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1.
Eur J Gastroenterol Hepatol ; 36(7): 952-960, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38829945

RESUMO

BACKGROUND AND AIMS: Acute-on-chronic liver failure (ACLF) is the most severe form of acutely decompensated cirrhosis and is characterized by the presence of intense systemic inflammation. Leucocyte quantification can serve as an indirect indicator of systemic inflammation. In our study, we investigated the predictive value of hematological ratios (neutrophils to lymphocytes, monocyte to lymphocytes, platelets to lymphocytes, lymphocytes to C-reactive protein, and neutrophils to lymphocytes and platelets) in acute decompensation (AD) and ACLF patients and their relation to disease severity and early mortality. PATIENTS AND METHODS: We included 60 patients with ACLF and AD, and 30 cirrhotic controls. Clinical data were collected, and survival was followed for 1 and 6 months. Blood samples were analyzed at admission for differential leucocytes and assessed for liver and renal function tests. The leukocyte ratios were calculated and compared, and their correlation with liver function indicators and prognosis was assessed. RESULTS: All ratios were significantly higher in AD and ACLF patients compared to control (except for lymphocyte to C-reactive protein ratio which was significantly lower), and were positively correlated with Child-Pugh score, model for end-stage liver disease (MELD)-Na, and ACLF severity scores. Multivariate regression revealed that neutrophil to lymphocyte ratio, monocyte to lymphocyte ratio, and MELD-Na were independent prognostic factors of 1-month and 6-month mortality. A unique prognostic nomogram incorporating MELD-Na, neutrophil to lymphocyte ratio, and monocyte to lymphocyte ratio could be proposed for predicting prognosis in AD and ACLF patients. CONCLUSIONS: Cheap, easy, and noninvasive hematological ratios are introduced as a tool for early identification and risk stratification of AD and ACLF patients.


Assuntos
Insuficiência Hepática Crônica Agudizada , Proteína C-Reativa , Neutrófilos , Valor Preditivo dos Testes , Índice de Gravidade de Doença , Humanos , Insuficiência Hepática Crônica Agudizada/sangue , Insuficiência Hepática Crônica Agudizada/mortalidade , Insuficiência Hepática Crônica Agudizada/diagnóstico , Masculino , Feminino , Pessoa de Meia-Idade , Prognóstico , Proteína C-Reativa/análise , Adulto , Estudos de Casos e Controles , Contagem de Leucócitos , Idoso , Contagem de Linfócitos , Monócitos , Linfócitos , Contagem de Plaquetas , Cirrose Hepática/sangue , Cirrose Hepática/complicações , Cirrose Hepática/mortalidade , Cirrose Hepática/diagnóstico , Plaquetas , Biomarcadores/sangue , Fatores de Tempo
2.
Platelets ; 35(1): 2358241, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38832819

RESUMO

Acquired disorders of platelet function are an underdiagnosed cause of bleeding tendency. A 14-year-old girl developed moderate mucocutaneous bleeding two weeks after a Mycoplasma pneumoniae infection successfully treated with clarithromycin. The patient was referred to us 7 months later for laboratory investigation of the persisting bleeding diathesis. The patient's personal and family histories were negative for bleeding disorders. Complete blood count, von Willebrand Factor levels and coagulation tests were normal; platelet aggregation, ATP secretion, δ-granules content and serum thromboxane B2 levels were defective. At follow-up visits, laboratory parameters and the bleeding diathesis progressively normalized within 2 years. The patient's condition is compatible with a diagnosis of acquired Storage Pool Deficiency (SPD), associated with defective thromboxane A2 production. To our knowledge, this is the first case of acquired, transient SPD with spontaneous remission. The pathogenic role of Mycoplasma pneumoniae infection or clarithromycin is possible, albeit uncertain.


Assuntos
Deficiência do Pool Plaquetário , Tromboxano A2 , Humanos , Feminino , Adolescente , Deficiência do Pool Plaquetário/complicações , Tromboxano A2/metabolismo , Plaquetas/metabolismo , Transtornos Hemorrágicos
3.
Stem Cell Res Ther ; 15(1): 163, 2024 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-38853252

RESUMO

BACKGROUND: A rising population faces challenges with healing-impaired cutaneous wounds, often leading to physical disabilities. Adipose-derived stem cells (ASCs), specifically in the cell sheet format, have emerged as a promising remedy for impaired wound healing. Human platelet lysate (HPL) provides an attractive alternative to fetal bovine serum (FBS) for culturing clinical-grade ASCs. However, the potential of HPL sheets in promoting wound healing has not been fully investigated. This study aimed to explore the anti-fibrotic and pro-angiogenic capabilities of HPL-cultured ASC sheets and delve into the molecular mechanism. METHODS: A rat burn model was utilized to evaluate the efficacy of HPL-cultured ASC sheets in promoting wound healing. ASC sheets were fabricated with HPL, and those with FBS were included for comparison. Various analyses were conducted to assess the impact of HPL sheets on wound healing. Histological examination of wound tissues provided insights into aspects such as wound closure, collagen deposition, and overall tissue regeneration. Immunofluorescence was employed to assess the presence and distribution of transplanted ASCs after treatment. Further in vitro studies were conducted to decipher the specific factors in HPL sheets contributing to angiogenesis. RESULTS: HPL-cultured ASC sheets significantly accelerated wound closure, fostering ample and organized collagen deposition in the neo-dermis. Significantly more retained ASCs were observed in wound tissues treated with HPL sheets compared to the FBS counterparts. Moreover, HPL sheets mitigated macrophage recruitment and decreased subsequent wound tissue fibrosis in vivo. Immunohistochemistry also indicated enhanced angiogenesis in the HPL sheet group. The in vitro analyses showed upregulation of C-C motif chemokine ligand 5 (CCL5) and angiogenin in HPL sheets, including both gene expression and protein secretion. Culturing endothelial cells in the conditioned media compared to media supplemented with CCL5 or angiogenin suggested a correlation between CCL5 and the pro-angiogenic effect of HPL sheets. Additionally, through neutralizing antibody experiments, we further validated the crucial role of CCL5 in HPL sheet-mediated angiogenesis in vitro. CONCLUSIONS: The present study underscores CCL5 as an essential factor in the pro-angiogenic effect of HPL-cultured ASC sheets during the wound healing process. These findings highlight the potential of HPL-cultured ASC sheets as a promising therapeutic option for healing-impaired cutaneous wounds in clinical settings. Furthermore, the mechanism exploration yields valuable information for optimizing regenerative strategies with ASC products. BRIEF ACKNOWLEDGMENT: This research was supported by the National Science and Technology Council, Taiwan (NSTC112-2321-B-002-018), National Taiwan University Hospital (111C-007), and E-Da Hospital-National Taiwan University Hospital Joint Research Program (111-EDN0001, 112-EDN0002).


