Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 81.888
Filtrar
2.
JCI Insight ; 9(5)2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38456510

RESUMO

Thrombosis and inflammation are intimately linked and synergistically contribute to the pathogenesis of numerous thromboinflammatory diseases, including sickle cell disease (SCD). While platelets are central to thrombogenesis and inflammation, the molecular mechanisms of crosstalk between the 2 remain elusive. High-mobility group box 1 (HMGB1) regulates inflammation and stimulates platelet activation through Toll-like receptor 4. However, it remains unclear whether HMGB1 modulates other thrombotic agonists to regulate platelet activation. Herein, using human platelets, we demonstrate that HMGB1 significantly enhanced ADP-mediated platelet activation. Furthermore, inhibition of the purinergic receptor P2Y12 attenuated HMGB1-dependent platelet activation. Mechanistically, we show that HMGB1 stimulated ADP secretion, while concomitantly increasing P2Y12 levels at the platelet membrane. We show that in SCD patients, increased plasma HMGB1 levels were associated with heightened platelet activation and surface P2Y12 expression. Treatment of healthy platelets with plasma from SCD patients enhanced platelet activation and surface P2Y12, and increased sensitivity to ADP-mediated activation, and these effects were linked to plasma HMGB1. We conclude that HMGB1-mediated platelet activation involves ADP-dependent P2Y12 signaling, and HMGB1 primes platelets for ADP signaling. This complementary agonism between ADP and HMGB1 furthers the understanding of thromboinflammatory signaling in conditions such as SCD, and provides insight for therapeutic P2Y12 inhibition.


Assuntos
Anemia Falciforme , Proteína HMGB1 , Trombose , Humanos , Plaquetas/metabolismo , Proteína HMGB1/metabolismo , Inflamação/metabolismo , Ativação Plaquetária , Trombose/metabolismo
3.
PLoS One ; 19(3): e0299202, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38466712

RESUMO

BACKGROUND: Thrombus formation in vitro under flow conditions is one of the most widely used methods to study haemostasis and to evaluate the activity of potential antithrombotic compounds. Assessment of the results of these experiments is often based on a quantification of microscopic images of thrombi. In a majority of reported analysis all thrombi visualised in an image are quantified as one homogenous class. In some protocols, qualitative assessment of thrombi morphology based on a visual comparison of evaluated images with representative images of predefined classes of thrombi are performed by experienced analysts. In presented paper we show how the quantitative analysis can be improved by classification of thrombi on the basis of defined morphological features prior to quantification and we suggest that machine learning-based approach can improve this way of analysis. METHODS: We tested the applicability of machine learning-based segmentation and classification of thrombi images to improve the outcome of quantification of the results of flow chamber assays. For this, we used the public domain machine learning software Ilastik for bioimage analysis developed at the European Molecular Biology Laboratory. A model was trained to distinguish two classes of thrombi based on certain morphological features which apparently correspond to the stage of thrombus development. Thrombi formed in the presence of a model antiplatelet compound-abciximab or in control conditions were quantified with the use of this model and the results were compared to quantification where all thrombi were quantified as a homogenous class. RESULTS: Machine learning-based analysis was capable of effective distinguishing of two classes of morphologically distinct platelet aggregates. The use of the model which segmented and quantified only the objects recognized as compacted structures provided results which better mirrored the actual effect of an antiplatelet treatment than quantification based on all structures. CONCLUSIONS: Classification of thrombi enabled by machine learning increases the relevance of quantitative information and allows better evaluation of the results of in vitro thrombosis assays.


Assuntos
Plaquetas , Trombose , Humanos , Trombose/diagnóstico por imagem , Software
5.
Clin Lab ; 70(3)2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38469783

RESUMO

BACKGROUND: The rapid development of automatic blood cell analyzers has greatly optimized complete blood count results. However, erroneous results relevant to automatic blood cell analyzers still exist. Pseudothrombocytopenia can be observed in both cases of anticoagulant-induced platelet aggregation, and the presence of large and giant platelets. METHODS: A rare case of a MYH9-related disorder, in which marked underestimation of platelet count was led by large and giant platelets using the impedance count by an automated hematology analyzer. Moreover, lancet-shaped and Dohle body-like cytoplasmic inclusions were detected in almost all white blood cells of the patient. RESULTS: The platelet count was done by an optical platelet counter or a fluorescence platelet counter, and peripheral blood smear was evaluated. In addition, the diagnosis of MYH9-related disorder was established by the molecular findings. CONCLUSIONS: Identification of the peripheral blood smear and familial history will eliminate the need for further laboratory testing and bone marrow examination.


