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1.
Haematologica ; 105(1): 218-225, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31048354

RESUMO

Pancreatic cancer is associated with a high incidence of venous thromboembolism. Neutrophils have been shown to contribute to thrombosis in part by releasing neutrophil extracellular traps (NET). A recent study showed that increased plasma levels of the NET biomarker, citrullinated histone H3 (H3Cit), are associated with venous thromboembolism in patients with pancreatic and lung cancer but not in those with other types of cancer, including breast cancer. In this study, we examined the contribution of neutrophils and NET to venous thrombosis in nude mice bearing human pancreatic tumors. We found that tumor-bearing mice had increased circulating neutrophil counts and levels of granulocyte-colony stimulating factor, neutrophil elastase, H3Cit and cell-free DNA compared with controls. In addition, thrombi from tumor-bearing mice contained increased levels of the neutrophil marker Ly6G, as well as higher levels of H3Cit and cell-free DNA. Thrombi from tumor-bearing mice also had denser fibrin with thinner fibers consistent with increased thrombin generation. Importantly, either neutrophil depletion or administration of DNase I reduced the thrombus size in tumor-bearing but not in control mice. Our results, together with clinical data, suggest that neutrophils and NET contribute to venous thrombosis in patients with pancreatic cancer.

2.
Hematology Am Soc Hematol Educ Program ; 2019(1): 182-186, 2019 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-31808871

RESUMO

Cancer patients have an increased risk of venous thromboembolism (VTE). The rate of VTE varies with cancer type, with pancreatic cancer having one of the highest rates, suggesting that there are cancer type-specific mechanisms of VTE. Risk assessment scores, such as the Khorana score, have been developed to identify ambulatory cancer patients at high risk of VTE. However, the Khorana score performed poorly in discriminating pancreatic cancer patients at risk of VTE. Currently, thromboprophylaxis is not recommended for cancer outpatients. Recent clinical trials showed that factor Xa (FXa) inhibitors reduced VTE in high-risk cancer patients but also increased major bleeding. Understanding the mechanisms of cancer-associated thrombosis should lead to the development of safer antithrombotic drugs. Mouse models can be used to study the role of different prothrombotic pathways in cancer-associated thrombosis. Human and mouse studies support the notion that 2 prothrombotic pathways contribute to VTE in pancreatic cancer patients: tumor-derived, tissue factor-positive (TF+) extracellular vesicles (EVs), and neutrophils and neutrophil extracellular traps (NETs). In pancreatic cancer patients, elevated levels of plasma EVTF activity and citrullinated histone H3 (H3Cit), a NET biomarker, are independently associated with VTE. We observed increased levels of circulating tumor-derived TF+ EVs, neutrophils, cell-free DNA, and H3Cit in nude mice bearing human pancreatic tumors. Importantly, inhibition of tumor-derived human TF, depletion of neutrophils, or administration of DNAse I to degrade cell-free DNA (including NETs) reduced venous thrombosis in tumor-bearing mice. These studies demonstrate that tumor-derived TF+ EVs, neutrophils, and cell-free DNA contribute to venous thrombosis in a mouse model of pancreatic cancer.

3.
J Infect Dis ; 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31722433

RESUMO

BACKGROUND: Puumala (PUUV) orthohantavirus causes hemorrhagic fever with renal syndrome (HFRS). HFRS patients have an activated coagulation system with increased risk of disseminated intravascular coagulation (DIC) and venous thromboembolism (VTE). The aim of the study was to determine if circulating extracellular vesicle tissue factor (EVTF) activity levels associates with DIC and VTE (grouped as intravascular coagulation) in HFRS patients. METHODS: Longitudinal samples were collected from 88 HFRS patients. Patients were stratified into groups of those with intravascular coagulation (n=27) and those who did not (n=61). We measured levels of circulating EVTF activity, fibrinogen, activated partial prothrombin time, prothrombin time international normalized ratio, D-dimer, tissue plasminogen activator (tPA), plasminogen activator inhibitor 1 (PAI-1) and platelets. RESULTS: Plasma EVTF activity was transiently increased during HFRS. Levels of EVTF activity significantly associated with plasma tPA and PAI-1, suggesting endothelial cells as a potential source. Patients with intravascular coagulation had significantly higher peak EVTF activity levels compared to those who did not. The peak EVTF activity value predicting intravascular coagulation was 0.51 ng/L with 63% sensitivity and 61% specificity with AUC 0.63 (95% CI 0.51 - 0.76), p-value 0.046. CONCLUSIONS: Increased circulating EVTF activity during HFRS is associated with intravascular coagulation.

