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1.
Medicine (Baltimore) ; 100(6): e24651, 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33578593

RESUMO

ABSTRACT: This study aimed to explore the significance and prognostic value of serum tumor-associated carbohydrate antigen 19-9 (CA19-9), D-dimer, and tumor necrosis factor alpha-induced protein 3 (TNFAIP3/A20) in patients with pancreatic ductal adenocarcinoma (PDAC).Our study included 148 patients treated for PDAC at Northern Jiangsu People's Hospital Affiliated to Yangzhou University from January 2012 to December 2016. Cutoff prognostic values were predicted using the receiver operating characteristic (ROC) curve. The Kaplan-Meier method was used to assess the survival rates of patients. Univariate and multivariate COX regression analyses were used to evaluate the prognostic factors.The recommended cutoff values of neutrophil-lymphocyte rate (NLR), platelet-lymphocyte rate (PLR), CA19-9, and D-dimer were 2.04 (sensitivity, 0.59; specificity, 0.9; area under the ROC curve [AUC], 0.749; P < .001), 52.94 (sensitivity, 0.73; specificity, 0.95; AUC, 0.829; P < .001), 176.66 U/mL (sensitivity, 0.7; specificity, 0.9; AUC, 0.794; P < .001), and 1.18 mg/L (sensitivity, 0.82; specificity, 0.9; AUC, 0.845; P < .001), respectively. Positive TNFAIP3/A20 expression was considered as an inclusion criterion. Serum CA19-9 expression was related with lymph node metastasis (P = .010), tumor-lymph node-metastasis (TNM) stage (P < .001), and survival rate (P < .001). D-dimer was correlated with tumor differentiation grade (P = .014), tumor size (P = .045), TNM stage (P < .001), and survival rate (P < .001). TNFAIP3/A20 was correlated with tumor differentiation grade (P < .001), body mass index (BMI) (P < .001), TNM stage (P = .014), and survival rate (P < .001). Kaplan-Meier curves showed that PDAC patients had significant differences in CA19-9, D-dimer, and TNFAIP3/A20 expressions (P < .05). CA19-9, D-dimer, TNM stage, tumor differentiation grade, and TNFAIP3/A20 were independent prognostic markers for PDAC in univariate and multivariate COX analyses.CA19-9, D-dimer, and TNFAIP3/A20 were found to be independent prognostic markers for PDAC patients.


Assuntos
Biomarcadores Tumorais/sangue , Antígeno CA-19-9/sangue , Carcinoma Ductal Pancreático/mortalidade , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Plaquetas/patologia , Carcinoma Ductal Pancreático/sangue , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/cirurgia , China/epidemiologia , Feminino , Humanos , Metástase Linfática/patologia , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias/métodos , Neutrófilos/patologia , Prognóstico , Curva ROC , Sensibilidade e Especificidade , Taxa de Sobrevida
2.
Cell Death Dis ; 12(1): 50, 2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33414384

RESUMO

Novel coronavirus disease 2019 (COVID-19) is associated with a hypercoagulable state, characterized by abnormal coagulation parameters and by increased incidence of cardiovascular complications. With this study, we aimed to investigate the activation state and the expression of transmembrane proteins in platelets of hospitalized COVID-19 patients. We investigated transmembrane proteins expression with a customized mass cytometry panel of 21 antibodies. Platelets of 8 hospitalized COVID-19 patients not requiring intensive care support and without pre-existing conditions were compared to platelets of healthy controls (11 donors) with and without in vitro stimulation with thrombin receptor-activating peptide (TRAP). Mass cytometry of non-stimulated platelets detected an increased surface expression of activation markers P-Selectin (0.67 vs. 1.87 median signal intensity for controls vs. patients, p = 0.0015) and LAMP-3 (CD63, 0.37 vs. 0.81, p = 0.0004), the GPIIb/IIIa complex (4.58 vs. 5.03, p < 0.0001) and other adhesion molecules involved in platelet activation and platelet-leukocyte interactions. Upon TRAP stimulation, mass cytometry detected a higher expression of P-selectin in COVID-19 samples compared to controls (p < 0.0001). However, we observed a significantly reduced capacity of COVID-19 platelets to increase the expression of activation markers LAMP-3 and P-Selectin upon stimulation with TRAP. We detected a hyperactivated phenotype in platelets during SARS-CoV-2 infection, consisting of highly expressed platelet activation markers, which might contribute to the hypercoagulopathy observed in COVID-19. In addition, several transmembrane proteins were more highly expressed compared to healthy controls. These findings support research projects investigating antithrombotic and antiplatelet treatment regimes in COVID-19 patients, and provide new insights on the phenotypical platelet expression during SARS-CoV-2 infection.