Assuntos
Tecido Adiposo , Plaquetas , Quimiocina CCL5 , Neovascularização Fisiológica , Cicatrização , Animais , Humanos , Ratos , Plaquetas/metabolismo , Quimiocina CCL5/metabolismo , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Células-Tronco/metabolismo , Células-Tronco/citologia , Ratos Sprague-Dawley , Células Cultivadas , Masculino , Transplante de Células-Tronco/métodos , Angiogênese
4.
PeerJ ; 12: e17499, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38846752

RESUMO

Objective: The objective of this study was to delineate the profile of peripheral blood lymphocytic indices in patients afflicted with high-grade squamous intraepithelial lesions (HSIL) and cervical neoplasms, and to elucidate the correlation of these hematologic markers with the clinicopathological spectra in individuals diagnosed with cervical carcinoma. Methods: We adopted a retrospective case-control modality for this investigation. An aggregate of 39 HSIL patients and 42 cervical carcinoma patients, who were treated in our facility from July 2020 to September 2023, were meticulously selected. Each case of cervical malignancy was confirmed through rigorous histopathological scrutiny. Concomitantly, 31 healthy female individuals, who underwent prophylactic health evaluations during the corresponding timeframe, were enlisted as the baseline control group. We systematically gathered and analyzed clinical demographics, as well as the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), from peripheral blood samples. Pearson's correlation coefficient was deployed to dissect the interrelation between peripheral NLR and PLR concentrations and the clinicopathological features in the cervical cancer group. Results: Inter-group comparative analysis unveiled statistically substantial variances in the PLR and NLR values among the tripartite clusters (F = 36.941, 14.998, P < 0.001, respectively). Although discrepancy in NLR (P = 0.061) and PLR (P = 0.759) measures between the groups of cervical carcinoma and HSIL was not statistically appreciable, these indices were markedly elevated in the cervical carcinoma faction as juxtaposed with the normative control group (t = 5.094, 5.927; P < 0.001 for both parameters). A discernible gradation in peripheral blood PLR and NLR concentrations was noted when stratified by clinical stage and the profundity of myometrial invasion in cervical cancer subjects (P < 0.001). The correlation matrix demonstrated a positive liaison between peripheral blood PLR and the clinical gradation, as well as the invasiveness of the neoplastic cells into the muscularis propria (P < 0.05); a similar trend was observed with the NLR values (P < 0.05). Conclusion: Augmented NLR and PLR levels in peripheral blood specimens are indicative of HSIL and cervical malignancy. These hematological parameters exhibit a pronounced interconnection with clinical staging and muscular wall penetration depth, serving as potential discriminative biomarkers for the diagnosis and prognosis of cervical cancer.


Assuntos
Neutrófilos , Neoplasias do Colo do Útero , Humanos , Feminino , Neoplasias do Colo do Útero/sangue , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/imunologia , Estudos Retrospectivos , Adulto , Pessoa de Meia-Idade , Neutrófilos/patologia , Neutrófilos/imunologia , Estudos de Casos e Controles , Linfócitos/patologia , Linfócitos/imunologia , Lesões Intraepiteliais Escamosas/patologia , Lesões Intraepiteliais Escamosas/sangue , Contagem de Linfócitos , Plaquetas/patologia , Plaquetas/imunologia , Lesões Intraepiteliais Escamosas Cervicais/sangue , Lesões Intraepiteliais Escamosas Cervicais/patologia , Lesões Intraepiteliais Escamosas Cervicais/imunologia , Lesões Intraepiteliais Escamosas Cervicais/diagnóstico
6.
Open Biol ; 14(6): 240041, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38835242

RESUMO

Platelets are blood cells derived from megakaryocytes that play a central role in regulating haemostasis and vascular integrity. The microtubule cytoskeleton of megakaryocytes undergoes a critical dynamic reorganization during cycles of endomitosis and platelet biogenesis. Quiescent platelets have a discoid shape maintained by a marginal band composed of microtubule bundles, which undergoes remarkable remodelling during platelet activation, driving shape change and platelet function. Disrupting or enhancing this process can cause platelet dysfunction such as bleeding disorders or thrombosis. However, little is known about the molecular mechanisms underlying the reorganization of the cytoskeleton in the platelet lineage. Recent studies indicate that the emergence of a unique platelet tubulin code and specific pathogenic tubulin mutations cause platelet defects and bleeding disorders. Frequently, these mutations exhibit dominant negative effects, offering valuable insights into both platelet disease mechanisms and the functioning of tubulins. This review will highlight our current understanding of the role of the microtubule cytoskeleton in the life and death of platelets, along with its relevance to platelet disorders.