4.
J Thromb Haemost ; 17(12): 2169-2173, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31393055

RESUMO

BACKGROUND: Some clinical studies have shown that low-molecular-weight heparins (LMWHs) prolong the survival of cancer patients. In addition, various anticoagulants have been shown to reduce growth of tumors in mice. However, there are no studies on the effect of the factor Xa inhibitor rivaroxaban on growth of human pancreatic tumors in nude mice. OBJECTIVES: To test the hypothesis that the factor Xa inhibitor rivaroxaban reduces the growth of tissue factor (TF)-positive pancreatic tumors but not TF-negative pancreatic tumors in mice. METHODS: The TF-positive human pancreatic cancer cell line BxPc-3 and the TF-negative human pancreatic cancer cell line MIA PaCa-2 were injected subcutaneously into nude mice and tumors grown to a mean volume of ~100 mm3 . Mice were then divided into two groups. One group was fed chow containing rivaroxaban (0.5 g/kg chow) whereas the other group was fed chow without rivaroxaban. RESULTS: Rivaroxaban significantly prolonged prothrombin time in tumor-bearing mice. Rivaroxaban did not affect cell proliferation or growth of either BxPc-3 or MIA PaCa-2 tumors grown subcutaneously in nude mice. CONCLUSION: Our results indicate that inhibition of factor Xa with rivaroxaban does not affect the growth of two human pancreatic tumors in nude mice.

5.
Thromb Res ; 182: 64-74, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31450010

RESUMO

INTRODUCTION: The TF-FVIIa complex is the primary activator of coagulation. Elevated levels of microvesicle (MV) bearing tissue factor (TF)-dependent procoagulant activity are detectable in patients with an increased risk of thrombosis. Several methods have been described to measure MV TF activity but they are hampered by limited sensitivity and specificity. The aim of this work was to increase the sensitivity of the MV TF activity assay (called Chapel Hill assay). MATERIAL AND METHODS: Improvements of the MV TF activity assay included i/ speed and time of centrifugation, ii/ use of a more potent inhibitory anti-TF antibody iii/ use of FVII and a fluorogenic substrate to increase specificity. RESULTS: The specificity of the MV TF activity assay was demonstrated by the absence of activity on MV derived from a knock-out-TF cell line using an anti-human TF monoclonal antibody called SBTF-1, which shows a higher TF inhibitory effect than the anti-human TF monoclonal antibody called HTF-1. Experiments using blood from healthy individuals, stimulated or not by LPS, or plasma spiked with 3 different levels of MV, demonstrated that the new assay was more sensitive and this allowed detection of MV TF activity in platelet free plasma (PFP) samples from healthy individuals. However, the assay was limited by an inter-assay variability, mainly due to the centrifugation step. CONCLUSIONS: We have improved the sensitivity of the MV TF activity assay without losing specificity. This new assay could be used to evaluate levels of TF-positive MV as a potential biomarker of thrombotic risk in patients.

6.
Curr Opin Hematol ; 26(5): 349-356, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31261175

RESUMO

PURPOSE OF REVIEW: Tissue factor (TF) is released from cancer cells and tumors in the form of extracellular vesicles (EVs). This review summarizes our current knowledge of the mechanisms of release of TF-positive EVs (TF+EVs) from cancer cells and the effect of these TF+EVs on cultured endothelial cells. In addition, we will summarize the contribution of TF+EVs to thrombosis in mice, and the association between plasma EVTF activity and venous thrombosis as well as survival of cancer patients. RECENT FINDINGS: The release of TF+EVs from cancer cells is regulated by multiple factors, including hypoxia, epithelial-mesenchymal transition, and various intracellular signaling pathways. Cancer cell-derived, TF+EVs confer procoagulant activity to endothelial cells and induce the expression of adhesion proteins and IL-8. In addition, they contribute to thrombosis by directly activating the coagulation system and by generating thrombin that activates platelets in mouse models. Finally, there is an association between EVTF activity and venous thrombosis in pancreatic cancer patients as well as mortality in cancer patients. SUMMARY: Cancer cell-derived TF+EVs bind to and activate endothelial cells. In addition, they serve as biomarkers of survival of cancer patients and venous thrombosis in pancreatic cancer patients.