Assuntos
Plaquetas/patologia , Leucócitos/patologia , Trombose/epidemiologia , Adulto , Plaquetas/metabolismo , Plaquetas/virologia , /virologia , Estudos de Casos e Controles , Feminino , Alemanha/epidemiologia , Humanos , Leucócitos/metabolismo , Leucócitos/virologia , Masculino , Pessoa de Meia-Idade , Selectina-P/metabolismo , Fragmentos de Peptídeos/metabolismo , Fenótipo , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Trombose/virologia
3.
Cells ; 10(1)2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33430260

RESUMO

Sars-Cov-2 infection causes fever and cough that may rapidly lead to acute respiratory distress syndrome (ARDS). Few biomarkers have been identified but, unfortunately, these are individually poorly specific, and novel biomarkers are needed to better predict patient outcome. The aim of this study was to evaluate the diagnostic performance of circulating platelets (PLT)-derived extracellular vesicles (EVs) as biomarkers for Sars-Cov-2 infection, by setting a rapid and reliable test on unmanipulated blood samples. PLT-EVs were quantified by flow cytometry on two independent cohorts of Sars-CoV-2+ (n = 69), Sars-Cov-2- (n = 62) hospitalized patients, and healthy controls. Diagnostic performance of PLT-EVs was evaluated by receiver operating characteristic (ROC) curve. PLT-EVs count were higher in Sars-Cov-2+ compared to Sars-Cov-2- patients or HC. ROC analysis of the combined cohorts showed an AUC = 0.79 and an optimal cut-off value of 1472 EVs/µL, with 75% sensitivity and 74% specificity. These data suggest that PLT-EVs might be an interesting biomarker deserving further investigations to test their predictive power.


Assuntos
Plaquetas/metabolismo , Vesículas Extracelulares/metabolismo , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Plaquetas/patologia , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes
4.
Medicine (Baltimore) ; 100(1): e24014, 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33429764

RESUMO

INTRODUCTION: As a hematopoietic carcinogen, benzene induces human leukemia through its active metabolites such as benzoquinone, which may cause oxidative damage to cancer-related nuclear genes by increasing reactive oxygen species (ROS). Mitochondrion is the main regulatory organelle of ROS, genetic abnormality of mitochondrion can impede its regulation of ROS, leading to more severe oxidative damage. Mutations have been related to certain types of cancer in several mitochondrial genes, but they have never been completely analyzed genome-wide in leukemia. PATIENT CONCERNS: The patient was a 52-year-old female who had chronic exposure to benzene for several years. Her symptoms mainly included recurrent dizziness, fatigue, and they had lasted for nearly 8 years and exacerbated in recent weeks before diagnosis. DIAGNOSIS: Samples of peripheral blood were taken from the patient using evacuated tubes with EDTA anticoagulant on the second day of her hospitalization. At the same time blood routine and BCR/ABL genes of leukemic phenotype were tested. Platelets were isolated for mitochondrial DNA (mtDNA) extraction. The genetic analysis of ATP synthase Fo subunit 8 (complex V), ATP synthase Fo subunit 6 (complex V), cytochrome c oxidase subunit 1 (complex IV), cytochrome c oxidase subunit 2 (complex IV), cytochrome c oxidase subunit 3, Cytb, NADH dehydrogenase subunit 1 (complex I) (ND) 1, ND2, ND3, ND4, ND5, ND6, 12S-RNA, 16S-RNA, tRNA-Cysteine, A, N, tRNA-Leucine, E, displacement loop in platelet mtDNA were performed. All the detected gene mutations were validated using the conventional Sanger sequencing method. INTERVENTIONS: The patient received imatinib, a small molecule kinase inhibitor, and symptomatic treatments. OUTCOMES: After 3 months treatment her blood routine test indicators were restored to normal. CONCLUSION: A total of 98 mutations were found, and 25 mutations were frame shift. The ND6 gene mutation rate was the highest among all mutation points. Frame shifts were identified in benzene-induced leukemia for the first time. Many mutations in the platelet mitochondrial genome were identified and considered to be potentially pathogenic in the female patient with benzene-induced leukemia. The mutation rate of platelet mitochondrial genome in the benzene-induced leukemia patient is relatively high, and the complete genome analysis is helpful to fully comprehend the disease characteristics.


