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1.
Eur Heart J ; 38(12): 877-887, 2017 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-27122600

RESUMO

The left atrial appendage (LAA) is the main source of thromboembolism in patients with non-valvular atrial fibrillation (AF). As such, the LAA can be the target of specific occluding device therapies. Optimal management of patients with AF includes a comprehensive knowledge of the many aspects related to LAA structure and thrombosis. Here we provide baseline notions on the anatomy and function of the LAA, and then focus on current imaging tools for the identification of anatomical varieties. We also describe pathogenetic mechanisms of LAA thrombosis in AF patients, and examine the available evidence on treatment strategies for LAA thrombosis, including the use of non-vitamin K antagonist oral anticoagulants and interventional approaches.


Assuntos
Tromboembolia/prevenção & controle , Apêndice Atrial/anatomia & histologia , Apêndice Atrial/embriologia , Apêndice Atrial/fisiologia , Fibrilação Atrial/complicações , Velocidade do Fluxo Sanguíneo/fisiologia , Ecocardiografia , Endotélio Vascular/fisiologia , Humanos , Angiografia por Ressonância Magnética , Dispositivo para Oclusão Septal , Acidente Vascular Cerebral/prevenção & controle , Oclusão Terapêutica/instrumentação , Oclusão Terapêutica/métodos , Tromboembolia/etiologia , Tomografia Computadorizada por Raios X
2.
Int J Cancer ; 140(3): 696-704, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-27784132

RESUMO

The hypothesis that increased oxidative stress in breast cancer (BC) patients could induce enhanced lipid peroxidation, which, in turn, would contribute to platelet activation and poor clinical outcome is attractive. To address this issue, we investigated pre-surgical urinary 8-iso-prostaglandin (PG)F2α (marker of in vivo oxidative stress) and 11-dehydro-thromboxane (TX)B2 (marker of in vivo platelet activation) levels in patients with primary BC (n = 115) compared with control women paired for comorbidities and their association with patients' metabolic profile and clinical prognostic factors. The results obtained showed that presurgical urinary excretion of both biomarkers was enhanced in BC patients compared to controls and was associated with patients' estrogen receptor (ER) expression, but not HER2 status or Ki67 proliferation index. Accordingly, both urinary biomarkers were increased in patients with luminal-like BC molecular subtypes compared with triple negative or HER2-enriched tumors. ER status was an independent predictor of 8-iso-PGF2α urinary levels, which, in turn, significantly predicted 11-dehydro-TXB2 urinary levels together with disease stage and ER status. The prognostic value of 11-dehydro-TXB2 was then evaluated showing a significant correlation with BC pathological response to neoadjuvant treatment. Furthermore, among relapsing patients, those with elevated urinary biomarker levels were more likely to develop distant metastasis rather than local recurrence. In conclusion, we may speculate that enhanced oxidative stress due to estrogen-related mechanisms might cause a condition of persistent platelet activation capable of sustaining BC growth and progression through the release of bioactive stored molecules, ultimately contributing to tumor invasiveness. Further studies specifically addressing this hypothesis are presently needed.


Assuntos
Neoplasias da Mama/patologia , Estresse Oxidativo/fisiologia , Ativação Plaquetária/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/urina , Neoplasias da Mama/metabolismo , Neoplasias da Mama/urina , Dinoprosta/análogos & derivados , Dinoprosta/urina , Feminino , Humanos , Peroxidação de Lipídeos/fisiologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/urina , Receptores de Estrogênio/metabolismo , Tromboxano B2/análogos & derivados , Tromboxano B2/urina
3.
Diabetologia ; 59(10): 2134-44, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27421726