Assuntos
Plaquetas , Citoesqueleto , Megacariócitos , Microtúbulos , Humanos , Plaquetas/metabolismo , Megacariócitos/metabolismo , Megacariócitos/citologia , Citoesqueleto/metabolismo , Microtúbulos/metabolismo , Tubulina (Proteína)/metabolismo , Tubulina (Proteína)/genética , Animais , Transtornos Plaquetários/metabolismo , Transtornos Plaquetários/genética , Transtornos Plaquetários/patologia , Mutação
7.
BMC Pediatr ; 24(1): 391, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38862972

RESUMO

BACKGROUND: To examine the value of early echocardiographic indices for the right ventricular function combined with platelet(PLT) parameters for predicting bronchopulmonary dysplasia (BPD) in preterm infants. METHODS: This retrospective study included infants with gestational age (GA) below 32 weeks, who were admitted to the neonatal intensive care unit(NICU). The detection rate of tricuspid regurgitation jet velocity (TRVJ), ventricular septal flattening, pulmonary artery widening, right ventricular dilation, and right atrial enlargement on the 7th day of life (DOL 7) were compared between BPD and non-BPD infants. Echocardiographic indices of the right ventricular function including tricuspid annular plane systolic excursion (TAPSE) and right ventricular index of myocardial performance (RIMP) were measured on 1 day of life (DOL 1)、on DOL 7 and on 14 day of life (DOL 14) respectively. The PLT parameters including the PLT count, mean platelet volume (MPV), platelet hematocrit (PCT) level, and platelet distribution width (PDW) were measured on the DOL 1,DOL 7, and DOL 14. Multivariate logistic regression was used to analyze the relationship between these parameters and BPD. Receiver operating characteristic curve analysis was performed to assess the predictive value of the right ventricular function indices and PLT parameters for BPD. RESULTS: A total of 220 preterm infants were included in this study, and of these, 85 infants developed BPD among them. The RIMP of the BPD group on DOL 14 was higher than that of the non-BPD group (P < 0.05). The TAPSE of the BPD group on DOL 14 was lower than that of the non-BPD group (P < 0.05). The PLT count of the BPD group on DOL 1 was lower than that of the non-BPD group (P < 0.05), and the MPV of the BPD group on DOL 1 was higher than that of the non-BPD group (P < 0.05). Using multivariate logistic regression, GA、invasive mechanical ventilation duration ≥ 7 days、 PLT、 MPV、 TAPSE and RIMP were found to be independent risk factors for BPD. The area under the receiver operating characteristic curve was 0.846 (95CI: 0.794∼0.899), which improved when using right ventricular function indices combined with platelet parameters. CONCLUSION: TAPSE and RIMP combined with PLT count and MPV can help identify preterm infants at an increased risk of developing BPD.


Assuntos
Displasia Broncopulmonar , Recém-Nascido Prematuro , Humanos , Estudos Retrospectivos , Displasia Broncopulmonar/sangue , Displasia Broncopulmonar/diagnóstico , Recém-Nascido , Feminino , Masculino , Contagem de Plaquetas , Curva ROC , Ecocardiografia , Volume Plaquetário Médio , Valor Preditivo dos Testes , Função Ventricular Direita/fisiologia , Plaquetas
8.
Lipids Health Dis ; 23(1): 179, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38862998

RESUMO

BACKGROUND: Dry eye disease (DED) is a complication of dyslipidemia (DLP) that is caused by metabolic syndrome and increased inflammation. This research aimed to assess leukocyte and systemic inflammation index ratios as potential biomarkers for systemic inflammation in dyslipidemia patients with dry eye disease (DLP-DED). METHODS: Several blood biomarkers were studied in 32 patients with DLP-DED (study group) and 63 patients with DLP-only (control group). The evaluated blood biomarkers included specific systemic inflammation index ratios, such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), and neutrophil-to-lymphocyte and platelet ratio (NLPR), and lipid profiles, such as total cholesterol (TC), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), triglyceride (TG), albumin (ALB), and C-reactive protein (CRP) levels. RESULTS: Lymphocyte levels were significantly greater in the DLP-DED group than in the DLP-only group (P = 0.044). In addition, a significant negative correlation between HDL and the NLPR (P = 0.007; r= -0.428) and a significant negative correlation between the serum ALB concentration and the PLR (P = 0.008; r= -0.420) were identified as potential inflammatory predictors of DLP-DED. CONCLUSION: The findings of this study suggest that patients with DLP-DED may benefit from routine blood monitoring of their elevated lipid profile and blood inflammatory biomarkers, such as CRP, leukocytes, and systemic inflammation index ratios (NLR, PLR, MLR, and NLPR), to reduce the complications of DLP on ocular health. The correlation data suggest that the NLPR, PLR, serum ALB concentration, and serum HDL concentration may be valuable inflammatory biomarkers in DLP-DED patients. More research is required to ascertain the significance of the NLR, PLR, MLR, and NLPR and the additive role that leukocytes play.


Assuntos
Biomarcadores , Síndromes do Olho Seco , Dislipidemias , Inflamação , Humanos , Dislipidemias/sangue , Masculino , Feminino , Síndromes do Olho Seco/sangue , Pessoa de Meia-Idade , Inflamação/sangue , Estudos de Casos e Controles , Estudos Retrospectivos , Biomarcadores/sangue , Idoso , HDL-Colesterol/sangue , Triglicerídeos/sangue , Proteína C-Reativa/metabolismo , Leucócitos/metabolismo , Linfócitos , Neutrófilos/metabolismo , LDL-Colesterol/sangue , Adulto , Plaquetas/patologia , Plaquetas/metabolismo
9.
Ann Med ; 56(1): 2346546, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38847883

RESUMO

BACKGROUND: Although normal acute phase reactants (APRs) play an important role in assessing disease activity of rheumatoid arthritis (RA), some studies pointed out the discordance between disease activity and APR level. Neutrophil-to-lymphocyte ratios (NLRs), platelet-to-lymphocyte ratios (PLRs) and lymphocyte-to-monocyte ratios (LMRs) have been reported to be sensitive measures of inflammatory reaction. This study aims to explore the value of these haematological makers in assessment of APR-negative RA patients. METHODS: Out of a cohort of 418 consecutive patients with RA, we enrolled 135 patients with normal APR for this study. We performed ultrasound assessments to evaluate synovitis and bone erosion in the affected joints. Synovitis was evaluated by ultrasound grey scale (GS) and power Doppler (PD) with semi-quantitative scoring (0-3). Demographic, clinical and laboratory data were collected from the patients. Disease Activity Score-28 joints (DAS28), NLR, MLR and PLR were calculated. RESULTS: In RA patients with normal APR, PLR exhibited a positive correlation with ultrasound-detected synovitis and bone erosion, whereas NLR, MLR showed no significant correlation with ultrasonography parameters. The area under the ROC curve (AUC) for identifying synovitis with a GS grade ≥2 based on a PLR cutoff value of ≥159.6 was 0.7868 (sensitivity: 80.95%, specificity: 74.24%). For synovitis with a PD grade ≥2, the AUC was 0.7690, using a PLR cutoff value of ≥166.1 (sensitivity: 68.0%, specificity: 83.87%). CONCLUSIONS: Our findings suggested that PLR might be a reliable and cost-effective marker for identifying moderate-to-severe synovitis in RA patients with normal APR.