7.
Arterioscler Thromb Vasc Biol ; 39(9): 1724-1738, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31315434

RESUMO

Recent studies have demonstrated a role of neutrophils in both venous and arterial thrombosis. A key prothrombotic feature of neutrophils is their ability to release web-like structures composed of DNA filaments coated with histones and granule proteins referred to as neutrophil extracellular traps (NETs). NETs were discovered over a decade ago as part of our first line of host defense against invading microorganisms. Although NETs have a protective role against pathogens, recent data suggest that an uncontrolled and excessive NET formation within the vasculature may contribute to pathological thrombotic disorders. In vitro studies suggest that NETs promote vessel occlusion by providing a scaffold for platelets, red blood cells, extracellular vesicles, and procoagulant molecules, such as von Willebrand factor and tissue factor. In addition, NET components enhance coagulation by both activating the intrinsic pathway and degrading an inhibitor of the extrinsic pathway (tissue factor pathway inhibitor). NET formation has, therefore, been proposed to contribute to thrombus formation and propagation in arterial, venous, and cancer-associated thrombosis. This review will describe animal and human studies suggesting a role of NETs in the pathogenesis of various thrombotic disorders. Targeting NETs may be a novel approach to reduce thrombosis without affecting hemostasis.

9.
Immunity ; 50(6): 1401-1411.e4, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31076358

RESUMO

Inflammasome activation and subsequent pyroptosis are critical defense mechanisms against microbes. However, overactivation of inflammasome leads to death of the host. Although recent studies have uncovered the mechanism of pyroptosis following inflammasome activation, how pyroptotic cell death drives pathogenesis, eventually leading to death of the host, is unknown. Here, we identified inflammasome activation as a trigger for blood clotting through pyroptosis. We have shown that canonical inflammasome activation by the conserved type III secretion system (T3SS) rod proteins from Gram-negative bacteria or noncanonical inflammasome activation by lipopolysaccharide (LPS) induced systemic blood clotting and massive thrombosis in tissues. Following inflammasome activation, pyroptotic macrophages released tissue factor (TF), an essential initiator of coagulation cascades. Genetic or pharmacological inhibition of TF abolishes inflammasome-mediated blood clotting and protects against death. Our data reveal that blood clotting is the major cause of host death following inflammasome activation and demonstrate that inflammasome bridges inflammation with thrombosis.


Assuntos
Coagulação Sanguínea , Inflamassomos/metabolismo , Piroptose , Trombose/etiologia , Trombose/metabolismo , Animais , Infecções Bacterianas/complicações , Infecções Bacterianas/microbiologia , Biomarcadores , Caspases/metabolismo , Micropartículas Derivadas de Células/imunologia , Micropartículas Derivadas de Células/metabolismo , Modelos Animais de Doenças , Humanos , Lipopolissacarídeos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Monócitos/imunologia , Monócitos/metabolismo , Transdução de Sinais , Tromboplastina/metabolismo , Trombose/sangue , Trombose/mortalidade
10.
Semin Thromb Hemost ; 45(4): 385-395, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31096306

RESUMO

There is a strong relationship between tissue factor (TF) and cancer. Many cancer cells express high levels of both full-length TF and alternatively spliced (as) TF. TF expression in cancer is associated with poor prognosis. In this review, the authors summarize the regulation of TF expression in cancer cells and the roles of TF and asTF in tumor growth and metastasis. A variety of different signaling pathways, transcription factors and micro ribonucleic acids regulate TF gene expression in cancer cells. The TF/factor VIIa complex enhances tumor growth by activating protease-activated receptor 2 signaling and by increasing the expression of angiogenic factors, such as vascular endothelial growth factor. AsTF increases tumor growth by enhancing integrin ß1 signaling. TF and asTF also contribute to metastasis via multiple thrombin-dependent and independent mechanisms that include protecting tumor cells from natural killer cells. Finally, a novel anticancer therapy is using tumor TF as a target to deliver cytotoxic drugs to the tumor. TF may be useful in diagnosis, prognosis, and treatment of cancer.


Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , Transdução de Sinais/genética , Tromboplastina/genética , Humanos , Imunoconjugados/uso terapêutico , Terapia de Alvo Molecular/métodos , Metástase Neoplásica , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Prognóstico , Transdução de Sinais/efeitos dos fármacos , Tromboplastina/antagonistas & inibidores , Tromboplastina/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
11.
Res Pract Thromb Haemost ; 3(1): 44-48, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30656275

RESUMO

Tissue factor (TF) is the cellular receptor for plasma factor (F) VII/FVIIa and triggers blood coagulation. Extracellular vesicles (EVs) are small membrane vesicles that are released from activated cells and tumor cells. Different cell types, including activated monocytes and tumors cells release TF-positive EVs into the circulation. We developed an assay to measure levels of TF activity in EVs isolated from human plasma samples. We and others have used this assay to demonstrate increased levels of EV TF activity in a variety of diseases associated with thrombosis, including cancer. These studies suggest that EV TF can be used as a biomarker of thrombotic risk. The strength of this laboratory assay is that it is relatively sensitive and specific. However, the limitations of the assay are that it is labor intensive and the coefficient of variation is too high for it to be used as a clinical assay.

12.
Arterioscler Thromb Vasc Biol ; 39(1): 13-24, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30580574

RESUMO

Activation of the blood coagulation cascade leads to fibrin deposition and platelet activation that are required for hemostasis. However, aberrant activation of coagulation can lead to thrombosis. Thrombi can cause tissue ischemia, and fibrin degradation products and activated platelets can enhance inflammation. In addition, coagulation proteases activate cells by cleavage of PARs (protease-activated receptors), including PAR1 and PAR2. Direct oral anticoagulants have recently been developed to specifically inhibit the coagulation proteases FXa (factor Xa) and thrombin. Administration of these inhibitors to wild-type mice can be used to determine the roles of FXa and thrombin in different inflammatory diseases. These results can be compared with the phenotypes of mice with deficiencies of either Par1 (F2r) or Par2 (F2rl1). However, inhibition of coagulation proteases will have effects beyond reducing PAR signaling, and a deficiency of PARs will abolish signaling from all proteases that activate these receptors. We will summarize studies that examine the roles of coagulation proteases, particularly FXa and thrombin, and PARs in different mouse models of inflammatory disease. Targeting FXa and thrombin or PARs may reduce inflammatory diseases in humans.


Assuntos
Coagulação Sanguínea , Modelos Animais de Doenças , Fator Xa/fisiologia , Inflamação/etiologia , Receptores Ativados por Proteinase/fisiologia , Trombina/fisiologia , Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/etiologia , Animais , Apolipoproteínas E/fisiologia , Aterosclerose/tratamento farmacológico , Aterosclerose/etiologia , Inibidores do Fator Xa/uso terapêutico , Inflamação/tratamento farmacológico , Camundongos , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/etiologia , Trombina/antagonistas & inibidores
13.
Thromb Res ; 167: 128-134, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29843086

RESUMO

INTRODUCTION: Rivaroxaban selectively inhibits factor Xa (FXa), which plays a central role in blood coagulation. In addition, FXa activates protease-activated receptor-2 (PAR-2). We have shown that PAR-2-/- mice exhibit less cardiac dysfunction after cardiac injury. MATERIAL AND METHODS: Wild-type (WT) and PAR-2-/- mice were subjected to left anterior descending artery (LAD) ligation to induce cardiac injury and heart failure. Mice received either placebo or rivaroxaban chow either starting at the time of surgery or 3 days after surgery and continued up to 28 days. Cardiac function was measured by echocardiography pre-surgery and 3, 7 and 28 days after LAD ligation. We also measured anticoagulation, intravascular thrombi, infarct size, cardiac hypertrophy and inflammation at various times. RESULTS: Rivaroxaban increased the prothrombin time and inhibited the formation of intravascular thrombi in mice subjected to LAD ligation. WT mice receiving rivaroxaban immediately after surgery had similar infarct sizes at day 1 as controls but exhibited significantly less impairment of cardiac function at day 3 and beyond compared to the placebo group. Rivaroxaban also inhibited the expansion of the infarct at day 28. Rivaroxaban did not significantly affect the expression of inflammatory mediators or a neutrophil marker at day 2 after LAD ligation. Delaying the start of rivaroxaban administration until 3 days after surgery failed to preserve cardiac function. In addition, rivaroxaban did not reduce cardiac dysfunction in PAR-2-/- mice. CONCLUSIONS: Early administration of rivaroxaban preserves cardiac function in mice after LAD ligation.