RESUMO

AIMS/HYPOTHESIS: Activation of inflammatory pathways is involved in the pathogenesis of type 2 diabetes mellitus. On the basis of its role in vascular inflammation and in metabolic disorders, we hypothesised that the TNF superfamily (TNFSF) member 14 (LIGHT/TNFSF14) could be involved in the pathogenesis of type 2 diabetes mellitus. METHODS: Plasma levels of LIGHT were measured in two cohorts of type 2 diabetes mellitus patients (191 Italian and 40 Norwegian). Human pancreatic islet cells and arterial endothelial cells were used to explore regulation and relevant effects of LIGHT in vitro. RESULTS: Our major findings were: (1) in both diabetic cohorts, plasma levels of LIGHT were significantly raised compared with sex- and age-matched healthy controls (n = 32); (2) enhanced release from activated platelets seems to be an important contributor to the raised LIGHT levels in type 2 diabetes mellitus; (3) in human pancreatic islet cells, inflammatory cytokines increased the release of LIGHT and upregulated mRNA and protein levels of the LIGHT receptors lymphotoxin ß receptor (LTßR) and TNF receptor superfamily member 14 (HVEM/TNFRSF14); (4) in these cells, LIGHT attenuated the insulin release in response to high glucose at least partly via pro-apoptotic effects; and (5) in human arterial endothelial cells, glucose boosted inflammatory response to LIGHT, accompanied by an upregulation of mRNA levels of HVEM (also known as TNFRSF14) and LTßR (also known as LTBR). CONCLUSIONS/INTERPRETATION: Our findings show that patients with type 2 diabetes mellitus are characterised by increased plasma LIGHT levels. Our in vitro findings suggest that LIGHT may contribute to the progression of type 2 diabetes mellitus by attenuating insulin secretion in pancreatic islet cells and by contributing to vascular inflammation.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Inflamação/sangue , Inflamação/metabolismo , Ilhotas Pancreáticas/metabolismo , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Idoso , Western Blotting , Diabetes Mellitus Tipo 2/genética , Células Endoteliais/metabolismo , Células Endoteliais/fisiologia , Feminino , Humanos , Inflamação/genética , Insulina/metabolismo , Ilhotas Pancreáticas/fisiopatologia , Leucócitos Mononucleares/metabolismo , Receptor beta de Linfotoxina/genética , Receptor beta de Linfotoxina/metabolismo , Masculino , Pessoa de Meia-Idade , RNA Mensageiro , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética
4.
J Biol Chem ; 290(6): 3592-600, 2015 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-25505240

RESUMO

Regulatory mechanisms of ALX/FPR2, the lipoxin A4 receptor, expression have considerable relevance in inflammation resolution. Because microRNAs (miRs) are emerging as key players in inflammation resolution, here we examined microRNA-mediated regulation of ALX/FPR2 (lipoxin A4 receptor/formyl peptide receptor 2) expression. By matching data from bioinformatic algorithms, we found 27 miRs predicted to bind the 3'-UTR of ALX/FPR2. Among these, we selected miR-181b because of its link with inflammation. Using a luciferase reporter system, we assessed miR-181b binding to ALX/FPR2 3'-UTR. Consistent with this, miR-181b overexpression in human macrophages significantly down-regulated ALX/FPR2 protein levels (-25%), whereas miR-181b knockdown gave a significant increase in ALX/FPR2 (+60%). miR-181b levels decreased during monocyte to macrophage differentiation (-50%), whereas ALX/FPR2 expression increased significantly (+60%). miR-181b overexpression blunted lipoxin A4 (0.1-10 nm)- and resolvin D1 (0.01-10 nm)-stimulated phagocytic activity of macrophages. These results unravel novel regulatory mechanisms of ALX/FPR2 expression and ligand-evoked macrophages proresolution responses mediated by miR-181b, thus uncovering novel components of the endogenous inflammation resolution circuits.


Assuntos
Macrófagos/metabolismo , MicroRNAs/metabolismo , Receptores de Formil Peptídeo/metabolismo , Receptores de Lipoxinas/metabolismo , Transdução de Sinais , Regiões 3' não Traduzidas , Ácidos Docosa-Hexaenoicos/farmacologia , Humanos , Lipoxinas/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , MicroRNAs/genética , Fagocitose , Receptores de Formil Peptídeo/genética , Receptores de Lipoxinas/genética
5.
Circulation ; 132(20): 1891-7, 2015 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-26408273

RESUMO

BACKGROUND: Patients with a first episode of unprovoked venous thromboembolism have a high risk of recurrence after discontinuation of anticoagulant therapy. Extending anticoagulation reduces the risk of recurrence but is associated with increased bleeding. Sulodexide, a glycosaminoglycan, exerts antithrombotic and profibrinolytic actions with a low bleeding risk when administered orally, but its benefit for preventing recurrent venous thromboembolism is not well known. METHODS AND RESULTS: In this multicenter, double-blind study, 615 patients with first-ever unprovoked venous thromboembolism who had completed 3 to 12 months of oral anticoagulant treatment were randomly assigned to sulodexide 500 lipasemic units twice daily or placebo for 2 years, in addition to elastic stockings. The primary efficacy outcome was recurrence of venous thromboembolism. Major or clinically relevant bleeding was the primary safety outcome. Venous thromboembolism recurred in 15 of the 307 patients who received sulodexide and in 30 of the 308 patients who received placebo (hazard ratio, 0.49; 95% confidence interval [CI], 0.27-0.92; P=0.02). The analysis in which lost to follow-up was assigned to failure yielded a risk ratio among treated versus control subjects of 0.54 (95% confidence interval, 0.35-0.85; P=0.009). No major bleeding episodes occurred; 2 patients in each treatment group had a clinically relevant bleeding episode. Adverse events were similar in the 2 groups. CONCLUSION: Sulodexide given after discontinuation of anticoagulant treatment reduced the risk of recurrence in patients with unprovoked venous thromboembolism, with no apparent increase of bleeding risk. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrialsregister.eu/. Identifier: EudraCT number 2009-016923-77.