Assuntos
Artrite Reumatoide , Biomarcadores , Linfócitos , Sinovite , Humanos , Sinovite/diagnóstico por imagem , Sinovite/sangue , Sinovite/diagnóstico , Artrite Reumatoide/sangue , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/complicações , Feminino , Masculino , Pessoa de Meia-Idade , Biomarcadores/sangue , Adulto , Plaquetas , Proteínas de Fase Aguda/análise , Idoso , Índice de Gravidade de Doença , Contagem de Plaquetas , Curva ROC , Contagem de Linfócitos , Neutrófilos
10.
Front Immunol ; 15: 1409443, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38863693

RESUMO

Introduction: This study aimed to develop a prognostic nomogram for predicting the recurrence-free survival (RFS) of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients with low preoperative platelet-albumin-bilirubin (PALBI) scores after transarterial chemoembolization (TACE) combined with local ablation treatment. Methods: We gathered clinical data from 632 HBV-related HCC patients who received the combination treatment at Beijing You'an Hospital, affiliated with Capital Medical University, from January 2014 to January 2020. The patients were divided into two groups based on their PALBI scores: low PALBI group (n=247) and high PALBI group (n=385). The low PALBI group was then divided into two cohorts: training cohort (n=172) and validation cohort (n=75). We utilized eXtreme Gradient Boosting (XGBoost), random survival forest (RSF), and multivariate Cox analysis to pinpoint the risk factors for RFS. Then, we developed a nomogram based on the screened factors and assessed its risk stratification capabilities and predictive performance. Results: The study finally identified age, aspartate aminotransferase (AST), and prothrombin time activity (PTA) as key predictors. The three variables were included to develop the nomogram for predicting the 1-, 3-, and 5-year RFS of HCC patients. We confirmed the nomogram's ability to effectively discern high and low risk patients, as evidenced by Kaplan-Meier curves. We further corroborated the excellent discrimination, consistency, and clinical utility of the nomogram through assessments using the C-index, area under the curve (AUC), calibration curve, and decision curve analysis (DCA). Conclusion: Our study successfully constructed a robust nomogram, effectively predicting 1-, 3-, and 5-year RFS for HBV-related HCC patients with low preoperative PALBI scores after TACE combined with local ablation therapy.


Assuntos
Bilirrubina , Carcinoma Hepatocelular , Neoplasias Hepáticas , Aprendizado de Máquina , Recidiva Local de Neoplasia , Nomogramas , Humanos , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/diagnóstico , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/etiologia , Masculino , Feminino , Pessoa de Meia-Idade , Bilirrubina/sangue , Vírus da Hepatite B , Quimioembolização Terapêutica/métodos , Prognóstico , Plaquetas , Hepatite B/complicações , Adulto , Albumina Sérica/análise , Estudos Retrospectivos , Contagem de Plaquetas
11.
J Obstet Gynaecol ; 44(1): 2361858, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38864403

RESUMO

BACKGROUND: Cervical cancer ranks as the second most fatal tumour globally among females. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been widely applied to the diagnosis of cancers. METHODS: The clinicopathologic data of 180 patients with stage IB2-IIB cervical cancer who underwent radical concurrent chemoradiotherapy from January 2018 to December 2019 were retrospectively analysed. Receiver operating characteristic (ROC) curves were plotted to analyse the optimal cut-off values of NLR and PLR for predicting the therapeutic effects of concurrent chemoradiotherapy. The associations of PLR and other clinicopathological factors with 1-year survival rates were explored through univariate analysis and multivariate Cox regression analysis, respectively. RESULTS: NLR was significantly associated with the therapeutic effects of neoadjuvant therapy, with the optimal cut-off value of 2.89, area under the ROC curve (AUC) of 0.848 (95% confidence interval [CI]: 0.712-0.896), sensitivity of 0.892 (95% CI: 0.856-0.923) and specificity of 0.564 (95% CI: 0.512-0.592). PLR had a significant association with the therapeutic effects of neoadjuvant therapy, with the optimal cut-off value of 134.27, AUC of 0.766 (95% CI: 0.724-0.861), sensitivity of 0.874 (95% CI: 0.843-0.905) and specificity of 0.534 (95% CI: 0.512-0.556). Lymphatic metastasis ([95% CI: 1.435-5.461], [95% CI: 1.336-4.281], depth of invasion ([95% CI: 1.281-3.546], [95% CI: 1.183-3.359]) and tumour size ([95% CI: 1.129-3.451], [95% CI: 1.129-3.451]) were independent factors influencing the overall survival and disease-free survival (DFS) of patients with cervical cancer. NLR (95%CI: 1.256-4.039) and PLR (95%CI:1.281-3.546) were also independent factors affecting DFS. CONCLUSION: NLR and PLR in the peripheral blood before treatment may predict DFS of patients with stage IB2-IIB cervical cancer.


The clinicopathologic data of 180 patients with stage IB2-IIB cervical cancer who underwent radical concurrent chemoradiotherapy were retrospectively analysed. Receiver operating characteristic curves showed that neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were significantly associated with the therapeutic effects of neoadjuvant therapy. Univariate and multivariate regression analysis revealed that lymphatic metastasis, depth of invasion and tumour size were independent factors influencing the overall survival and disease-free survival (DFS) of patients with cervical cancer. NLR and PLR in the peripheral blood before treatment may predict the DFS of patients with stage IB2-IIB cervical cancer.