Assuntos
Inibidores do Fator Xa/uso terapêutico , Cardiopatias/tratamento farmacológico , Infarto do Miocárdio/prevenção & controle , Rivaroxabana/uso terapêutico , Animais , Modelos Animais de Doenças , Inibidores do Fator Xa/farmacologia , Humanos , Camundongos , Rivaroxabana/farmacologia
14.
Thromb Res ; 166: 54-59, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29656167

RESUMO

INTRODUCTION: The procoagulant activity of extracellular vesicles (EV) exposing tissue factor (TF) is a promising biomarker for venous thromboembolism (VTE) in cancer patients. We evaluated an in-house EV-TF activity assay (the fibrin generation test) for the prediction of cancer-associated VTE. We also compared the results with the fibrin generation tests to an EV-TF-dependent factor Xa generation assay in samples from pancreatic cancer patients. MATERIALS AND METHODS: Data collected in a multinational, prospective cohort study were used. Patients with various types of advanced cancer were enrolled if chemotherapy was scheduled or started in the previous 3 months. Patients were followed for 6 months for the occurrence of VTE. The fibrin generation test was performed at baseline to measure EV-TF procoagulant activity. RESULTS: The fibrin generation test was performed in 648 patients with advanced cancer. The mean age was 62 years; 58% had distant metastasis. Forty patients (6.1%) developed VTE. Overall, a high fibrin generation test result was associated with a two-fold increased risk for VTE (HR 2.0; 95%-CI, 1.1-3.6). The association was stronger in patients with pancreatic cancer (HR 4.1; 95%-CI, 0.91-19) than in those with other tumor types (HR 1.5; 95%-CI, 0.72-3.1). Correlation between the FGT and the TF-dependent factor Xa generation assay in patients with pancreatic cancer was poor (Spearman's R = 0.35). CONCLUSION: This study shows that a high EV-TF procoagulant activity as measured by the fibrin generation test is associated with an increased risk of VTE in cancer patients, in particular in those with pancreatic cancer. Future studies should aim to further improve the feasibility and accuracy of EV-TF activity assays.


Assuntos
Vesículas Extracelulares/metabolismo , Neoplasias/complicações , Tromboplastina/metabolismo , Tromboembolia Venosa/etiologia , Estudos de Coortes , Vesículas Extracelulares/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Tromboembolia Venosa/patologia
15.
Thromb Res ; 165: 1-5, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29539580

RESUMO

INTRODUCTION: Increased levels of circulating tissue factor (TF)-positive microvesicles (MVs) may increase the risk of thrombosis. Indeed, TF-positive MVs are detected in plasma of patients with various types of diseases. In this study, we measured levels of MV TF activity in non-cancer severely ill patients and cancer patients. METHODS: We used an in-house MV TF activity assay to measure MV TF activity. RESULTS: MV TF activity was significantly increased in a population of cancer patients but not in a population of non-cancer severely ill patients compared with healthy controls. However, in the population of severely ill patients, those with infection had significantly elevated levels of MV TF activity compared with controls. Interestingly, patients with adenocarcinoma had higher levels of MV TF activity compared with patients with non-adenocarcinoma tumors. Levels of MV TF activity were not associated with venous thromboembolism in cancer patients. MV TF activity was associated with reduced survival in cancer patients. CONCLUSION: Cancer patients as well as severely ill patients with infection have higher levels of MV TF activity compared with healthy controls. Patients with adenocarcinoma have higher levels of MV TF activity compared with patients with other types of cancer. An elevated level of MV TF activity was associated with reduced survival in cancer patients.