Assuntos
Anticoagulantes/administração & dosagem , Glicosaminoglicanos/administração & dosagem , Prevenção Secundária/métodos , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/prevenção & controle , Adulto , Idoso , Método Duplo-Cego , Esquema de Medicação , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva
6.
Cytokine ; 83: 269-274, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27180202

RESUMO

BACKGROUND: The pathophysiological hallmark of Rickettsia conorii (R. conorii) infection comprises infection of endothelial cells with perivascular infiltration of T-cells and macrophages. Although interferon (IFN)-γ-induced protein 10 (IP-10)/CXCL10 is induced during vascular inflammation, data on CXCL10 in R. conorii infection is scarce. METHODS: Serum CXCL10 was analyzed in two cohorts of southern European patients with R. conorii infection using multiplex cytokine assays. The mechanism of R. conorii-induced CXCL10 release was examined ex vivo using human whole blood interacting with endothelial cells. RESULTS: (i) At admission, R. conorii infected patients had excessively increased CXCL10 levels, similar in the Italian (n=32, ∼56-fold increase vs controls) and the Spanish cohort (n=38, ∼68-fold increase vs controls), followed by a marked decrease after recovery. The massive CXCL10 increase was selective since it was not accompanied with similar changes in other cytokines. (ii) Heat-inactivated R. conorii induced a marked CXCL10 increase when whole blood and endothelial cells were co-cultured. Even plasma obtained from R. conorii-exposed whole blood induced a marked CXCL10 release from endothelial cells, comparable to the levels found in serum of R. conorii-infected patients. Bacteria alone did not induce CXCL10 production in endothelial cells, macrophages or smooth muscle cells. CONCLUSIONS: We show a massive and selective serum CXCL10 response in R. conorii-infected patients, likely reflecting release from infected endothelial cells characterized by infiltrating T cells and monocytes. The CXCL10 response could contribute to T-cell infiltration within the infected organ, but the pathologic consequences of CXCL10 in clinical R. conorii infection remain to be defined.


Assuntos
Febre Botonosa/sangue , Quimiocina CXCL10/biossíntese , Células Endoteliais/metabolismo , Rickettsia conorii , Adulto , Idoso , Idoso de 80 Anos ou mais , Febre Botonosa/patologia , Estudos de Coortes , Células Endoteliais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Monócitos/patologia , Linfócitos T/metabolismo , Linfócitos T/patologia
7.
Circ J ; 80(2): 502-11, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26632534

RESUMO

BACKGROUND: Circulating pentraxin 3 (PTX3), the main regulator of the inflammatory response, rapidly increases following cardiovascular events, and low PTX3 is associated with high body mass index. METHODS AND RESULTS: We conducted a 12-month longitudinal study, to test the hypothesis that laparoscopic adjustable gastric banding (LAGB)-induced weight loss was associated with changes in platelet activation markers and PTX3. Twelve obese patients, scheduled to undergo LAGB, were enrolled at the University Obesity Center. Urinary 11-dehydro-thromboxane (Tx)B2excretion rate was measured on radioimmunoassay, and PTX3 and CD40L were determined on immunoassay. Plasma PTX3 increased by 178.8 and 214.9% (P<0.0001), respectively, 6 and 12 months after LAGB. High-sensitivity CRP decreased by 24 and 29.7% (P<0.0001), whereas CD40L decreased by 64.3 and 58.6% (P=0.002), respectively. Urinary 11-dehydro-TxB2decreased from 1,443 to 715 and 564 pg/mg creatinine, respectively 6 months and 12 months after LAGB (P<0.0001). PTX3 was inversely related to platelet activation markers, 11-dehydro-TxB2and CD40L. Moreover, multiple regression analysis on pooled data showed that plasma PTX3 was an independent predictor of urinary 11-dehydro-TxB2. CONCLUSIONS: There is an association between inflammation, platelet activation and metabolic dysfunction in obesity, and PTX3 is a key player within these circuits.