Assuntos
Quimiorradioterapia , Linfócitos , Terapia Neoadjuvante , Neutrófilos , Neoplasias do Colo do Útero , Humanos , Feminino , Neoplasias do Colo do Útero/terapia , Neoplasias do Colo do Útero/sangue , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/patologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Quimiorradioterapia/métodos , Adulto , Terapia Neoadjuvante/métodos , Plaquetas , Curva ROC , Contagem de Linfócitos , Idoso , Contagem de Plaquetas , Prognóstico , Valor Preditivo dos Testes , Estadiamento de Neoplasias , Taxa de Sobrevida , Contagem de Leucócitos
12.
Platelets ; 35(1): 2358244, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38845541

RESUMO

Thromboembolic events are common in patients with essential thrombocythemia (ET). However, the pathophysiological mechanisms underlying the increased thrombotic risk remain to be determined. Here, we perform the first phenotypical characterization of platelet expression using single-cell mass cytometry in six ET patients and six age- and sex-matched healthy individuals. A large panel of 18 transmembrane regulators of platelet function and activation were analyzed, at baseline and after ex-vivo stimulation with thrombin receptor-activating peptide (TRAP). We detected a significant overexpression of the activation marker CD62P (p-Selectin) (p = .049) and the collagen receptor GPVI (p = .044) in non-stimulated ET platelets. In contrast, ET platelets had a lower expression of the integrin subunits of the fibrinogen receptor GPIIb/IIIa CD41 (p = .036) and CD61 (p = .044) and of the von Willebrand factor receptor CD42b (p = .044). Using the FlowSOM algorithm, we identified 2 subclusters of ET platelets with a prothrombotic expression profile, one of them (cluster 3) significantly overrepresented in ET (22.13% of the total platelets in ET, 2.94% in controls, p = .035). Platelet counts were significantly increased in ET compared to controls (p = .0123). In ET, MPV inversely correlated with platelet count (r=-0.96). These data highlight the prothrombotic phenotype of ET and postulate GPVI as a potential target to prevent thrombosis in these patients.


Essential thrombocythemia (ET) is a rare disease characterized by an increased number of platelets in the blood. As a complication, many of these patients develop a blood clot, which can be life-threatening. So far, the reason behind the higher risk of blood clots is unclear. In this study, we analyzed platelet surface markers that play a critical role in platelet function and platelet activation using a modern technology called mass cytometry. For this purpose, blood samples from 6 patients with ET and 6 healthy control individuals were analyzed. We found significant differences between ET platelets and healthy platelets. ET platelets had higher expression levels of p-Selectin (CD62P), a key marker of platelet activation, and of the collagen receptor GPVI, which is important for clot formation. These results may be driven by a specific platelet subcluster overrepresented in ET. Other surface markers, such as the fibrinogen receptor GPIIb/IIIa CD41, CD61, and the von Willebrand factor receptor CD42b, were lower expressed in ET platelets. When ET platelets were treated with the clotting factor thrombin (thrombin receptor-activating peptide, TRAP), we found a differential response in platelet activation compared to healthy platelets. In conclusion, our results show an increased activation and clotting potential of ET platelets. The platelet surface protein GPVI may be a potential drug target to prevent abnormal blood clotting in ET patients.


Assuntos
Plaquetas , Trombocitemia Essencial , Trombose , Humanos , Trombocitemia Essencial/metabolismo , Trombocitemia Essencial/complicações , Plaquetas/metabolismo , Masculino , Feminino , Trombose/metabolismo , Trombose/etiologia , Pessoa de Meia-Idade , Idoso , Citometria de Fluxo/métodos , Ativação Plaquetária , Estudos de Casos e Controles , Adulto
13.
BMC Psychiatry ; 24(1): 427, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38849781

RESUMO

AIMS: Herein, we examined the correlation between platelet/high-density lipoprotein cholesterol ratio (PHR) and symptoms of depression among United States adults. METHODS: Data acquired from the 2007-2018 National Health and Nutrition Examination Survey, involving individuals ≥ 20 years of age, with available PHR and depression diagnosis information. We employed weighted uni- and multivariable logistic regression analyses to assess the distinct correlation between PHR and depressive symptoms. Additionally, we conducted subgroup, interaction, and restricted cubic spline analyses. RESULTS: In all, 28,098 subjects were recruited for analysis, with 8.04% depression status and 19.31 ± 0.11 mean PHR value. Depressive symptoms increased with higher quartiles of PHR. Following fully confounder adjustments in model 2, participants with the largest PHR quartiles exhibited a 53% (OR: 1.53, 95%CI: 1.00-2.33, P = 0.05) raised depressive symptoms, relative to participants with least PHR quartiles. Based on the two-piece-wise regression, the breakpoint was PHR = 23.76, and a positive association was more evident when PHR < 23.76 (OR = 1.06, 95%CI: 1.02-1.10, P = 0.01). When PHR ≥ 23.76, the correlation disappeared (P = 0.85). Using subgroup and interaction analyses, we revealed a positive relationship between PHR and depressive symptoms almost consistent among various population settings. CONCLUSIONS: A convenient biomarker, the PHR was independently associated with an increased risk of depressive symptoms and may be a promising new bioindicator for the prediction of depression diagnosis.


Assuntos
HDL-Colesterol , Depressão , Inquéritos Nutricionais , Humanos , Masculino , Feminino , Estados Unidos/epidemiologia , Depressão/sangue , Depressão/epidemiologia , Adulto , Estudos Transversais , Pessoa de Meia-Idade , HDL-Colesterol/sangue , Plaquetas , Adulto Jovem , Idoso
14.
Theranostics ; 14(8): 3267-3281, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38855181