Assuntos
Plaquetas/patologia , Leucemia/etiologia , Leucemia/genética , Mitocôndrias/genética , Antineoplásicos/uso terapêutico , Benzeno/efeitos adversos , Exposição Ambiental/efeitos adversos , Feminino , Genoma Mitocondrial/genética , Genoma Mitocondrial/fisiologia , Humanos , Mesilato de Imatinib/uso terapêutico , Pessoa de Meia-Idade , Mitocôndrias/fisiologia
5.
PLoS One ; 15(12): e0243928, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33338056

RESUMO

BACKGROUND: Circulating tumour cells (CTCs) represent a morphologically distinct subset of cancer cells, which aid the metastatic spread. The ExPeCT trial aimed to examine the effectiveness of a structured exercise programme in modulating levels of CTCs and platelet cloaking in patients with metastatic prostate cancer. METHODS: Participants (n = 61) were randomised into either standard care (control) or exercise arms. Whole blood was collected for all participants at baseline (T0), three months (T3) and six months (T6), and analysed for the presence of CTCs, CTC clusters and platelet cloaking. CTC data was correlated with clinico-pathological information. RESULTS: Changes in CTC number were observed within group over time, however no significant difference in CTC number was observed between groups over time. Platelet cloaking was identified in 29.5% of participants. A positive correlation between CTC number and white cell count (WCC) was observed (p = 0.0001), in addition to a positive relationship between CTC clusters and PSA levels (p = 0.0393). CONCLUSION: The presence of platelet cloaking has been observed in this patient population for the first time, in addition to a significant correlation between CTC number and WCC. TRIAL REGISTRATION: ClincalTrials.gov identifier NCT02453139.


Assuntos
Biomarcadores Tumorais/sangue , Plaquetas/metabolismo , Células Neoplásicas Circulantes/metabolismo , Neoplasias da Próstata/sangue , Idoso , Plaquetas/patologia , Contagem de Células , Humanos , Masculino , Metástase Neoplásica , Células Neoplásicas Circulantes/patologia , Prognóstico , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia
6.
Nat Commun ; 11(1): 5778, 2020 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-33188196

RESUMO

Breakdown of vascular barriers is a major complication of inflammatory diseases. Anucleate platelets form blood-clots during thrombosis, but also play a crucial role in inflammation. While spatio-temporal dynamics of clot formation are well characterized, the cell-biological mechanisms of platelet recruitment to inflammatory micro-environments remain incompletely understood. Here we identify Arp2/3-dependent lamellipodia formation as a prominent morphological feature of immune-responsive platelets. Platelets use lamellipodia to scan for fibrin(ogen) deposited on the inflamed vasculature and to directionally spread, to polarize and to govern haptotactic migration along gradients of the adhesive ligand. Platelet-specific abrogation of Arp2/3 interferes with haptotactic repositioning of platelets to microlesions, thus impairing vascular sealing and provoking inflammatory microbleeding. During infection, haptotaxis promotes capture of bacteria and prevents hematogenic dissemination, rendering platelets gate-keepers of the inflamed microvasculature. Consequently, these findings identify haptotaxis as a key effector function of immune-responsive platelets.


Assuntos
Plaquetas/patologia , Vasos Sanguíneos/patologia , Quimiotaxia , Inflamação/patologia , Pneumonia/sangue , Complexo 2-3 de Proteínas Relacionadas à Actina/metabolismo , Adulto , Animais , Movimento Celular , Microambiente Celular , Modelos Animais de Doenças , Fibrinogênio/metabolismo , Humanos , Lipopolissacarídeos , Lesão Pulmonar/microbiologia , Lesão Pulmonar/patologia , Staphylococcus aureus Resistente à Meticilina/fisiologia , Camundongos Endogâmicos C57BL , Microvasos/patologia , Pneumonia/microbiologia , Pseudópodes/metabolismo
7.
Int J Mol Sci ; 21(21)2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33153161

RESUMO

Progressive respiratory failure is seen as a major cause of death in severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2)-induced infection. Relatively little is known about the associated morphologic and molecular changes in the circulation of these patients. In particular, platelet and erythrocyte pathology might result in severe vascular issues, and the manifestations may include thrombotic complications. These thrombotic pathologies may be both extrapulmonary and intrapulmonary and may be central to respiratory failure. Previously, we reported the presence of amyloid microclots in the circulation of patients with coronavirus disease 2019 (COVID-19). Here, we investigate the presence of related circulating biomarkers, including C-reactive protein (CRP), serum ferritin, and P-selectin. These biomarkers are well-known to interact with, and cause pathology to, platelets and erythrocytes. We also study the structure of platelets and erythrocytes using fluorescence microscopy (using the markers PAC-1 and CD62PE) and scanning electron microscopy. Thromboelastography and viscometry were also used to study coagulation parameters and plasma viscosity. We conclude that structural pathologies found in platelets and erythrocytes, together with spontaneously formed amyloid microclots, may be central to vascular changes observed during COVID-19 progression, including thrombotic microangiopathy, diffuse intravascular coagulation, and large-vessel thrombosis, as well as ground-glass opacities in the lungs. Consequently, this clinical snapshot of COVID-19 strongly suggests that it is also a true vascular disease and considering it as such should form an essential part of a clinical treatment regime.