Assuntos
Proteína C-Reativa/metabolismo , Derivação Gástrica , Obesidade/sangue , Obesidade/cirurgia , Ativação Plaquetária , Componente Amiloide P Sérico/metabolismo , Adulto , Ligante de CD40/sangue , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/urina , Tromboxano B2/análogos & derivados , Tromboxano B2/urina
8.
Prostaglandins Other Lipid Mediat ; 120: 28-39, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25986598

RESUMO

Platelet activation plays a key role in atherothrombosis in type 2 diabetes mellitus (T2DM) and increased in vivo platelet activation with enhanced thromboxane (TX) biosynthesis has been reported in patients with impairment of glucose metabolism even in the earlier stages of disease and in the preclinical phases. In this regards, platelets appear as addresses and players carrying and transducing metabolic derangement into vascular injury. The present review critically addresses key pathophysiological aspects including (i) hyperglycemia, glycemic variability and insulin resistance as determinants and predictors of platelet activation, (ii) inflammatory mediators derived from platelets, such as soluble CD40 ligand, soluble CD36, Dickkopf-1 and probably soluble receptor for advanced glycation-end-products (sRAGE), which expand the functional repertoire of platelets from players of hemostasis and thrombosis to powerful amplifiers of inflammation by promoting the release of cytokines and chemokines, cell activation, and cell-cell interactions; (iii) molecular mechanisms underpinning the less-than-expected antithrombotic protection by aspirin (ASA), despite regular antiplatelet prophylaxis at the standard dosing regimen, and (iv) stratification of patients deserving different antiplatelet strategies, based on the metabolic phenotype. Taken together, these pathophysiological aspects may contribute to the development of promising mechanism-based therapeutic strategies to reduce the progression of atherothrombosis in diabetic subjects.


Assuntos
Plaquetas , Diabetes Mellitus Tipo 2/sangue , Animais , Plaquetas/efeitos dos fármacos , Plaquetas/fisiologia , Doenças Cardiovasculares/complicações , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/fisiopatologia , Humanos , Estresse Oxidativo/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Inibidores da Agregação Plaquetária/uso terapêutico , Tromboxanos/metabolismo
9.
Eur Heart J ; 35(33): 2213-23b, 2014 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-25024407

RESUMO

Although the female gender is generally less represented in cardiovascular studies, observational and randomized investigations suggest that-compared with men-women may obtain different benefits from antiplatelet therapy. Multiple factors, including hormonal mechanisms and differences in platelet biology, might contribute to such apparent gender peculiarities. The thrombotic and bleeding risks, as well as outcomes after a cardiovascular event, appear to differ between genders, partly in relation to differences in age, comorbidities and body size. Equally, the benefits of antiplatelet therapy may differ in women compared with men in different vascular beds, during primary or secondary prevention and according to the type of an antiplatelet agent used. This document is an attempt to bring together current evidence, clinical practices and gaps of knowledge on gender-specific platelet function and antiplatelet therapy. On the basis of the available data, we provide suggestions on current indications of antiplatelet therapy for cardiovascular prevention in women with different clinical features; no strong recommendation may be given because the available data derive from observational studies or post hoc/subgroup analyses of randomized studies without systematic adjustments for baseline risk profiles.


Assuntos
Plaquetas/fisiologia , Inibidores da Agregação Plaquetária/uso terapêutico , Caracteres Sexuais , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/prevenção & controle , Efeitos Psicossociais da Doença , Angiopatias Diabéticas/prevenção & controle , Quimioterapia Combinada , Feminino , Hemorragia/etiologia , Humanos , Masculino , Testes de Função Plaquetária , Gravidez , Complicações Cardiovasculares na Gravidez/prevenção & controle , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/prevenção & controle , Trombose/etiologia , Resultado do Tratamento
10.
Pain Pract ; 15(7): 662-70, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25040199

RESUMO

INTRODUCTION: Several studies have documented increased cardiovascular risk factors, particularly hypercholesterolemia, in the migraine population with respect to controls. However, no studies have investigated the possible relationship between headache severity parameters and lipid serum levels. METHODS: This study evaluated the lipid asset in 52 migraine patients (17 with and 36 without aura) before and after treatment with drugs for migraine prophylaxis for 3 months. RESULTS: High frequency (HF, ≥ 8/month) and intensity (HI, ≥ 5 Numeric Rating Score) vs. low frequency (LF, < 8/month) and intensity (LI, < 5) of crises were associated with significantly higher cholesterol levels, both total (TC, HF vs. LF, P < 0.0001; HI vs. LI, P < 0.0001) and LDL (LDL-c, HF vs. LF, P < 0.0001, and HI vs. LI, P < 0.0001). In treated patients, a significant decrease in number and intensity of crises was associated with a significant reduction of TC and LDL-c (P < 0.001). A direct linear correlation was also found between frequency and intensity of crises and lipid levels (TC/frequency, P < 0.0001; TC/intensity, P < 0.0001; LDL-c/frequency, P < 0.0001; LDL-c/intensity, P < 0.0001). No significant difference was found in the evaluated parameters for the subgroups of patients with and without aura. DISCUSSION: This study shows a significant positive association between migraine frequency and intensity with total and LDL cholesterol, demonstrating for the first time a significant reduction of these lipid parameters after migraine prophylaxis. However, in view of the retrospective design of the study and the small population size, these results should be considered as preliminary, to be confirmed by future prospective controlled trials.