Assuntos
Perda Auditiva Neurossensorial , Trombocitopenia , Trombocitopenia/congênito , Humanos , Contagem de Plaquetas/métodos , Trombocitopenia/diagnóstico , Trombocitopenia/genética , Plaquetas , Perda Auditiva Neurossensorial/diagnóstico , Cadeias Pesadas de Miosina/genética
6.
Int J Mol Sci ; 25(5)2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38473772

RESUMO

Thrombosis is a multifaceted process involving various molecular components, including the coagulation cascade, platelet activation, platelet-endothelial interaction, anticoagulant signaling pathways, inflammatory mediators, genetic factors and the involvement of various cells such as endothelial cells, platelets and leukocytes. A comprehensive understanding of the molecular signaling pathways and cell interactions that play a role in thrombosis is essential for the development of precise therapeutic strategies for the treatment and prevention of thrombotic diseases. Ongoing research in this field is constantly uncovering new molecular players and pathways that offer opportunities for more precise interventions in the clinical setting. These molecular insights into thrombosis form the basis for the development of targeted therapeutic approaches for the treatment and prevention of thrombotic disease. The aim of this review is to provide an overview of the pathogenesis of thrombosis and to explore new therapeutic options.


Assuntos
Células Endoteliais , Trombose , Humanos , Coagulação Sanguínea , Anticoagulantes , Plaquetas
7.
Int J Mol Sci ; 25(5)2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38474244

RESUMO

Adrenaline has recently been found to trigger phosphatidylserine (PS) exposure on blood platelets, resulting in amplification of the coagulation process, but the mechanism is only fragmentarily established. Using a panel of platelet receptors' antagonists and modulators of signaling pathways, we evaluated the importance of these in adrenaline-evoked PS exposure by flow cytometry. Calcium and sodium ion influx into platelet cytosol, after adrenaline treatment, was examined by fluorimetric measurements. We found a strong reduction in PS exposure after blocking of sodium and calcium ion influx via Na+/H+ exchanger (NHE) and Na+/Ca2+ exchanger (NCX), respectively. ADP receptor antagonists produced a moderate inhibitory effect. Substantial limitation of PS exposure was observed in the presence of GPIIb/IIIa antagonist, phosphoinositide-3 kinase (PI3-K) inhibitors, or prostaglandin E1, a cyclic adenosine monophosphate (cAMP)-elevating agent. We demonstrated that adrenaline may develop a procoagulant response in human platelets with the substantial role of ion exchangers (NHE and NCX), secreted ADP, GPIIb/IIIa-dependent outside-in signaling, and PI3-K. Inhibition of the above mechanisms and increasing cytosolic cAMP seem to be the most efficient procedures to control adrenaline-evoked PS exposure in human platelets.


Assuntos
Plaquetas , Ativação Plaquetária , Humanos , Plaquetas/metabolismo , Cálcio/metabolismo , Epinefrina/metabolismo , Inibidores da Agregação Plaquetária/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Sódio/metabolismo , Trombina/metabolismo
8.
Int J Mol Sci ; 25(5)2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38474270

RESUMO

Neutrophils present the host's first line of defense against bacterial infections. These immune effector cells are mobilized rapidly to destroy invading pathogens by (a) reactive oxygen species (ROS)-mediated oxidative bursts and (b) via phagocytosis. In addition, their antimicrobial service is capped via a distinct cell death mechanism, by the release of their own decondensed nuclear DNA, supplemented with a variety of embedded proteins and enzymes. The extracellular DNA meshwork ensnares the pathogenic bacteria and neutralizes them. Such neutrophil extracellular DNA traps (NETs) have the potential to trigger a hemostatic response to pathogenic infections. The web-like chromatin serves as a prothrombotic scaffold for platelet adhesion and activation. What is less obvious is that platelets can also be involved during the initial release of NETs, forming heterotypic interactions with neutrophils and facilitating their responses to pathogens. Together, the platelet and neutrophil responses can effectively localize an infection until it is cleared. However, not all microbial infections are easily cleared. Certain pathogenic organisms may trigger dysregulated platelet-neutrophil interactions, with a potential to subsequently propagate thromboinflammatory processes. These may also include the release of some NETs. Therefore, in order to make rational intervention easier, further elucidation of platelet, neutrophil, and pathogen interactions is still needed.