Assuntos
Plaquetas/patologia , Doenças Cardiovasculares/virologia , Infecções por Coronavirus/sangue , Infecções por Coronavirus/patologia , Eritrócitos/patologia , Ferritinas/sangue , Selectina-P/sangue , Pneumonia Viral/sangue , Pneumonia Viral/patologia , Betacoronavirus/isolamento & purificação , Coagulação Sanguínea/fisiologia , Plaquetas/virologia , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/patologia , Infecções por Coronavirus/virologia , Eritrócitos/virologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/virologia , Trombose/patologia , Trombose/virologia
8.
J Stroke Cerebrovasc Dis ; 29(11): 105205, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33066901

RESUMO

BACKGROUND: As access to patient emboli is limited, embolus analogs (EAs) have become critical to the research of large vessel occlusion (LVO) stroke and the development of thrombectomy technology. To date, techniques for fabricating standardized human blood-derived EAs are limited in the variety of compositions, and the mechanical properties relevant to thrombectomy are not quantified. METHODS: EAs were made by mixing human banked red blood cells (RBCs), plasma, and platelet concentrate in 10 different volumetric percentage combinations to mimic the broad range of patient emboli causing LVO strokes. The samples underwent histologic analysis and tensile testing to mimic the pulling action of thrombectomy devices, and were compared to patient emboli. RESULTS: EAs had histologic compositions of 0-96% RBCs, 0.78%-92% fibrin, and 2.1%-22% platelets, which can be correlated with the ingredients using a regression model. At fracture, EAs elongated from 81% to 136%, and the ultimate tensile stress ranged from 16 to 949 kPa. These EAs' histologic compositions and tensile properties showed great similarity to those of emboli retrieved from LVO stroke patients, indicating the validity of such EA fabrication methods. EAs with lower RBC and higher fibrin contents are more extensible and can withstand higher tensile stress. CONCLUSIONS: EAs fabricated and tested using the proposed new methods provide a platform for stroke research and pre-clinical development of thrombectomy devices.


Assuntos
Plaquetas/metabolismo , Eritrócitos/metabolismo , Fibrina/metabolismo , Embolia Intracraniana/sangue , Plasma/metabolismo , Acidente Vascular Cerebral/sangue , Pesquisa Médica Translacional/métodos , Fenômenos Biomecânicos , Plaquetas/patologia , Eritrócitos/patologia , Humanos , Embolia Intracraniana/patologia , Estresse Mecânico , Acidente Vascular Cerebral/patologia , Resistência à Tração
9.
Anticancer Res ; 40(10): 5715-5725, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988897

RESUMO

BACKGROUND/AIM: The platelet distribution width (PDW) and serum C-reactive protein (CRP) levels are known to be predictive of prognosis in various malignancies. Our aim was to determine whether combining PDW and serum CRP levels produces a prognostic indicator for esophageal cancer (EC) patients. PATIENTS AND METHODS: A total of 168 EC patients who underwent neoadjuvant therapy prior to esophagectomy were included in this study. RESULTS: We defined a combined PDW and CRP (CPC) score as follows: patients with both low pretherapeutic PDW (≤12.4 fl) and high postoperative serum CRP levels (≥0.5 mg/dl) were assigned a score of 2, while patients with one or neither of those were assigned a score of 1 or 0. A multivariable analysis showed that the CPC score was a significant risk factor for overall (p=0.006) and recurrence-free (p=0.004) survival. CONCLUSION: The CPC score is a strong prognostic indicator in EC patients.


Assuntos
Plaquetas/metabolismo , Proteína C-Reativa/metabolismo , Neoplasias Esofágicas/sangue , Prognóstico , Idoso , Plaquetas/patologia , Carcinoma de Células Escamosas , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Esofagectomia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Fatores de Risco
10.
J Clin Invest ; 130(11): 5674-5676, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-32925166

RESUMO

In a stunningly short period of time, the unexpected coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has turned the unprepared world topsy-turvy. Although the rapidity with which the virus struck was indeed overwhelming, scientists throughout the world have been up to the task of deciphering the mechanisms by which SARS-CoV-2 induces the multisystem and multiorgan inflammatory responses that, collectively, contribute to the high mortality rate in affected individuals. In this issue of the JCI, Skendros and Mitsios et al. is one such team who report that the complement system plays a substantial role in creating the hyperinflammation and thrombotic microangiopathy that appear to contribute to the severity of COVID-19. In support of the hypothesis that the complement system along with neutrophils and platelets contributes to COVID-19, the authors present empirical evidence showing that treatment with the complement inhibitor compstatin Cp40 inhibited the expression of tissue factor in neutrophils. These results confirm that the complement axis plays a critical role and suggest that targeted therapy using complement inhibitors is a potential therapeutic option to treat COVID-19-induced inflammation.