Assuntos
LDL-Colesterol/sangue , Transtornos de Enxaqueca/sangue , Transtornos de Enxaqueca/diagnóstico , Medição da Dor/métodos , Índice de Gravidade de Doença , Adulto , Idoso , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco
11.
Oncologist ; 19(5): 562-7, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24710308

RESUMO

Reduced estimated glomerular filtration rate (eGFR) has been associated with increased venous thromboembolism (VTE) risk in the general population. VTE incidence significantly increases in cancer patients, especially those undergoing chemotherapy. Despite the evidence that a substantial number of cancer patients have unrecognized renal impairment, as indicated by reduced eGFR in the presence of serum creatinine levels within the reference value, chemotherapy dosage is routinely adjusted for serum creatinine values. Among chemotherapies, platinum-based regimens are associated with the highest rates of VTE. A cohort study was designed to assess the value of pretreatment eGFR in the risk prediction of a first VTE episode in cancer outpatients without previous history of VTE who were scheduled for platinum-based chemotherapy. Methods. Serum creatinine and eGFR were evaluated before the start of standard platinum-based chemotherapy in a cohort of 322 consecutive patients with primary or relapsing/recurrent solid cancers, representative of a general practice population. Results. Patients who experienced a first VTE episode in the course of chemotherapy had lower mean eGFR values compared with patients who remained VTE free. Multivariate Cox analysis demonstrated that eGFR had an independent value for risk prediction of a first VTE episode during treatment, with a 3.15 hazard ratio. Indeed, 14% of patients with reduced eGFR had VTE over 1-year follow-up compared with 6% of patients with normal eGFR values. Conclusion. The results suggest that reductions in eGFR, even in the presence of normal serum creatinine, are associated with an increased VTE risk in cancer outpatients undergoing platinum-based chemotherapy regimens. Determining eGFR before chemotherapy could represent a simple predictor of VTE, at no additional cost to health care systems.


Assuntos
Taxa de Filtração Glomerular/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Compostos de Platina/efeitos adversos , Tromboembolia Venosa/induzido quimicamente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Estudos de Coortes , Creatinina/sangue , Feminino , Humanos , Rim/patologia , Masculino , Pessoa de Meia-Idade , Compostos de Platina/uso terapêutico , Adulto Jovem
12.
Haematologica ; 99(10): 1638-44, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25085351

RESUMO

Mean platelet volume has been proposed as a predictor for venous thromboembolism in cancer. We, therefore, investigated the effects of different anti-cancer drugs on mean platelet volume in order to assess its possible value in the risk prediction of a first thromboembolic episode in cancer outpatients during treatment. Pre-treatment mean platelet volumes were retrospectively evaluated in 589 ambulatory patients at the beginning of a new chemotherapy regimen. Moreover, serial changes were evaluated at baseline and before each chemotherapy cycle on 385 of the 589 patients who consented to have additional blood withdrawals during treatment. Cox proportional hazards survival analysis demonstrated a 2.7 hazard ratio (P=0.01) of developing a first venous thromboembolic episode during chemotherapy for patients with baseline mean platelet volumes below the 10(th) percentile (<7.3 fL). This index significantly declined during the first three months of chemotherapy (-6%; P<0.0001) reverting to baseline at the end of treatment. Multivariate regression analysis showed that normal baseline volumes (P=0.012) and platinum-based regimens (P=0.017) were both independent predictors of mean platelet volume decline during chemotherapy which, in turn, was associated with a 2.4 hazard ratio (P=0.044) of venous thromboembolism. In conclusion, low pre-chemotherapy mean platelet volume might be regarded as a predictor of increased venous thromboembolism risk in cancer patients and chemotherapy further decreases platelet volumes, possibly due to drug-induced platelet activation and destruction. Changes in mean platelet volumes during chemotherapy might provide additional information on thromboembolic risk of patients treated with anti-cancer drugs, particularly platinum compounds.


