0.001). CONCLUSIONS: Elevated insulin level in the first 14 days after TBI may present insulin resistance in TBI, which was associated with consistent platelet activation, thus increasing risk of DVT.

Morphofunctional state of platelets in their concentrates depending on storage time

Background.Evaluation of the functional state of platelets in the composition of concentrates is necessary to improve the methods of their production, optimize storage conditions and terms, increase therapeutic efficacy, and reduce the risk of transfusion complications.
 Aim.Comprehensive study of the morphofunctional state of platelets during the storage of their concentrates.
 Material and methods.202samples of human platelet apheresis concentrates were studied for storage periods of up to 17days at a temperature of 2224C. The functional state of platelets was assessed using flow cytometry for the expression of P-selectin, active IIb3 integrin, and phosphatidylserines before and after biochemical stimulation. In addition, the mitochondrial potential of platelets, the concentration of intracellular adenosine triphosphate, contractile properties, induced aggregation, and morphological characteristics were studied according to scanning electron microscopy. Statistical analysis was performed by analysis of variance (ANOVA or KruskalWallis).
 Results.In non-activated platelets during storage, the spontaneous expression of P-selectin increased by an average of 7times, and phosphatidylserines by 3times. The induced expression of P-selectin, integrin IIb3 and phosphatidylserines was the highest on the day of receiving the concentrate and gradually decreased during storage to 1/2of the initial level. Platelet aggregation activity in response to collagen stimulation progressively decreased by an average of 100times, in response to the TRAP peptide by 1.5times. In contrast to the expression of activation markers, the ability of platelets to compress plasma clots in most samples changed slightly, within a few percent; in single samples, the contractile function dropped to zero by 47days of storage, which was combined with platelet hyperactivation and depletion. The mitochondrial potential of platelets and the content of adenosine triphosphate were relatively constant. Morphologically, discoid platelets predominated, however, starting from the 1st day of storage, spindle-shaped platelets, and from the 3rd day spherical forms and microaggregates of platelets accumulated.
 Conclusion.Platelets in the composition of concentrates initially have a high functional potential, which gradually decreases due to progressive spontaneous activation with a simultaneous decrease in reactivity and structural changes.

Active regression model for clinical grading of COVID-19.

In the therapeutic process of COVID-19, the majority of indicators that physicians have for assisting treatment have come from clinical tests represented by proteins, metabolites, and immune levels in patients' blood. Therefore, this study constructs an individualized treatment model based on deep learning methods, aiming to realize timely intervention based on clinical test indicator data of COVID-19 patients and provide an important theoretical basis for optimizing medical resource allocation. This study collected clinical data from a total of 1,799 individuals, including 560 controls for non-respiratory infectious diseases (Negative), 681 controls for other respiratory virus infections (Other), and 558 coronavirus infections (Positive) for COVID-19. We first used the Student T-test to screen for statistically significant differences (Pvalue<0.05); we then used the Adaptive-Lasso method stepwise regression to screen the characteristic variables and filter the features with low importance; we then used analysis of covariance to calculate the correlation between variables and filter the highly correlated features; and finally, we analyzed the feature contribution and screened the best combination of features. Feature engineering reduced the feature set to 13 feature combinations. The correlation coefficient between the projected results of the artificial intelligence-based individualized diagnostic model and the fitted curve of the actual values in the test group was 0.9449 which could be applied to the clinical prognosis of COVID-19. In addition, the depletion of platelets in patients with COVID-19 is an important factor affecting their severe deterioration. With the progression of COVID-19, there is a slight decrease in the total number of platelets in the patient's body, particularly as the volume of larger platelets sharply decreases. The importance of plateletCV (count*mean platelet volume) in evaluating the severity of COVID-19 patients is higher than the count of platelets and mean platelet volume. In general, we found that for patients with COVID-19, the increase in mean platelet volume was a predictor for SARS-Cov-2. The rapid decrease of platelet volume and the decrease of total platelet volume are dangerous signals for the aggravation of SARS-Cov-2 infection. The analysis and modeling results of this study provide a new perspective for individualized accurate diagnosis and treatment of clinical COVID-19 patients.

Single vesicle analysis reveals the release of tetraspanin positive extracellular vesicles into circulation with high intensity intermittent exercise.