RESUMO

Background: Myocardial infarction (MI) as a consequence of atherosclerosis-associated acute thrombosis is a leading cause of death and disability globally. Antiplatelet and anticoagulant drugs are standard therapies in preventing and treating MI. However, all clinically used drugs are associated with bleeding complications, which ultimately limits their use in patients with a high risk of bleeding. We have developed a new recombinant drug, targ-HSA-TAP, that combines targeting and specific inhibition of activated platelets as well as anticoagulation. This drug is designed and tested for a prolonged circulating half-life, enabling unique thromboprophylaxis without bleeding complications. Methods: Targ-HSA-TAP combines a single-chain antibody (scFv) that targets activated glycoprotein IIb/IIIa on activated platelets, human serum albumin (HSA) for prolonged circulation, and tick anticoagulant peptide (TAP) for coagulation FX inhibition. A non-binding scFv is employed as a non-targeting control (non-targ-HSA-TAP). Its efficacy was investigated in vivo using murine models of acute thrombosis and cardiac ischemia-reperfusion (I/R) injury. Results: Our experiments confirmed the targeting specificity of targ-HSA-TAP to activated platelets and demonstrated effective prevention of platelet aggregation and thrombus formation, as well as FXa inhibition in vitro. Thromboprophylactic administration of targ-HSA-TAP subcutaneously in mice prevented occlusion of the carotid artery after ferric chloride injury as compared to non-targ-HSA-TAP and PBS-control treated mice. By comparing the therapeutic outcomes between targ-TAP and targ-HSA-TAP, we demonstrate the significant improvements brought by the HSA fusion in extending the drug's half-life and enhancing its therapeutic window for up to 16 h post-administration. Importantly, tail bleeding time was not prolonged with targ-HSA-TAP in contrast to the clinically used anticoagulant enoxaparin. Furthermore, in a murine model of cardiac I/R injury, mice administered targ-HSA-TAP 10 h before injury demonstrated preserved cardiac function, with significantly higher ejection fraction and fractional shortening, as compared to the non-targ-HSA-TAP and PBS control groups. Advanced strain analysis revealed reduced myocardial deformation and histology confirmed a reduced infarct size in targ-HSA-TAP treated mice compared to control groups. Conclusion: The inclusion of HSA represents a significant advancement in the design of targeted therapeutic agents for thromboprophylaxis. Our activated platelet-targeted targ-HSA-TAP is a highly effective antithrombotic drug with both anticoagulant and antiplatelet effects while retaining normal hemostasis. The long half-life of targ-HSA-TAP provides the unique opportunity to use this antithrombotic drug for more effective, long-lasting and safer anti-thrombotic prophylaxis. In cases where MI occurs, this prophylactic strategy reduces thrombus burden and effectively reduces cardiac I/R injury.


Assuntos
Plaquetas , Hemorragia , Albumina Sérica Humana , Trombose , Animais , Camundongos , Trombose/prevenção & controle , Trombose/tratamento farmacológico , Humanos , Hemorragia/prevenção & controle , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Modelos Animais de Doenças , Masculino , Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Anticorpos de Cadeia Única/farmacologia , Anticorpos de Cadeia Única/uso terapêutico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Infarto do Miocárdio/tratamento farmacológico , Camundongos Endogâmicos C57BL , Proteínas Recombinantes de Fusão/farmacologia , Proteínas Recombinantes de Fusão/uso terapêutico
15.
PLoS One ; 19(5): e0303869, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38809853

RESUMO

OBJECTIVE: Carotid atherosclerosis is a chronic inflammatory disease, which is a major cause of ischemic stroke. The purpose of this study was to analyze the relationship between carotid atherosclerosis and novel inflammatory markers, including platelet to lymphocyte ratio (PLR), neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), platelet to neutrophil ratio (PNR), neutrophil to lymphocyte platelet ratio (NLPR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), and aggregate index of systemic inflammation (AISI), in order to find the best inflammatory predictor of carotid atherosclerosis. METHOD: We included 10015 patients who underwent routine physical examinations at the physical examination center of our hospital from January 2016 to December 2019, among whom 1910 were diagnosed with carotid atherosclerosis. The relationship between novel inflammatory markers and carotid atherosclerosis was analyzed by logistic regression, and the effectiveness of each factor in predicting carotid atherosclerosis was evaluated by receiver operating characteristic (ROC) curve and area under the curve (AUC). RESULT: The level of PLR, LMR and PNR in the carotid atherosclerosis group were lower than those in the non-carotid atherosclerosis group, while NLR, NLPR, SII, SIRI and AISI in the carotid atherosclerosis group were significantly higher than those in the non-carotid atherosclerosis group. Logistic regression analysis showed that PLR, NLR, LMR, PNR, NLPR, SII, SIRI, AISI were all correlated with carotid atherosclerosis. The AUC value of NLPR was the highest, which was 0.67, the cut-off value was 0.78, the sensitivity was 65.8%, and the specificity was 57.3%. The prevalence rate of carotid atherosclerosis was 12.4% below the cut-off, 26.6% higher than the cut-off, and the prevalence rate increased by 114.5%. CONCLUSION: New inflammatory markers were significantly correlated with carotid atherosclerosis, among which NLPR was the optimum inflammatory marker to predict the risk of carotid atherosclerosis.


Assuntos
Biomarcadores , Doenças das Artérias Carótidas , Inflamação , Humanos , Doenças das Artérias Carótidas/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Biomarcadores/sangue , Estudos Retrospectivos , Inflamação/sangue , Estudos de Casos e Controles , Idoso , Neutrófilos , Curva ROC , Plaquetas/patologia , Plaquetas/metabolismo , Linfócitos , Monócitos/metabolismo
16.
J Thromb Haemost ; 22(6): 1749-1757, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38811291

RESUMO

BACKGROUND: An iron overload status induces ferroptosis, an iron-dependent nonapoptotic cell death, in various pathological conditions. We previously reported that hemin (heme), protoporphyrin-IX with ferric iron, activates platelets via C-type lectin-like receptor-2 (CLEC-2) and glycoprotein VI/FcRγ, but protoporphyrin-IX alone blocks CLEC-2-dependent platelet activation. Therefore, we hypothesized that free iron has the ability to activate platelets. OBJECTIVES: This study aimed to elucidate platelet activation mechanisms of iron (ferric chloride), including the identification of signaling pathways and receptors, and to examine whether platelets regulate ferroptosis. METHODS: Platelet aggregometry, platelet activation marker expression, and protein phosphorylation were examined in ferric chloride-stimulated human and murine platelets. Inhibitors of platelet activation signaling pathways and receptor-deleted platelets were utilized to identify the responsible signaling pathway and receptor. The effect of platelets on ferroptosis of endothelial cells was investigated in vitro. RESULTS: Ferric chloride induced platelet activation dependent on Src family kinase pathways in humans and mice. Ferric chloride-induced platelet aggregation was almost lost in CLEC-2-depleted murine platelets and wild-type platelets preincubated with recombinant CLEC-2 proteins. Furthermore, coculture of wild-type platelets, but not CLEC-2-deficient platelets, attenuated ferroptosis of endothelial cells in vitro. CONCLUSION: Ferric chloride activates platelets via CLEC-2 and Src family kinase pathways, and platelets have a protective role in the ferroptosis of endothelial cells dependent on CLEC-2.