Assuntos
Betacoronavirus/metabolismo , Ativação do Complemento/efeitos dos fármacos , Infecções por Coronavirus , Pandemias , Peptídeos Cíclicos/farmacologia , Pneumonia Viral , Tromboplastina/biossíntese , Microangiopatias Trombóticas , Plaquetas/metabolismo , Plaquetas/patologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/patologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Inflamação/virologia , Neutrófilos/metabolismo , Neutrófilos/patologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/metabolismo , Pneumonia Viral/patologia , Índice de Gravidade de Doença , Microangiopatias Trombóticas/tratamento farmacológico , Microangiopatias Trombóticas/metabolismo , Microangiopatias Trombóticas/patologia , Microangiopatias Trombóticas/virologia
11.
J Cancer Res Ther ; 16(4): 731-736, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32930111

RESUMO

Background: Chronic state of inflammation is an important factor in advanced cancer which is used by tumor cells for maintaining survival and growth. Hematological parameters such as neutrophil/lymphocyte ratio (NLR), thrombocyte/lymphocyte ratio (TLR), and lymphocyte/monocyte ratio (LMR) are reliable indicators of systemic inflammation. We aimed to elucidate the effect of hematological parameters and clinical features of patients on the prognosis of advanced-stage non-small cell lung cancer (NSCLC). Methods: We included 102 Stage IV NSCLC patients who presented to the oncology clinic between 2010 and 2016. Pretreatment clinical parameters and NLR, TLR, and LMR were retrieved from the medical records. The cutoff values, calculated with receiver operating curve analysis, for NLR, LMR, and TLR were 2.5, 3, and 183, respectively. All patients were divided into two groups according to cutoff values and analyzed accordingly. Results: Median overall survival and progression-free survival were 10 and 6 months, respectively. In univariate analysis, high NLR, high TLR, and low LMR were found to be significantly associated with survival. Among clinical parameters having eastern cooperative oncology group performance score 0-1, older age (≥70 years) single metastatic disease was prognostic. In multivariate Cox regression analysis, only the number of metastatic lesions and LMR were found to be independent predictors for survival. Conclusion: Among hematological parameters, only LMR was found to be an independent predictor of survival in patients with advanced-stage NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Inflamação/sangue , Neoplasias Pulmonares/patologia , Neutrófilos/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/imunologia , Plaquetas/imunologia , Plaquetas/patologia , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/imunologia , Feminino , Humanos , Inflamação/patologia , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/patologia , Metástase Neoplásica , Prognóstico , Estudos Retrospectivos
13.
Eur J Haematol ; 105(6): 741-750, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32749010

RESUMO

BACKGROUND: Abnormal coagulation parameters have been reported in COVID-19-infected patients. Although the underlying mechanism of COVID-19 coagulopathy remains unknown, it has been suggested to be a form of disseminated intravascular coagulation (DIC). OBJECTIVES: The aim of our study was to analyze the coagulation parameters of patients with COVID-19, determine whether coagulation factors consumption occurs and identify potential prognostic biomarkers of the disease. PATIENTS/METHODS: Blood samples from hospitalized patients with COVID-19 pneumonia were collected. We performed basic coagulation tests and quantification of coagulation factors and physiological inhibitor proteins. Laboratory data were compared with clinical data and outcomes. RESULTS: The study involved 206 patients (63.6% male). D-dimer was particularly elevated (median 450 ng/mL; IQR 222.5-957.3). Free protein S levels were below the normal range (median 56.6%; IQR: 43.6-68.9), and factor VIII showed an increasing trend (median 173.4%; IQR: 144.1-214.9). However, all coagulation factors were within normal limits. We found no correlation between abnormal coagulation parameters and thrombosis, except for higher D-dimer (HR 1.99; 95% CI 1.3-3.1; P = .002). CONCLUSIONS: COVID-19 is associated with coagulopathy that correlates with poor prognosis. However, we did not demonstrate a consumption of coagulation factors, as seen in DIC.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/complicações , Síndrome da Liberação de Citocina/complicações , Coagulação Intravascular Disseminada/complicações , Fator VIII/metabolismo , Pneumonia Viral/complicações , Trombose Venosa/complicações , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Testes de Coagulação Sanguínea , Plaquetas/patologia , Plaquetas/virologia , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/diagnóstico , Síndrome da Liberação de Citocina/mortalidade , Síndrome da Liberação de Citocina/virologia , Coagulação Intravascular Disseminada/diagnóstico , Coagulação Intravascular Disseminada/mortalidade , Coagulação Intravascular Disseminada/virologia , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Humanos , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Prognóstico , Proteína S/metabolismo , Estudos Retrospectivos , Índice de Gravidade de Doença , Análise de Sobrevida , Trombose Venosa/diagnóstico , Trombose Venosa/mortalidade , Trombose Venosa/virologia
14.
Circulation ; 142(12): 1176-1189, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32755393