Small extracellular vesicles (sEVs) are released from all cell types and participate in the intercellular exchange of proteins, lipids, metabolites and nucleic acids. Proteomic, flow cytometry and nanoparticle tracking analyses suggest sEVs are released into circulation with exercise. However, interpretation of these data may be influenced by sources of bias introduced by different analytical approaches. Seven healthy participants carried out a high intensity intermittent training (HIIT) cycle protocol consisting of 4×30s at a work-rate corresponding to 200% of individual max power (watts) interspersed by 4.5min of active recovery. EDTA-treated blood was collected before and immediately after the final effort. Platelet-poor (PPP) and platelet-free (PFP) plasma was derived by one or two centrifugal spins at 2500g, respectively (15min, room temperature). Platelets were counted on an automated haemocytometer. Plasma samples were assessed with the Exoview R100 platform, which immobilises sEVs expressing common tetraspanin markers CD9, CD63, CD81 and CD41a on microfluidic chips and with the aid of fluorescence imaging, counts their abundance at a single sEV resolution, importantly, without a pre-isolation step. There was a lower number of platelets in the PFP than PPP, which was associated with a lower number of CD9, CD63 and CD41a positive sEVs. HIIT induced an increase in fluorescence counts in CD9, CD63 and CD81 positive sEVs in both PPP and PFP. These data support the concept that sEVs are released into circulation with exercise. Furthermore, platelet-free plasma is the preferred, representative analyte to study sEV dynamics and phenotype during exercise. KEY POINTS: Small extracellular vesicles (sEV) are nano-sized particles containing protein, metabolites, lipid and RNA that can be transferred from cell to cell. Previous findings implicate that sEVs are released into circulation with exhaustive, aerobic exercise, but since there is no gold standard method to isolate sEVs, these findings may be subject to bias introduced by different approaches. Here, we use a novel method to immobilise and image sEVs, at single-vesicle resolution, to show sEVs are released into circulation with high intensity intermittent exercise. Since platelet depletion of plasma results in a reduction in sEVs, platelet-free plasma is the preferred analyte to examine sEV dynamics and phenotype in the context of exercise.

EFFICACY OF TOPICAL TRANEXAMIC ACID TO REDUCE BLOOD LOSS AFTER CORONARY ARTERY BYPASS GRAFTING (CABG)

Background: Coronary Artery Bypass Grafting (CABG) with the use of cardiopulmonary bypass technique has a coagulopathy issue. Many factors act on the coagulation process such as heparin level, thrombocytopenia, increased fibrinolysis and acquired platelet dysfunction. The human body responds to stress with dramatic resilience. For example, bleeding diathesis is common with on pump, after injury clotting mechanisms are immediately activated to reduce blood loss, the blood volume is restored by shifting the fluids from extracellular compartment and redistribution of blood flow occurs. Fibrinolytic cascade is activated with CPB usage. Before it was thought that excessive bleeding after CPB was due to platelet dysfunction and depletion. Recently, it was suggested by many lines of information that fibrinolytic cascade activation leads to bleeding during postoperative period. Multiple agents like Tranexamic acid and Aminocaproic acid etc are anti-fibrinolytic agents that can be administered to minimize the bleeding postoperatively.&#x0D; Objectives: To compare the efficacy of topical application of Tranexamic acid to reduce blood loss after Coronary Artery Bypass Grafting (CABG).&#x0D; Methods: It is randomized controlled trial. This research program was carried out at the Unit of Cardiothoracic &amp; Vascular Surgery, Institute of Shaikh Zayed Hospital, Lahore from December 6th, 2017 to December 5th, 2018. First patient evaluated on 11th December 2017. Seventy patients were enrolled, who were eligible for this study, achieving the inclusion criteria. Two groups of the selected population were made by randomization. Group A comprised 35 patients to whom 1 gm of diluted Tranexamic Acid using 100 ml normal saline solution is poured to the pericardial cavity. Group B involved 35 patients as well, whom were given standard of care treatment which in this case is 100 ml normal saline. Since 100ml normal saline did not contain any active ingredient for treatment, therefore it was considered as placebo. Intervention (Placebo or TXA) was considered efficacious if it resulted in blood loss of less than 500ml in 72 hours from immediately post-op to 72 hours post-op. The efficacy of drugs within groups is compared by the use of Chi-square test. Independent sample t-test was applied for data analysis of blood loss with p-value ≤0.05 being taken as significant.&#x0D; Results: In our study, total70patients were enrolled. Group-A (Tranexamic Acid) and Group-B (Placebo) were made. In group-A, there were 30 (85.7%) male and 5(14.3%) female patients. In group-B, 28(80.0%) were male and 7(20.0%) were female. In our study population, mean age of patients were 52.4±9.9 years and 53.6±10.1 years in group A&amp;B respectively. In group-A, there were 22(62.9%) patients in which the intervention showed efficacy (blood loss &lt;500ml), while only 09(25.7%) patients in group-B showed blood loss of &lt;500ml, p-value of 0.002 being statistically significant.&#x0D; Conclusion: Topical application of Tranexamic Acid reduces blood loss after Coronary Artery Bypass Grafting (CABG).

Immune-mediated platelet depletion augments Alzheimer's disease neuropathological hallmarks in APP-PS1 mice.

In Alzheimer's disease (AD), platelets become dysfunctional and might contribute to amyloid beta deposition. Here, we depleted platelets in one-year-old APP Swedish PS1 dE9 (APP-PS1) transgenic mice for five days, using intraperitoneal injections of an anti-CD42b antibody, and assessed changes in cerebral amyloidosis, plaque-associated neuritic dystrophy and gliosis. In APP-PS1 female mice, platelet depletion shifted amyloid plaque size distribution towards bigger plaques and increased neuritic dystrophy in the hippocampus. In platelet-depleted females, plaque-associated Iba1+ microglia had lower amounts of fibrillar amyloid beta cargo and GFAP+ astrocytic processes showed a higher overlap with thioflavin S+ amyloid plaques. In contrast to the popular hypothesis that platelets foster plaque pathology, our data suggest that platelets might limit plaque growth and attenuate plaque-related neuritic dystrophy at advanced stages of amyloid plaque pathology in APP-PS1 female mice. Whether the changes in amyloid plaque pathology are due to a direct effect on amyloid beta deposition or are a consequence of altered glial function needs to be further elucidated.