Assuntos
Plaquetas , Cloretos , Compostos Férricos , Ferroptose , Lectinas Tipo C , Camundongos Endogâmicos C57BL , Ativação Plaquetária , Agregação Plaquetária , Transdução de Sinais , Animais , Plaquetas/metabolismo , Plaquetas/efeitos dos fármacos , Compostos Férricos/farmacologia , Humanos , Ativação Plaquetária/efeitos dos fármacos , Lectinas Tipo C/metabolismo , Cloretos/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Ferroptose/efeitos dos fármacos , Quinases da Família src/metabolismo , Fosforilação , Camundongos Knockout , Células Endoteliais/metabolismo , Células Endoteliais/efeitos dos fármacos , Camundongos , Células Endoteliais da Veia Umbilical Humana/metabolismo
17.
Front Immunol ; 15: 1404228, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38812519

RESUMO

Introduction: Adipose tissue mesenchymal stem/stromal cells (ASC) can be used as advanced therapy medicinal product in regenerative and cancer medicine. We previously demonstrated Supernatant Rich in Growth Factors (SRGF) can replace fetal bovine serum (FBS) to expand ASC by a clinical grade compliant protocol. The therapeutic potential of ASC is based also on their homing capacity toward inflammatory/cancer sites: oriented cell migration is a fundamental process in this scenario. We investigated the impact of SRGF on ASC migration properties. Methods: The motility/migration potential of ASC expanded in 5% SRGF was analyzed, in comparison to 10% FBS, by standard wound healing, bidimensional chemotaxis and transwell assays, and by millifluidic transwell tests. Mechanisms involved in the migration process were investigated by transient protein overexpression. Results: In comparison to standard 10% FBS, supplementation of the cell culture medium with 5% SRGF, strongly increased migration properties of ASC along the chemotactic gradient and toward cancer cell derived soluble factors, both in static and millifluidic conditions. We showed that, independently from applied migratory stimulus, SRGF expanded ASC were characterized by far lower expression of α-smooth muscle actin (αSMA), a protein involved in the cell migration machinery. Overexpression of αSMA induced a significant and marked decrease in migration capacity of SRGF expanded ASC. Discussion: In conclusion, 5% SRGF addition in the cell culture medium increases the migration potential of ASC, reasonably through appropriate downregulation of αSMA. Thus, SRGF could potentially improve the therapeutic impact of ASC, both as modulators of the immune microenviroment or as targeted drug delivery vehicles in oncology.


Assuntos
Tecido Adiposo , Plaquetas , Movimento Celular , Peptídeos e Proteínas de Sinalização Intercelular , Células-Tronco Mesenquimais , Humanos , Movimento Celular/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Plaquetas/metabolismo , Células Cultivadas , Meios de Cultura/farmacologia , Actinas/metabolismo , Feminino
18.
Arq Neuropsiquiatr ; 82(5): 1-8, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38811022

RESUMO

BACKGROUND: Increasing evidence suggests that inflammatory biomarkers play a significant role in cerebral venous sinus thrombosis (CVST). The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) are related to thrombotic conditions and indicators of systemic inflammation. OBJECTIVE: To analyze the correlation between inflammatory biomarkers and the extent of thrombus, determined by the CVST-Score. METHODS: A total of 40 patients with CVST (24 female subjects; 60%) and 40 age- and sex-matched healthy controls were retrospectively evaluated. Inflammatory biomarkers, including C-reactive protein (CRP), PLR, NLR, MLR, and the CVST-Score, were recorded to assess the relationship between biomarkers and thrombus burden. The patients were grouped according to symptom duration (group 1: 0-3 days; group 2: 4-7 days; and group 3: 8-30 days) to compare biomarker levels. RESULTS: The CRP, NLR, and PLR were significantly higher in the CVST group (p < 0.001; p = 0.003; p = 0.014 respectively). The NLR and PLR presented a significant positive correlation with the CVST-Score (p = 0.003, r = 0.464; p = 0.040, r = 0.326 respectively). The NLR was significantly higher in group 1 compared with groups 2 and 3 (p = 0.016 and p = 0.014 respectively). In group 1, there was a stronger positive correlation between the CVST-Score and the NLR (p = 0.026, r = 0.591) and the PLR (p = 0.012, r = 0.648). The multiple linear regression analysis revealed that the NLR is a key factor in predicting the CVST-Score (p = 0.019). CONCLUSION: The NLR and PLR are associated with thrombus burden in CVST, especially in patients admitted to the hospital in the early stages. The NLR is an independent factor to predict the thrombus burden in CVST.


ANTECEDENTES: Há evidências crescentes de que biomarcadores inflamatórios desempenham um papel importante na trombose venosa cerebral (TVC). A razão neutrófilo-linfócito (NLR), a razão plaqueta-linfócito (PLR) e a razão monócito-linfócito (MLR) estão relacionadas a condições trombóticas e são indicadores de inflamação sistêmica. OBJETIVO: Analisar a correlação entre NLR, PLR, MLR e a extensão do trombo, determinada pelo escore de TVC. MéTODOS: Avaliamos retrospectivamente 40 pacientes com TVC (24 mulheres; 60%) e 40 controles pareados por idade e sexo. Biomarcadores inflamatórios, incluindo proteína C reativa (PCR), PLR, NLR, MLR e escore de TVC, foram registrados para avaliar a relação entre biomarcadores e carga trombótica. Os pacientes foram agrupados de acordo com a duração dos sintomas (grupo 1: 0­3 dias; grupo 2: 4­7 dias; e grupo 3: 8­30 dias) para a comparação dos níveis de biomarcadores. RESULTADOS: A PCR, a NLR e a PLR foram significativamente maiores no grupo com TVC (p < 0,001; p = 0,003; e p = 0,014, respectivamente). A NLR e a PLR apresentaram correlação positiva significativa com o escore de TVC (p = 0,003, r = 0,464; e p = 0,040, r = 0,326, respectivamente). A NLR foi significativamente maior no grupo 1 em comparação aos grupos 2 e 3 (p = 0,016 e p = 0,014, respectivamente). No grupo 1, houve correlação mais forte entre o escore de TVC e a NLR (p = 0,026, r = 0,591) e a PLR (p = 0,012, r = 0,648). A análise de regressão linear múltipla identificou a NLR como fator-chave na predição do escore de TVC (p = 0,019). CONCLUSãO: A NLR e a PLR estão associadas à carga trombótica na TVC, especialmente em pacientes admitidos precocemente, e a RNL é um fator independente na previsão da carga trombótica.