Assuntos
Volume Plaquetário Médio , Neoplasias/complicações , Tromboembolia Venosa/sangue , Tromboembolia Venosa/etiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Neoplasias/mortalidade , Prognóstico , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/mortalidade , Adulto Jovem
13.
BMC Infect Dis ; 14: 70, 2014 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-24507453

RESUMO

BACKGROUND: Based on their essential role in concerting immunological and inflammatory responses we hypothesized that the homeostatic chemokines CCL19 and CCL21 may play a pathogenic role in rickettsiae infection. METHODS: Serum levels of CCL19 and CCL21 in patients with R. africae and R. conorii infection were analyzed by enzyme immunoassays. Lungs from R. conorii infected mice were examined for CCL19, CCL21 and CCR7 expression by immunohistochemistry. RESULTS: We found that patients with R. africae infection (n = 15) and in particular those with R. conorii infection (n = 16) had elevated serum levels of CCL19 on admission, with a decline during follow-up. While a similar pattern was seen for CCL21 in R. africae infection, patients with R. conorii infection showed persistently increased CCL21 levels during follow-up. In experimental R. conorii infection, we found strong immunostaining of CCL19 and CCL21 in the lungs, particularly in individuals that had received lethal doses. Immunofluorescence showed co-localization of CCR7 to endothelial cells, macrophages and fibroblasts within the lung tissue of R. conorii infected mice. CONCLUSIONS: Our findings suggest that the CCL19/CCL21/CCR7 axis is up-regulated during R. africae and in particular during R. conorii infection, which may potentially contribute to the pathogenesis of these disorders.


Assuntos
Quimiocina CCL19/sangue , Quimiocina CCL21/sangue , Infecções por Rickettsia/sangue , Rickettsia conorii/fisiologia , Adulto , Idoso , Animais , Quimiocina CCL19/genética , Quimiocina CCL21/genética , Feminino , Homeostase , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C3H , Pessoa de Meia-Idade , Receptores CCR7/sangue , Receptores CCR7/genética , Infecções por Rickettsia/genética , Infecções por Rickettsia/microbiologia , Regulação para Cima , Adulto Jovem
14.
Blood ; 115(5): 1054-61, 2010 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-19887674

RESUMO

We tested whether cyclooxygenase 2 (COX-2) expression and unacetylated COX-1 in newly formed platelets might contribute to persistent thromboxane (TX) biosynthesis in aspirin-treated essential thrombocythemia (ET). Forty-one patients on chronic aspirin (100 mg/day) and 24 healthy subjects were studied. Platelet COX-2 expression was significantly increased in patients and correlated with thiazole orange-positive platelets (r = 0.71, P < .001). The rate of TXA(2) biosynthesis in vivo, as reflected by urinary 11-dehydro-TXB(2) (TXM) excretion, and the maximal biosynthetic capacity of platelets, as reflected by serum TXB(2), were higher in patients compared with aspirin-treated healthy volunteers. Serum TXB(2) was significantly reduced by the selective COX-2 inhibitor NS-398 added in vitro. Patients were randomized to adding the selective COX-2 inhibitor, etoricoxib, or continuing aspirin for 7 days. Etoricoxib significantly reduced by approximately 25% TXM excretion and serum TXB(2). Fourteen of the 41 patients were studied again 21 (+/- 7) months after the first visit. Serum TXB(2) was consistently reduced by approximately 30% by adding NS398 in vitro, while it was completely suppressed with 50 microM aspirin. Accelerated platelet regeneration in most aspirin-treated ET patients may explain aspirin-persistent TXA(2) biosynthesis through enhanced COX-2 activity and faster renewal of unacetylated COX-1. These findings may help in reassessing the optimal antiplatelet strategy in ET.


Assuntos
Aspirina/uso terapêutico , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Piridinas/uso terapêutico , Sulfonas/uso terapêutico , Trombocitemia Essencial/tratamento farmacológico , Tromboxanos/biossíntese , Adulto , Inibidores de Ciclo-Oxigenase/uso terapêutico , Quimioterapia Combinada , Etoricoxib , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/uso terapêutico , Trombocitemia Essencial/metabolismo , Trombocitemia Essencial/patologia , Tromboxano A2/biossíntese , Tromboxano A2/sangue , Tromboxano A2/urina , Tromboxano B2/análogos & derivados , Tromboxano B2/biossíntese , Tromboxano B2/sangue , Tromboxano B2/urina , Tromboxanos/sangue , Tromboxanos/urina , Resultado do Tratamento
15.
Prostaglandins Other Lipid Mediat ; 98(3-4): 48-55, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22330860

RESUMO

Atherothrombosis is a leading cause of death in patients with diabetes mellitus. Among factors contributing to the diabetic prothrombotic state, platelet activation plays a pivotal role. Numerous studies have investigated the benefits of antiplatelet therapy for primary and secondary cardiovascular prevention in diabetic patients. However, there are limited evidences that low-dose aspirin may be effective in this clinical setting. Several disease-specific factors have been identified as potential determinants of aspirin treatment failure. In this review, the main determinants of interindividual variability in response to antiplatelet agents are discussed, with particular emphasis on the pharmacokinetic and pharmacodynamic mechanisms of clinical efficacy and safety of antiplatelet drugs in patients with diabetes mellitus.