RESUMO

BACKGROUND: Severe acute respiratory syndrome corona virus 2 infection causes severe pneumonia (coronavirus disease 2019 [COVID-19]), but the mechanisms of subsequent respiratory failure and complicating renal and myocardial involvement are poorly understood. In addition, a systemic prothrombotic phenotype has been reported in patients with COVID-19. METHODS: A total of 62 subjects were included in our study (n=38 patients with reverse transcriptase polymerase chain reaction-confirmed COVID-19 and n=24 non-COVID-19 controls). We performed histopathologic assessment of autopsy cases, surface marker-based phenotyping of neutrophils and platelets, and functional assays for platelet, neutrophil functions, and coagulation tests, as well. RESULTS: We provide evidence that organ involvement and prothrombotic features in COVID-19 are linked by immunothrombosis. We show that, in COVID-19, inflammatory microvascular thrombi are present in the lung, kidney, and heart, containing neutrophil extracellular traps associated with platelets and fibrin. Patients with COVID-19 also present with neutrophil-platelet aggregates and a distinct neutrophil and platelet activation pattern in blood, which changes with disease severity. Whereas cases of intermediate severity show an exhausted platelet and hyporeactive neutrophil phenotype, patients severely affected with COVID-19 are characterized by excessive platelet and neutrophil activation in comparison with healthy controls and non-COVID-19 pneumonia. Dysregulated immunothrombosis in severe acute respiratory syndrome corona virus 2 pneumonia is linked to both acute respiratory distress syndrome and systemic hypercoagulability. CONCLUSIONS: Taken together, our data point to immunothrombotic dysregulation as a key marker of disease severity in COVID-19. Further work is necessary to determine the role of immunothrombosis in COVID-19.


Assuntos
Infecções por Coronavirus/diagnóstico , Pneumonia Viral/diagnóstico , Insuficiência Respiratória/etiologia , Betacoronavirus/genética , Betacoronavirus/isolamento & purificação , Transtornos da Coagulação Sanguínea/diagnóstico , Transtornos da Coagulação Sanguínea/etiologia , Plaquetas/citologia , Plaquetas/metabolismo , Plaquetas/patologia , Estudos de Casos e Controles , Infecções por Coronavirus/complicações , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Armadilhas Extracelulares/metabolismo , Humanos , Rim/patologia , Pulmão/patologia , Neutrófilos/citologia , Neutrófilos/metabolismo , Neutrófilos/patologia , Pandemias , Fenótipo , Ativação Plaquetária , Pneumonia Viral/complicações , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Insuficiência Respiratória/diagnóstico , Índice de Gravidade de Doença , Trombose/complicações , Trombose/diagnóstico
15.
Adv Biol Regul ; 77: 100735, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32773098

RESUMO

The novel Corona virus infection (Covid-19) first identified in China in December 2019 has rapidly progressed in pandemic leading to significant mortality and unprecedented challenge for healthcare systems. Although the clinical spectrum of Covid-19 is variable, acute respiratory failure and systemic coagulopathy are common in severe Covid-19 patients. Lung is an important target of the SARS-CoV-2 virus causing eventually acute respiratory distress syndrome associated to a thromboinflammatory state. The cytokinic storm, thromboinflammation and pulmonary tropism are the bedrock of tissue lesions responsible for acute respiratory failure and for prolonged infection that may lead to multiple organ failure and death. The thrombogenicity of this infectious disease is illustrated by the high frequency of thromboembolic events observed even in Covid-19 patients treated with anticoagulation. Increased D-Dimers, a biomarker reflecting activation of hemostasis and fibrinolysis, and low platelet count (thrombocytopenia) are associated with higher mortality in Covid-19 patients. In this review, we will summarize our current knowledge on the thromboembolic manifestations, the disturbed hemostatic parameters, and the thromboinflammatory conditions associated to Covid-19 and we will discuss the modalities of anticoagulant treatment or other potential antithrombotic options.


Assuntos
Anticoagulantes/uso terapêutico , Betacoronavirus/patogenicidade , Infecções por Coronavirus/complicações , Síndrome da Liberação de Citocina/complicações , Coagulação Intravascular Disseminada/complicações , Pneumonia Viral/complicações , Embolia Pulmonar/complicações , Insuficiência Respiratória/complicações , Doença Aguda , Biomarcadores/sangue , Plaquetas/efeitos dos fármacos , Plaquetas/patologia , Plaquetas/virologia , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/diagnóstico , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/virologia , Coagulação Intravascular Disseminada/diagnóstico , Coagulação Intravascular Disseminada/tratamento farmacológico , Coagulação Intravascular Disseminada/virologia , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Heparina/uso terapêutico , Interações Hospedeiro-Patógeno , Humanos , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/tratamento farmacológico , Embolia Pulmonar/virologia , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/tratamento farmacológico , Insuficiência Respiratória/virologia , Análise de Sobrevida
16.
Stroke ; 51(9): 2810-2816, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32811390