Assuntos
Biomarcadores , Proteína C-Reativa , Linfócitos , Neutrófilos , Trombose dos Seios Intracranianos , Humanos , Feminino , Masculino , Trombose dos Seios Intracranianos/sangue , Trombose dos Seios Intracranianos/diagnóstico por imagem , Biomarcadores/sangue , Adulto , Proteína C-Reativa/análise , Estudos Retrospectivos , Pessoa de Meia-Idade , Estudos de Casos e Controles , Inflamação/sangue , Contagem de Plaquetas , Adulto Jovem , Plaquetas , Contagem de Linfócitos , Valores de Referência , Estatísticas não Paramétricas , Monócitos , Fatores de Tempo
19.
Front Endocrinol (Lausanne) ; 15: 1356929, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38800491

RESUMO

Background: The primary aim of this study was to investigate the correlation between diabetic retinopathy (DR) and the HALP score (hemoglobin, albumin, lymphocyte, and platelet) in individuals with diabetes within the United States population. Methods: This cross-sectional investigation was based on the National Health and Nutrition Examination Survey (NHANES) database from 2003-2018. The following module calculated the HALP score: HALP score = [lymphocytes (/L) × hemoglobin (g/L) × albumin (g/L)]/platelets (/L). By performing the receiver operating characteristic (ROC) analysis, the optimal cutoff value of HALP was ascertained. Restricted cubic splines (RCS), multivariable logistic regression analysis, sensitivity analysis, and subgroup analysis were conducted to evaluate the effect of the HALP score on DR patients. Finally, the decision curve analysis (DCA) and clinical impact curve (CIC) were conducted to estimate the predictive power and clinical utility of the HALP score with clinical indicators. Results: According to the cutoff value (42.9) determined by the ROC curve, the participants were stratified into a lower HALP group (HALPlow) and a higher HALP group (HALPhigh). An L-shaped relationship between HALP score and DR risk was presented in the RCS model (P for nonlinearity <0.001). The DR risk sharply decreased with the increase of HALP, and the decline reached a plateau when HALP was more than 42.9. After fully adjustment, the multivariate logistic regression analysis found that HALPlow was an independent risk factor for DR (OR = 1.363, 95% CI: 1.111-1.671, P < 0.001). Besides, sensitivity analysis showed consistent results. Furthermore, the combination of HALP score and clinical indicators demonstrated predictive power and clinical utility, as shown by the ROC curve, DCA, and CIC. Conclusion: The HALP score has an L-shaped correlation with the risk of DR, and thus, the HALP score may contribute to the timely intervention of diabetes patients.


Assuntos
Plaquetas , Retinopatia Diabética , Hemoglobinas , Linfócitos , Inquéritos Nutricionais , Humanos , Retinopatia Diabética/sangue , Retinopatia Diabética/epidemiologia , Retinopatia Diabética/diagnóstico , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Transversais , Estados Unidos/epidemiologia , Hemoglobinas/análise , Hemoglobinas/metabolismo , Plaquetas/patologia , Adulto , Fatores de Risco , Idoso , Albumina Sérica/análise , Albumina Sérica/metabolismo , Curva ROC , Biomarcadores/sangue
20.
Biochem Biophys Res Commun ; 720: 150099, 2024 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-38749192

RESUMO

Binding of activated factor IX (fIXa) to the phosphatidylserine-expressing procoagulant platelets is a critical step in blood coagulation, which is necessary for the membrane-dependent intrinsic tenase complex assembly and factor X activation. However, the nature and parameters of the fIXa binding sites on the procoagulant platelet surface remain unclear. We used flow cytometry to elucidate the quantitative details of the fluorescently labeled fIXa binding to gel-filtered activated platelets. FIXa bound to the procoagulant platelet subpopulation only, with the parameters (maximal number of binding sites at 58900 ± 3400, Kd at 1000 ± 170 nM) similar to binding observed with phospholipid vesicles. No specific high-affinity binding sites for fIXa were detected, and binding proceeded similarly for different methods of procoagulant platelet production (thrombin, thrombin receptor activation peptide, collagen-related peptide, their combinations, or calcium ionophore A23187). Factor VIII, known to form a high affinity complex with fIXa, enhanced fIXa binding to platelets. In contrast, only competition effects were observed for factor X, which binds fIXa with much lower affinity. Unexpectedly, fIXa itself, fIX, and prothrombin also dose-dependently enhance fIXa binding at concentrations below 1000 nM, suggesting the formation of membrane-bound fIXa dimers and fIXa-prothrombin complexes on platelets. These findings provide a novel perspective on the fIXa binding site on procoagulant platelets, which does not have any major differences from pure phospholipid-based model membranes, exhibits inherently low affinity (3-5 orders of magnitude below the physiologically relevant fIXa concentration) but is significantly enhanced by its cofactor VIII, and regulated by previously unknown membrane interactions.


Assuntos
Plaquetas , Fator IXa , Ligação Proteica , Humanos , Plaquetas/metabolismo , Fator IXa/metabolismo , Sítios de Ligação , Coagulação Sanguínea , Trombina/metabolismo , Fator X/metabolismo , Citometria de Fluxo , Fosfatidilserinas/metabolismo , Proteínas de Transporte , Peptídeos
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