Assuntos
Micropartículas Derivadas de Células/patologia , Estado Terminal/mortalidade , Microvasos/metabolismo , Neoplasias/patologia , Idoso , Feminino , Humanos , Masculino , Neoplasias/mortalidade
16.
Thromb Res ; 164 Suppl 1: S48-S53, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29306575

RESUMO

Cancer patients have an increased risk of venous thromboembolism (VTE) compared with the general population. Mouse models are used to better understand the mechanisms of cancer-associated thrombosis. Several mouse models of cancer-associated thrombosis have been developed that use different mouse strains, tumors, tumor sites and thrombosis models. In this review, we summarize these different models. These models have been used to determine the role of different pathways in cancer-associated thrombosis. For instance, they have revealed roles for tumor-derived tissue factor-positive microvesicles and neutrophil extracellular traps in thrombosis in tumor-bearing mice. A better understanding of the mechanisms of cancer-associated thrombosis may allow the development of new therapies to reduce thrombosis in cancer patients.


Assuntos
Neoplasias/complicações , Trombose/etiologia , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Neoplasias/patologia , Fatores de Risco , Trombose/patologia
17.
J Cardiovasc Transl Res ; 11(3): 221-229, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29344841

RESUMO

D-dimer has emerged as a biomarker of cardiovascular event risk, yet pathophysiological factors associated with plasma D-dimer levels in stable coronary artery disease (CAD) subjects are poorly understood. In 106 stable CAD subjects undergoing intravascular ultrasound with virtual histology (IVUS-VH), we measured D-dimer, lipoprotein(a) (Lp(a)), plasminogen, biomarkers reflecting oxidation-specific epitopes (OSE) such as oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB), OxPL on plasminogen (OxPL-PLG), and autoantibodies to phosphorylcholine-BSA [PC-BSA] and a malondialdehyde [MDA] mimotope. In univariate analysis, D-dimer was positively associated with Lp(a), OxPL-apoB, OxPL-PLG, and coronary artery calcium, and inversely associated with autoantibodies to OSE and plaque fibrosis. D-dimer levels > 500 ng/ml also showed positive association with plaque necrosis. After multivariate analysis, D-dimer remained significantly associated with Lp(a) and plaque calcium. While further studies are needed, results provide evidence that plasma D-dimer levels are associated with levels of OxPLs and IVUS-VH indices linked to plaque erosion and rupture.


Assuntos
Autoanticorpos/sangue , Doença da Artéria Coronariana/sangue , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Fosfolipídeos/sangue , Placa Aterosclerótica , Adulto , Idoso , Idoso de 80 Anos ou mais , Apolipoproteína B-100/sangue , Autoanticorpos/imunologia , Biomarcadores/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/imunologia , Doença da Artéria Coronariana/patologia , Estudos Transversais , Feminino , Humanos , Lipoproteína(a)/sangue , Masculino , Pessoa de Meia-Idade , Necrose , Oxirredução , Fosfolipídeos/imunologia , Valor Preditivo dos Testes , Ruptura Espontânea , Ultrassonografia de Intervenção
18.
Blood ; 130(13): 1499-1506, 2017 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-28807983

RESUMO

Cancer patients have an increased risk of venous thromboembolism (VTE). In this review, we summarize common and cancer type-specific pathways of VTE in cancer patients. Increased levels of leukocytes, platelets, and tissue factor-positive (TF+) microvesicles (MVs) are all potential factors that alone or in combination increase cancer-associated thrombosis. Patients with lung or colorectal cancer often exhibit leukocytosis. Neutrophils could increase VTE in cancer patients by releasing neutrophil extracellular traps whereas monocytes may express TF. Thrombocytosis is often observed in gastrointestinal, lung, breast, and ovarian cancer and this could decrease the threshold required for VTE. Soluble P-selectin has been identified as a biomarker of cancer-associated thrombosis in a general cancer population and may reflect activation of the endothelium. P-selectin expression by the endothelium may enhance VTE by increasing the recruitment of leukocytes. Studies in patients with pancreatic or brain cancer suggest that elevated levels of PAI-1 may contribute to VTE. Although elevated levels of TF+ MVs have been observed in patients with different types of cancer, an association between TF+ MVs and VTE has been observed only in pancreatic cancer. Podoplanin expression is associated with VTE in patients with brain cancer and may activate platelets. Future studies should measure multiple biomarkers in each cancer type to determine whether combinations of biomarkers can be used as predictors of VTE. A better understanding of the pathways that increase VTE in cancer patients may lead to the development of new therapies to reduce the morbidity and mortality associated with thrombosis.