RESUMO

BACKGROUND AND PURPOSE: Identification of acute ischemic stroke (AIS) cause is crucial for guidance of secondary prevention. Previous studies have yielded inconsistent results regarding possible correlations between AIS cause and thrombus composition, as assessed by semiquantitative histological analysis. Here, we performed a correlation analysis between AIS cause and AIS thrombus cellular composition and content, as assessed using quantitative biochemical assays. METHODS: Homogenates of 250 patients with AIS thrombi were prepared by mechanical grinding. Platelet, red blood cell, and leukocyte content of AIS thrombi were estimated by quantification of GP (glycoprotein) VI, heme, and DNA in thrombus homogenates. AIS cause was defined as cardioembolic, noncardioembolic, or embolic stroke of undetermined source, according to the TOAST classification (Trial of ORG 10172 in Acute Stroke Treatment). RESULTS: Cardioembolic thrombi were richer in DNA (35.8 versus 13.8 ng/mg, P<0.001) and poorer in GPVI (0.104 versus 0.117 ng/mg, P=0.045) than noncardioembolic ones. The area under the receiver operating characteristic curve of DNA content to discriminate cardioembolic thrombi from noncardioembolic was 0.72 (95% CI, 0.63-0.81). With a threshold of 44.7 ng DNA/mg thrombus, 47% of thrombi from undetermined cause would be classified as cardioembolic with a specificity of 90%. CONCLUSIONS: Thrombus DNA content may provide an accurate biomarker for identification of cardioembolic thrombi in patients with AIS with embolic stroke of undetermined source. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03268668.


Assuntos
Isquemia Encefálica/genética , DNA/genética , Embolia/genética , Cardiopatias/genética , Trombose Intracraniana/genética , Acidente Vascular Cerebral/genética , Idoso , Idoso de 80 Anos ou mais , Contagem de Células Sanguíneas , Plaquetas/patologia , Isquemia Encefálica/sangue , Diagnóstico Diferencial , Embolia/complicações , Feminino , Cardiopatias/complicações , Humanos , Trombose Intracraniana/sangue , Trombose Intracraniana/etiologia , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Sensibilidade e Especificidade , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/etiologia
17.
Eur J Haematol ; 105(6): 773-778, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32794205

RESUMO

BACKGROUND: A lot remains unknown about the features and laboratory findings that may predict worse outcomes in patients with coronavirus disease 2019 (COVID-19). The aim of this study was to evaluate the difference in complete blood count parameters and differential counts in patients hospitalized with COVID-19 who survived compared to those who died. DESIGN: We performed a single-center retrospective study including 242 patients with confirmed COVID-19. We described the characteristics of the complete blood count parameters in these patients. Mann-Whitney U test was used to compare hematologic parameters of patients who died and those who survived; multivariate logistic regression was used to look for associations with mortality. RESULTS: Patients with COVID-19 who died had significantly lower median absolute monocyte count (AMC) (0.4 vs 0.5, P = .039) and median platelet count (169 vs 213, P = .009) compared to those who survived. Patients who died had a significantly higher neutrophil-to-lymphocyte ratio (6.4 vs 4.5, P = .001). The NLR was positively associated with death (OR = 1.038; 95% CI, 1.003-1.074, P = .031), while AMC was inversely associated with death (OR = 0.200; 95% CI, 0.052-0.761, P = .018). CONCLUSION: Among patients with COVID-19, a lower AMC and higher NLR are associated with higher mortality.


Assuntos
Betacoronavirus/patogenicidade , Plaquetas/patologia , Infecções por Coronavirus/diagnóstico , Linfócitos/patologia , Neutrófilos/patologia , Pneumonia Viral/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Contagem de Células Sanguíneas , Plaquetas/virologia , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Feminino , Humanos , Linfócitos/virologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/virologia , Pandemias , Pneumonia Viral/mortalidade , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Análise de Sobrevida
18.
PLoS One ; 15(8): e0236966, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32776968

RESUMO

Platelet-leukocyte aggregates (PLAs) are associated with increased thrombosis risk. The influence of PLA formation is especially important for cancer patients, since thrombosis accounts for approximately 10% of cancer-associated deaths. Our objective was to characterize and quantify PLAs in whole blood samples from lung cancer patients compared to healthy volunteers with the intent to analyze PLA formation in the context of lung cancer-associated thrombosis. Consenting lung cancer patients (57) and healthy volunteers (56) were enrolled at the Dana Cancer Center at the University of Toledo Health Science Campus. Peripheral blood samples were analyzed by flow cytometry. Patient medical history was reviewed through electronic medical records. Most importantly, we found lung cancer patients to have higher percentages of platelet-T cell aggregates (PTCAs) than healthy volunteers among both CD4+ T lymphocyte and CD8+ T lymphocyte populations. Our findings demonstrate that characterization of PTCAs may have clinical utility in differentiating lung cancer patients from healthy volunteers and stratifying lung cancer patients by history of thrombosis.