Assuntos
Armadilhas Extracelulares , Humanos , Armadilhas Extracelulares/metabolismo , Neutrófilos/metabolismo , Plaquetas/metabolismo , Inflamação/metabolismo , DNA/metabolismo
9.
Biomark Med ; 18(3): 115-122, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38436264

RESUMO

Aims: This study investigated the nonlinear associations between neutrophil-to-lymphocyte (NLR)/platelet-to-lymphocyte (PLR) and recovery rates in sudden sensorineural hearing loss (SSNHL). Methods: Total of 244 SSNHL patients were included. The primary outcome was recovery rate. Results: A nonlinear association was detected between NLR and recovery rate using the LOWESS method, with a knot of 3. Patients with NLR ≥3 had a higher recovery rate than NLR <3. Using the linear-spline function, NLR was significantly associated with high recovery rate when NLR was <3. However, when NLR was ≥3, this association became nonsignificant. The trend test showed a similar result. PLR was not associated with recovery rate. Conclusion: The association between NLR and recovery rate is nonlinear, with a knot of around three. PLR is not associated with recovery rate.


Assuntos
Perda Auditiva Neurossensorial , Perda Auditiva Súbita , Humanos , Neutrófilos , Prognóstico , Contagem de Linfócitos , Estudos Retrospectivos , Linfócitos , Plaquetas
11.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 36(2): 189-194, 2024 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-38442937

RESUMO

OBJECTIVE: To evaluate the effects of recombinant human thrombopoietin (rhTPO) on platelet count (PLT) and liver function in acute liver failure (ALF) rats by observing the dynamic changes of PLT, thrombopoietin (TPO) and liver function during ALF. METHODS: Twenty-four male Sprague-Dawley (SD) rats were divided into model group, TPO group and interleukin-11 (IL-11) group using a random number table method, with eight rats in each group. All rats were intraperitoneally injected with D-galactosamine (D-GalN, 1 500 mg/kg, dosed within 72 hours) to induce the ALF model. After modeling, rats in TPO group was received subcutaneous injection of 15 µg/kg of rhTPO for 5 days, and rats in IL-11 group was received subcutaneous injection of 0.45 mg/kg of IL-11 for 5 days. Venous blood samples were collected before and at 1, 3, 5, 7 and 12 days after molding for whole blood cell detection. The level of TPO in serum was detected by enzyme-linked immunosorbent assay (ELISA). Liver function indexes including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil) and albumin (ALB) were measured before and at 1, 3 and 5 days after modeling. The rats were sacrificed 12 days after the modeling, and the pathological changes of liver tissue were observed by hematoxylin-eosin (HE) staining. RESULTS: Two rats in each group died within 24-48 hours after modeling. HE staining showed that all three groups of ALF rats showed large flake necrosis of hepatocytes, disorder of hepatic lobular structure, mesh scaffold collapse, hepatic sinus congestion and hemorrhage, and flake infiltration of inflammatory cells on day 12 after modeling. The levels of serum ALT, AST and TBil of rats in each group were significantly increased 1 day after modeling and then decreased. The level of ALB decreased significantly on the first day after modeling and then increased, but there was no significant difference in the trend of liver function indexes among the three groups. PLT in the three groups decreased rapidly on day 1 after modeling, and then recovered gradually with the improvement of liver function. The PLT of the TPO group rose to the peak value 7 days after molding and was significantly higher than that of the model group [PLT (×109/L): 1 673.3±347.5 vs. 855.3±447.0, P < 0.05], while there was no significant difference between the IL-11 group and the model group [PLT (×109/L): 1 350.3±386.6 vs. 855.3±447.0, P > 0.05]. The level of serum TPO of the three groups increased significantly on day 1 after modeling, then decreased, and dropped to the lowest value on day 5, but there was no significant difference in the trend of serum TPO level among the three groups. CONCLUSIONS: PLT in ALF rats decreased rapidly in the early stage and recovered gradually with the improvement of liver function, and the serum TPO level increased first and then decreased. Injection of rhTPO can significantly increase PLT in ALF rats, but has no significant effect on liver function and survival rate.