Aggregation platelets function in persons with vibration disease

The article considers the changes in the rheological properties of blood and the aggregation function of platelets in interns exposed to local vibration and combined effects of local and general vibration. In recent years, the medical and social significance of vibration disease (VD) as a disease is associated with the loss of working capacity and the young age of people who have lost their professional ability to work. In confirmation of this, we can observe a high incidence of VD among workers of aircraft factories, in the mining industry, among operators of heavy vehicles and construction equipment. The study aims to consider the aggregation activity of platelets in persons with vibration disease during exposure to local vibration and combined exposure to local and general vibration, to draw attention to the need to study the aggregation function of platelets in persons with occupational diseases. Group one consisted of 47 patients with vibration disease from exposure to local vibration, group two included 52 patients with vibration disease from combined exposure to local and general vibration. In these groups, the researchers observed the induced platelet aggregation activity on an optical aggregometer using an adenosine diphosphate (ADP) inductor at concentrations of 5.0, 2.5, 0.1 μM/L. The authors have carried out statistical processing of the results. We have taken the differences as statistically significant at p≤0.05. Persons with vibration disease had reduced indicators of platelet aggregation activity in comparison with reference values, the number of platelets and thrombocrit in the blood within normal limits. At the same time, the correlation analysis showed the presence of positive correlations between the aggregatogram indicators under the action of an inductor of high (5.0 mmol/L) and low concentrations (2.5 mmol/L), 0.1 mmol/L). Evaluation of platelet aggregation activity in individuals with vibration disease with exposure to local vibration and with combined exposure to local and general vibration established low response rates in response to the introduction of an inducer (lower than reference), in more than 50% of cases, indicating "depletion of platelets". The study of the induced platelet activity did not reveal the peculiarities of its manifestation both in persons exposed to local vibration and in workers exposed to the combined effects of local and general vibration. Limitations. Limitations of the study may be differences in the methodology and reference intervals of the study of aggregation activity in different laboratories and a small sample of patients included in this study. Ethics. All patients had previously signed an informational consent to participate in the study. The research plan, the content of the informed consent to participate in the research, as well as the materials of the article were approved by the local Ethics committee of the East Siberian Institute of Medical and Environmental Research.

Platelets mediate acute hepatic microcirculatory injury in a protease-activated-receptor-4-dependent manner after extended liver resection

BackgroundSmall-for-size syndrome (SFSS) is a major complication following extended liver resection. The role of platelets in the early development of SFSS remains to be cleared. We aimed to investigate the impact of platelets and PAR-4, a receptor for platelet activation, on the acute phase microcirculatory injury after liver resection by in vivo microscopy analyzing the changes in leukocyte recruitment, platelet-neutrophil interaction, and microthrombosis-induced perfusion failure. MethodsSixty-percent partial hepatectomy (PH) models using C57BL/6 mice receiving platelet depletion with anti-GPIbα, PAR-4 blockade with tcY-NH2, or vehicle treatment with saline were used. Sham-operated animals served as controls. Epifluorescence microscopic analysis was performed 2 h after PH to quantify the leukocyte recruitment and microcirculatory changes. Sinusoidal neutrophil recruitment, platelet-neutrophil interaction, and microthrombosis were evaluated using two-photon microscopy. ICAM-1 expression and liver liver injury were assessed in tissue/blood samples. ResultsThe increments of leukocyte recruitment in post-sinusoidal venules and sinusoidal perfusion failure, the upregulation of ICAM-1 expression, and the deterioration of liver function 2 h after 60% PH were alleviated in the absence of platelets or by PAR-4 blockade. Intensified platelet-neutrophil interaction and microthrombosis in sinusoids were observed 2 h after 60% PH, which significantly attenuated after PAR-4 blockade. ConclusionPlatelets play a critical role in acute liver injury after extended liver resection within 2 h. The deactivation of platelets via PAR-4 blockade ameliorated liver function deterioration by suppressing early leukocyte recruitment, platelet-neutrophil interaction, and microthrombosis in hepatic sinusoids.

Etiology, clinic, and current treatment options for immune thrombocytopenia: a review of the literature

Jurgita Zakaravičiūtė1, Vaida Vaitiekūnaitė1, Agnė Pinauskaitė1 1Lithuanian University of Health Sciences, Faculty of Medicine, Kaunas Abstract Background. Immune thrombocytopenia (ITP) is an autoimmune disease defined by low platelet count and presents with an increased risk of bleeding. The diagnosis is based on the rejection of other potential diseases and the determination of platelet depletion. Observation […]