Assuntos
Diabetes Mellitus/tratamento farmacológico , Inibidores da Agregação Plaquetária/uso terapêutico , Complicações do Diabetes/tratamento farmacológico , Diabetes Mellitus/prevenção & controle , Humanos , Trombose/complicações , Trombose/tratamento farmacológico , Tromboxanos/metabolismo , Resultado do Tratamento
16.
Handb Exp Pharmacol ; (210): 261-86, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22918735

RESUMO

Atherothrombosis is the major cause of mortality and morbidity in Western countries. Several clinical conditions are characterized by increased incidence of cardiovascular events and enhanced thromboxane (TX)-dependent platelet activation. Enhanced TX generation may be explained by mechanisms relatively insensitive to aspirin. More potent drugs possibly overcoming aspirin efficacy may be desirable. Thromboxane synthase inhibitors (TXSI) and thromboxane receptor antagonists (TXRA) have the potential to prove more effective than aspirin due to their different mechanism of action along the pathway of TXA(2). TXSI prevent the conversion of PGH(2) to TXA(2), reducing TXA(2) synthesis mainly in platelets, whereas TXRA block the downstream consequences of TXA(2) receptors (TP) activation.TXA(2) is a potent inducer of platelet activation through its interaction with TP on platelets. TP are activated not only by TXA(2), but also by prostaglandin (PG) D(2), PGE(2), PGF(2α), PGH(2), PG endoperoxides (i.e., 20-HETE), and isoprostanes, all representing aspirin-insensitive mechanisms of TP activation. Moreover, TP are also expressed on several cell types such as macrophages or monocytes, and vascular endothelial cells, and exert antiatherosclerotic, antivasoconstrictive, and antithrombotic effects, depending on the cellular target.Thus, targeting TP receptor, a common downstream pathway for both platelet and extraplatelet TXA(2) as well as for endoperoxides and isoprostanes, may be a useful antiatherosclerotic and a more powerful antithrombotic intervention in clinical settings, such as diabetes mellitus, characterized by persistently enhanced thromboxane (TX)-dependent platelet activation through isoprostane formation and low-grade inflammation, leading to extraplatelet sources of TXA(2). Among TXRA, terutroban is an orally active drug in clinical development for use in secondary prevention of thrombotic events in cardiovascular disease. Despite great expectations on this drug supported by a large body of preclinical and clinical evidence and pathophysiological rationale, the PERFORM trial failed to demonstrate the superiority of terutroban over aspirin in secondary prevention of cerebrovascular and cardiovascular events among ~20,000 patients with stroke. However, the clinical setting and the design of the study in which the drug has been challenged may explain, at least in part, this unexpected finding.Drugs with dual action, such as dual TXS inhibitors/TP antagonist and dual COXIB/TP antagonists are currently in clinical development. The theoretical rationale for their benefit and the ongoing clinical studies are herein discussed.


Assuntos
Receptores de Tromboxanos/antagonistas & inibidores , Tromboxano-A Sintase/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Aspirina/uso terapêutico , Aterosclerose/tratamento farmacológico , Ensaios Clínicos como Assunto , Humanos , Receptores de Tromboxanos/fisiologia , Transdução de Sinais , Acidente Vascular Cerebral/tratamento farmacológico , Trombose/prevenção & controle
17.
FASEB J ; 24(10): 3970-80, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20530751

RESUMO

Inflammatory lung disease is a primary cause of morbidity and mortality in cystic fibrosis (CF). Mechanisms of unresolved acute inflammation in CF are not completely known, although the involvement of cystic fibrosis transmembrane conductance regulator (CFTR) in nonrespiratory cells is emerging. Here we examined CFTR expression and function in human platelets (PLTs) and found that they express a biologically active CFTR. CFTR blockade gave an ∼50% reduction in lipoxin A(4) (LXA(4)) formation during PLT/polymorphonuclear leukocytes (PMN) coincubations by inhibiting the lipoxin synthase activity of PLT 12-lipoxygenase. PLTs from CF patients generated ∼40% less LXA(4) compared to healthy subject PLTs. CFTR inhibition increased PLT-dependent PMN viability (33.0±5.7 vs. 61.2±8.2%; P=0.033), suppressed nitric oxide generation (0.23±0.04 vs. 0.11±0.002 pmol/10(8) PLTs; P=0.004), while reducing AKT (1.02±0.12 vs. 0.71±0.007 U; P=0.04), and increasing p38 MAPK phosphorylation (0.650±0.09 vs. 1.04±0.24 U; P=0.03). Taken together, these findings indicate that PLTs from CF patients are affected by the molecular defect of CFTR. Moreover, this CF PLT abnormality may explain the failure of resolution in CF.