Assuntos
Falência Hepática Aguda , Trombopoetina , Humanos , Masculino , Ratos , Animais , Trombopoetina/farmacologia , Interleucina-11/farmacologia , Ratos Sprague-Dawley , Plaquetas , Falência Hepática Aguda/tratamento farmacológico , Amarelo de Eosina-(YS) , Albuminas
12.
Methods Mol Biol ; 2774: 279-301, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38441772

RESUMO

The in vitro differentiation of pluripotent stem cells into desired lineages enables mechanistic studies of cell transitions into more mature states that can provide insights into the design principles governing cell fate control. We are interested in reprogramming pluripotent stem cells with synthetic gene circuits to drive mouse embryonic stem cells (mESCs) down the hematopoietic lineage for the production of megakaryocytes, the progenitor cells for platelets. Here, we describe the methodology for growing and differentiating mESCs, in addition to inserting a transgene to observe its expression throughout differentiation. This entails four key methods: (1) growing and preparing mouse embryonic fibroblasts for supporting mESC growth and expansion, (2) growing and preparing OP9 feeder cells to support the differentiation of mESCs, (3) the differentiation of mESCs into megakaryocytes, and (4) utilizing an integrase-mediated docking site to insert transgenes for their stable integration and expression throughout differentiation. Altogether, this approach demonstrates a streamline differentiation protocol that emphasizes the reprogramming potential of mESCs that can be used for future mechanistic and therapeutic studies of controlling cell fate outcomes.


Assuntos
Megacariócitos , Células-Tronco Embrionárias Murinas , Animais , Camundongos , Fibroblastos , Plaquetas , Diferenciação Celular/genética
13.
Sci Rep ; 14(1): 6118, 2024 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-38480828

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease characterized by subclinical inflammation and is related to obesity and metabolic syndrome (MS), but it is also frequently observed in nonobese populations. We aimed to evaluate the relationship between the white blood cell count-to-mean platelet volume ratio (WBC/MPV), platelet-to-lymphocyte count ratio (PLR) and lymphocyte-monocyte ratio (LMR) in association with NAFLD, considering the presence of obesity and MS. Additionally, we aimed to investigate whether these parameters exhibited similar correlations in metabolic dysfunction-associated steatotic liver disease (MASLD) as observed in NAFLD. This cross-sectional study included subjects who underwent a comprehensive health evaluation, including blood tests and abdominal ultrasonography. Subgroup analyses were conducted based on obesity and MS. Out of a total 5929 subjects (3271 males, mean age 49.7 ± 10.6 years), 2253 (38.0%) had NAFLD. WBC/MPV was significantly higher, and PLR was significantly lower in subjects with NAFLD. In the analysis restricted to the nonobese (BMI < 25 kg/m2) population without MS, both WBC/MPV and PLR were independently associated with NAFLD: WBC/MPV (adjusted OR 3.366; 95% CI 2.238-5.066) and PLR (adjusted OR 0.997; 95% CI 0.996-0.999). When assessing the risk of NAFLD based on the WBC/MPV and PLR quartiles, the adjusted OR and 95% CI for the lowest quartile compared to the highest were 2.055 (95% CI 1.626-2.602) for WBC/MPV and 0.660 (95% CI 0.523-0.832) for PLR in the nonobese, metabolically healthy group. The levels of WBC/MPV and PLR were independently associated with NAFLD. Furthermore, in MASLD, an association with WBC/MPV, PLR and LMR was identified, similar to the results observed in NAFLD, even after adjusting for confounding variables. In conclusion, the present study demonstrated a significant association between NAFLD and platelet-related parameters, especially in nonobese, metabolically healthy subjects.


Assuntos
Síndrome Metabólica , Hepatopatia Gordurosa não Alcoólica , Masculino , Humanos , Adulto , Pessoa de Meia-Idade , Estudos Transversais , Plaquetas , Volume Plaquetário Médio , Obesidade
14.
Sci Rep ; 14(1): 6231, 2024 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-38485973

RESUMO

The human population is ageing worldwide. The World Health Organization estimated that the world's population of people aged 60 years and older will increase to at least 30%, coinciding with a growing frequency of cognitive and cardiovascular disease. Recently, in preclinical studies platelet Factor 4 (PF4) was presented as a pro-cognitive factor. This molecule is released by platelets in the circulation and could be present in blood products destined for transfusion. We wondered if PF4 levels are correlated to the age of the blood donor or to the storage time of platelet concentrates (PCs) intended for transfusion? We observed higher levels of PF4 in PCs from elderly donors compared to younger donors, while PC storage time did not determine PF4 levels expression.