Assuntos
Plaquetas/patologia , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/complicações , Linfócitos T/patologia , Trombose/sangue , Trombose/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Estudos de Casos e Controles , Agregação Celular , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto Jovem
19.
Int J Hematol ; 112(6): 878-882, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32712863

RESUMO

A 66-year-old woman had experienced abnormal bleeding since the age of 7. Thrombocytopenia was not detected until she was 48, and immune thrombocytopenia was diagnosed at age 66. She also reported experiencing hearing disturbance since the age of 30 and acute renal failure since the age of 61 but reported no visual disturbance. Her younger son, who was 40 years old, also experienced abnormal bleeding since the age of 6, but immune thrombocytopenia was diagnosed as late as age 35. He had no other associated disorders. Laboratory examinations of both mother and son revealed a low platelet count (8000 and 29,000 µL, respectively), giant platelets and Döhle body-like granulocyte inclusion bodies. The mother had a high creatinine level (15.4 mg/dL) and normal liver enzyme levels. MYH9 genetic analysis identified a heterozygous mutation, c.101T>A, p.Val34Glu at exon 2 in both patients. These clinical and laboratory findings were consistent with a diagnosis of an MYH9-related disorder with different phenotypes observed in the same family. MYH9-related disorders were recognised in 2003, but were often misdiagnosed as immune thrombocytopenia, and hence, they have rarely been reported in Taiwan.


Assuntos
Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Mutação , Cadeias Pesadas de Miosina/genética , Púrpura Trombocitopênica Idiopática , Trombocitopenia/congênito , Adulto , Idoso , Biomarcadores/sangue , Plaquetas/patologia , Creatinina/sangue , Diagnóstico Diferencial , Feminino , Granulócitos/citologia , Granulócitos/patologia , Perda Auditiva Neurossensorial/sangue , Humanos , Corpos de Inclusão/patologia , Masculino , Pessoa de Meia-Idade , Relações Mãe-Filho , Fenótipo , Contagem de Plaquetas , Taiwan , Trombocitopenia/sangue , Trombocitopenia/diagnóstico , Trombocitopenia/genética
20.
Blood Adv ; 4(13): 2967-2978, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32609845

RESUMO

Thrombocytopenia is a common complication of influenza virus infection, and its severity predicts the clinical outcome of critically ill patients. The underlying cause(s) remain incompletely understood. In this study, in patients with an influenza A/H1N1 virus infection, viral load and platelet count correlated inversely during the acute infection phase. We confirmed this finding in a ferret model of influenza virus infection. In these animals, platelet count decreased with the degree of virus pathogenicity varying from 0% in animals infected with the influenza A/H3N2 virus, to 22% in those with the pandemic influenza A/H1N1 virus, up to 62% in animals with a highly pathogenic A/H5N1 virus infection. This thrombocytopenia is associated with virus-containing platelets that circulate in the blood. Uptake of influenza virus particles by platelets requires binding to sialoglycans and results in the removal of sialic acids by the virus neuraminidase, a trigger for hepatic clearance of platelets. We propose the clearance of influenza virus by platelets as a paradigm. These insights clarify the pathophysiology of influenza virus infection and show how severe respiratory infections, including COVID-19, may propagate thrombocytopenia and/or thromboembolic complications.


Assuntos
Plaquetas/virologia , Vírus da Influenza A/patogenicidade , Influenza Humana/complicações , Ácido N-Acetilneuramínico/metabolismo , Polissacarídeos/metabolismo , Trombocitopenia/etiologia , Animais , Plaquetas/metabolismo , Plaquetas/patologia , Modelos Animais de Doenças , Furões , Interações Hospedeiro-Patógeno , Humanos , Vírus da Influenza A Subtipo H1N1/patogenicidade , Vírus da Influenza A Subtipo H1N1/fisiologia , Vírus da Influenza A Subtipo H3N2/patogenicidade , Vírus da Influenza A Subtipo H3N2/fisiologia , Virus da Influenza A Subtipo H5N1/patogenicidade , Virus da Influenza A Subtipo H5N1/fisiologia , Vírus da Influenza A/fisiologia , Influenza Humana/metabolismo , Influenza Humana/patologia , Influenza Humana/virologia , Infecções por Orthomyxoviridae/complicações , Infecções por Orthomyxoviridae/metabolismo , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/virologia , Trombocitopenia/metabolismo , Trombocitopenia/patologia , Trombocitopenia/virologia , Internalização do Vírus
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