Assuntos
Plaquetas/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/sangue , Mediadores da Inflamação/fisiologia , Apoptose , Linhagem Celular , Feminino , Humanos , Imuno-Histoquímica , Masculino , Microscopia Eletrônica de Transmissão , Fosforilação , Proteínas Quinases/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
18.
Stress ; 14(3): 282-9, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21434833

RESUMO

Few studies have assessed the effects of stress on in vivo platelet activation. In the present study, hypobaric hypoxia induced by rapid decompression during high-altitude simulated flight in a hypobaric chamber was used to evaluate the effects of environmental stress on salivary cortisol and urinary thromboxane metabolite (TXM) excretion, a noninvasive marker of in vivo platelet function. Twenty-one male aviators (mean ± SD age = 36 ± 7 years) experiencing hypoxia by removing their oxygen mask for 4-5 min during a simulated flight to 25,000 ft (7,620 m; pO(2) = 59.17 mmHg) and a matched control group of thirteen flying instructors wearing oxygen masks during the challenge, were studied. Hypobaric hypoxia induced a transient significant increase (P < 0.001) in the aviators' salivary cortisol concentration; the overall pattern of diurnal cortisol fluctuation was maintained in both groups. Urinary TXM showed a significant ∼30% reduction (P < 0.01) after the chamber session in aviators exposed to hypobaric hypoxia, but not in controls. A significant inverse correlation was found between salivary cortisol and urinary TXM in aviators (r = - 0.64, P = 0.0015). Salivary cortisol was a significant predictor (P < 0.001) for urinary TXM concentrations in aviators. In conclusion, here we observed that an acute stress-induced salivary cortisol increase was associated with reduced urinary thromboxane biosynthesis, providing the first indirect evidence for an inhibitory effect of acute stress on in vivo platelet function.


Assuntos
Doença da Altitude/fisiopatologia , Hidrocortisona/metabolismo , Hipóxia/fisiopatologia , Saliva/química , Estresse Fisiológico/fisiologia , Tromboxano B2/análogos & derivados , Adulto , Dinoprosta/análogos & derivados , Dinoprosta/urina , Humanos , Masculino , Tromboxano B2/urina
20.
Blood ; 112(4): 1085-90, 2008 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-18541722

RESUMO

Polycythemia vera (PV) is associated with high morbidity and mortality for thrombosis. We hypothesized that in PV altered sensitivity to aspirin might be related to dysfunction of the endothelial repair and/or of the nitric oxide (NO) system. Urinary thromboxane (TX) A(2) metabolite (TXM), endothelial colony-forming cells (ECFCs), plasma asymmetric dimethylarginine (ADMA) and von Willebrand factor (VWF) were measured in 37 PV patients on low-dose aspirin and 12 healthy controls. Patients showed an approximately 2-fold increase in median TXM and plasma ADMA levels (P < .001), while ECFC numbers were reduced by approximately 7-fold (P < .001) as compared with non-aspirinated control. These differences were more pronounced in patients with previous thrombosis. An 8-week course of aspirin did not affect ECFCs in 6 controls. VWF and TXM correlated directly with ADMA, and inversely with ECFCs. By multiple regression analysis, lower ECFC quartiles (beta = -0.39; SE = 0.17; P = .028) and higher VWF levels (beta = 0.338, SE = 0.002, P = .034) were independent predictors of higher TXM quartiles (R(2) = 0.39). Serum TXB(2), measured in 22 patients, was approximately 10-fold higher than aspirin-treated controls. PV patients appear to have an unbalanced ECFC/NO axis, and an apparent altered sensitivity of platelet TXA(2) production, all potentially contributing to aspirin-insensitive TXM formation. Thus, additional antithrombotic strategies may be beneficial in PV.


Assuntos
Aspirina/administração & dosagem , Células Endoteliais/patologia , Policitemia Vera/sangue , Policitemia Vera/tratamento farmacológico , Células-Tronco/patologia , Tromboxanos/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Arginina/análogos & derivados , Arginina/sangue , Aspirina/farmacologia , Sangue , Estudos de Casos e Controles , Ensaio de Unidades Formadoras de Colônias , Células Endoteliais/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Células-Tronco/efeitos dos fármacos , Tromboxano A2/sangue , Tromboxano B2/sangue
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