Assuntos
Fator Plaquetário 4 , Plaquetoferese , Idoso , Humanos , Pessoa de Meia-Idade , Fator Plaquetário 4/metabolismo , Plaquetas/metabolismo , Transfusão de Plaquetas , Doadores de Sangue , Preservação de Sangue
15.
Sci Rep ; 14(1): 6229, 2024 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-38486006

RESUMO

Distinct platelet activation patterns are elicited by the tyrosine kinase-linked collagen receptor glycoprotein VI (GPVI) and the G-protein coupled protease-activated receptors (PAR1/4) for thrombin. This is reflected in the different platelet Ca2+ responses induced by the GPVI agonist collagen-related peptide (CRP) and the PAR1/4 agonist thrombin. Using a 96 well-plate assay with human Calcium-6-loaded platelets and a panel of 22 pharmacological inhibitors, we assessed the cytosolic Ca2+ signaling domains of these receptors and developed an automated Ca2+ curve algorithm. The algorithm was used to evaluate an ultra-high throughput (UHT) based screening of 16,635 chemically diverse small molecules with orally active physicochemical properties for effects on platelets stimulated with CRP or thrombin. Stringent agonist-specific selection criteria resulted in the identification of 151 drug-like molecules, of which three hit compounds were further characterized. The dibenzyl formamide derivative ANO61 selectively modulated thrombin-induced Ca2+ responses, whereas the aromatic sulfonyl imidazole AF299 and the phenothiazine ethopropazine affected CRP-induced responses. Platelet functional assays confirmed selectivity of these hits. Ethopropazine retained its inhibitory potential in the presence of plasma, and suppressed collagen-dependent thrombus buildup at arterial shear rate. In conclusion, targeting of platelet Ca2+ signaling dynamics in a screening campaign has the potential of identifying novel platelet-inhibiting molecules.


Assuntos
Cálcio , Fenotiazinas , Inibidores da Agregação Plaquetária , Humanos , Inibidores da Agregação Plaquetária/farmacologia , Cálcio/metabolismo , Trombina/metabolismo , Sinalização do Cálcio , Glicoproteínas da Membrana de Plaquetas/metabolismo , Receptor PAR-1/metabolismo , Plaquetas/metabolismo , Ativação Plaquetária , Cálcio da Dieta/farmacologia , Agregação Plaquetária
16.
Medicine (Baltimore) ; 103(12): e37576, 2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38518025

RESUMO

Human Immunodeficiency Virus (HIV) infection is a global health challenge that requires continuous advancements in diagnostic and prognostic tools. Traditional markers, such as CD4 cell counts and viral load, have played a crucial role in monitoring disease progression and guiding therapeutic interventions. However, emerging research suggests that platelet index ratios may serve as valuable biomarkers in assessing immune health and managing HIV-associated complications. This paper explores the significance of platelet index ratios, including platelet-to-lymphocyte ratio and mean platelet volume-to-lymphocyte ratio, as potential indicators of immune system status in individuals living with HIV. The interplay between platelets, lymphocytes, and their ratios reflects the dynamic nature of the immune response and inflammatory processes during HIV infection. Understanding the role of platelet index ratios in HIV could lead to the development of accessible and cost-effective biomarkers for monitoring immune health. Implementation of these ratios in routine clinical practice may enhance the precision of disease prognosis and guide personalized treatment strategies. Additionally, the exploration of platelet index ratios may pave the way for innovative therapeutic interventions aimed at modulating immune responses in HIV-infected individuals. In conclusion, platelet index ratios represent promising emerging biomarkers for evaluating immune health and managing HIV-related complications. Further research and clinical validation are warranted to establish the utility of these ratios in routine HIV care, potentially revolutionizing the approach to monitoring and improving the health outcomes of individuals living with HIV.