Assuntos
Redes e Vias Metabólicas , Neoplasias/complicações , Trombose Venosa/etiologia , Biomarcadores , Humanos , Neoplasias/metabolismo , Trombose Venosa/diagnóstico , Trombose Venosa/patologia
19.
Gynecol Oncol ; 146(1): 146-152, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28501328

RESUMO

OBJECTIVE: Ovarian clear cell carcinoma (OCCC) and high grade serous ovarian cancer (HGSOC) are associated with the highest risk of VTE among patients with epithelial ovarian cancer (EOC). Tissue factor (TF) is a transmembrane glycoprotein which can trigger thrombosis. We sought to evaluate if there is an association between VTE and tumor expression of tissue factor (TF), plasma TF, and microvesicle TF (MV TF) activity in this high-risk population. METHODS: We performed a case-control study of OCCC and HGSOC patients with and without VTE. 105 patients who underwent surgery at a tertiary care center between January 1995 and October 2013 were included. Plasma TF was measured with an enzyme-linked immunosorbent assay. A TF-dependent Factor Xa generation assay was used to measure MV TF activity. Immunohistochemical (IHC) analysis was performed to evaluate tumor expression of TF. RESULTS: 35 women with OCCC or HGSOC diagnosed with VTE within 9months of surgery were included in the case group. Those with VTE had a worse OS, p<0.0001, with a greater than three-fold increase in risk of death, HR 3.33 (CI 1.75-6.35). There was no significant difference in median plasma TF level or MV TF activity level between patients with and without VTE. OCCC patients had greater expression of TF in their tumors than patients with HGSOC, p<0.0001. CONCLUSIONS: TFMV activity and plasma TF level were not predictive of VTE in this patient population. Given the extensive expression of TF in OCCC tumors, it is unlikely IHC expression will be useful in risk stratification for VTE in this population.


Assuntos
Neoplasias Epiteliais e Glandulares/sangue , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/patologia , Tromboplastina/metabolismo , Trombose Venosa/sangue , Trombose Venosa/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Epitelial do Ovário , Estudos de Casos e Controles , Técnica de Imunoensaio Enzimático de Multiplicação , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de Sobrevida , Tromboplastina/biossíntese
20.
Thromb Res ; 150: 65-72, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28043041

RESUMO

INTRODUCTION: Increased levels of tissue factor-positive extracellular vesicles (TF+EVs) have been detected in the plasma of patients with various diseases, including cancer and endotoxemia. Levels of TF+EVs in plasma samples can be measured by antigen and activity assays. The aim of the present study was to visualize TF+EVs by laser scanning confocal microscopy (LSCM). METHODS: EVs were isolated from the supernatant of two cultured human pancreatic cancer cell lines (Panc-1 and BxPc-3), from untreated or lipopolysaccharide (LPS) treated whole blood, and from plasma of pancreatic cancer patients. EV-TF activity was determined using an in-house assay. The EVs were labeled with 5(6)-carboxyfluorescein diacetate N-succinimidyl ester, which is converted to the impermeant green fluorescent molecule carboxyfluorescein inside the EVs. EVs were either captured using annexin V and detected using a fluorescent-labeled anti-TF antibody, or captured using an anti-TF antibody and detected using fluorescent-labeled annexin V. EVs were visualized by LSCM. RESULTS: TF+EVs were easily detected from high TF-expressing BxPc-3 cells using annexin V capture, whereas the addition of tyramide amplification was required to detect TF+EVs from low TF-expressing Panc-1 cells. Visualization of TF+EVs in plasma from LPS treated whole human blood and in plasma from pancreatic cancer patients required either capture with annexin V and detection with a fluorescent-labeled anti-TF antibody with tyramide signal amplification, or capture with an anti-TF antibody and detection with a fluorescent-labeled annexin V. CONCLUSION: LSCM enables visualization of TF+EVs in the supernatant from cultured cells and in clinical samples.


Assuntos
Vesículas Extracelulares/ultraestrutura , Receptores de Lipopolissacarídeos/análise , Microscopia Confocal/métodos , Tromboplastina/análise , Anexina A5/análise , Linhagem Celular , Linhagem Celular Tumoral , Vesículas Extracelulares/patologia , Humanos , Pâncreas/patologia , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/patologia
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