Assuntos
Infecções por HIV , Humanos , Infecções por HIV/complicações , Biomarcadores , Plaquetas , Contagem de Linfócito CD4 , Gerenciamento Clínico , Carga Viral
18.
Nat Commun ; 15(1): 2588, 2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38519457

RESUMO

We recently achieved the first-in-human transfusion of induced pluripotent stem cell-derived platelets (iPSC-PLTs) as an alternative to standard transfusions, which are dependent on donors and therefore variable in supply. However, heterogeneity characterized by thrombopoiesis-biased or immune-biased megakaryocytes (MKs) continues to pose a bottleneck against the standardization of iPSC-PLT manufacturing. To address this problem, here we employ microRNA (miRNA) switch biotechnology to distinguish subpopulations of imMKCLs, the MK cell lines producing iPSC-PLTs. Upon miRNA switch-based screening, we find imMKCLs with lower let-7 activity exhibit an immune-skewed transcriptional signature. Notably, the low activity of let-7a-5p results in the upregulation of RAS like proto-oncogene B (RALB) expression, which is crucial for the lineage determination of immune-biased imMKCL subpopulations and leads to the activation of interferon-dependent signaling. The dysregulation of immune properties/subpopulations, along with the secretion of inflammatory cytokines, contributes to a decline in the quality of the whole imMKCL population.


Assuntos
Células-Tronco Pluripotentes Induzidas , MicroRNAs , Humanos , Megacariócitos , Células-Tronco Pluripotentes Induzidas/metabolismo , Plaquetas/metabolismo , Trombopoese/genética , MicroRNAs/genética , MicroRNAs/metabolismo
19.
Biorheology ; 59(3-4): 63-80, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38461497

RESUMO

Leukocytes and platelets must adhere to the wall of blood vessels to carry out their protective functions in inflammation and haemostasis. Recruitment is critically dependent on rheological variables (wall shear rate and stress, red cell aggregation and haematocrit) which affect delivery to the vessel wall as well as velocities and forces experienced there. Leukocyte recruitment is efficient only up to wall shear rates of about 300 s-1 and usually restricted to low-shear post-capillary venules in inflammation. Being smaller, platelets experience lower velocities and shear forces adjacent to the wall and can adhere at much higher shear rates for haemostasis in arteries. In addition, we found quite different effects of variations in haematocrit or red cell aggregation on attachment of neutrophils or platelets, which also assist their separate recruitment in venules or arteries. However, it has become increasingly evident that inflammatory and thrombotic responses may occur together, with platelets promoting the adhesion and activation of neutrophils and monocytes. Indeed, it is 30 years since we demonstrated that platelets could cause neutrophils to aggregate in suspension and, when attached to a surface, could support selectin-mediated rolling of all leukocytes. Thrombin-activated platelets could further induce neutrophil activation and immobilisation. In some conditions, platelets could bind to intact endothelial monolayers and capture neutrophils or monocytes. Subsequently, we found that extracellular vesicles released by activated platelets (PEV) fulfilled similar functions when deposited on surfaces or bound to endothelial cells. In murine models, platelets or PEV could act as bridges for monocytes in inflamed vessels. Thus, leukocytes and platelets are rheologically adapted for their separate functions, while novel thrombo-inflammatory pathways using platelets or PEV may underlie pathogenic leukocyte recruitment.


Assuntos
Agregação Eritrocítica , Adesividade Plaquetária , Humanos , Animais , Camundongos , Adesividade Plaquetária/fisiologia , Células Endoteliais , Plaquetas/fisiologia , Leucócitos/fisiologia , Neutrófilos , Reologia , Inflamação/metabolismo , Adesão Celular , Selectina-P/metabolismo
20.
Commun Biol ; 7(1): 308, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38467823

RESUMO

Heparin-induced thrombocytopenia (HIT) is an adverse reaction to heparin leading to a reduction in circulating platelets with an increased risk of thrombosis. It is precipitated by polymerized immune complexes consisting of pathogenic antibodies that recognize a small chemokine platelet factor 4 (PF4) bound to heparin. Characterization of these immune complexes is extremely challenging due to the enormous structural heterogeneity of such macromolecular assemblies and their constituents. Native mass spectrometry demonstrates that up to three PF4 tetramers can be assembled on a heparin chain, consistent with the molecular modeling studies showing facile polyanion wrapping along the polycationic belt on the PF4 surface. Although these assemblies can accommodate a maximum of only two antibodies, the resulting immune complexes are capable of platelet activation despite their modest size. Taken together, these studies provide further insight into molecular mechanisms of HIT and other immune disorders where anti-PF4 antibodies play a central role.


Assuntos
Heparina , Trombocitopenia , Humanos , Heparina/efeitos adversos , Complexo Antígeno-Anticorpo , Fator Plaquetário 4/metabolismo , Trombocitopenia/induzido quimicamente , Plaquetas/metabolismo , Fatores Imunológicos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...