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1.
Transl Stroke Res ; 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31983048

RESUMO

Platelet microvesicles (PMV) have previously been found elevated in acute ischemic stroke (IS) and could be biomarkers for risk of recurrence. PMV surface antigens such as P-selectin and phosphatidylserine (PS) reflect platelet activation and procoagulance. Tissue factor-positive microvesicles (TF+MV) are considered procoagulant, in particular if co-expressing PS. We enumerated MV subpopulations with these surface antigens in a cohort of 211 patients with primarily non-cardioembolic IS or transient ischemic attack (TIA) and investigated their association with long-term outcome. MV concentrations were determined by flow cytometry in the acute and convalescent phase. Primary outcome was a composite of fatal and non-fatal recurrent IS or myocardial infarction. Secondary outcomes were recurrent IS and all-cause mortality. Outcome events were obtained from Swedish registers during a follow-up of 1100 patient years. Concentrations of PS-positive and PS-negative MV populations were elevated in patients compared with healthy controls in both the acute and convalescent phase. PS+TF+PMV displayed pronounced elevations, median fold change 77 in the acute phase (p < 0.0001) but were not associated with outcome, neither were PS+P-selectin+PMV. The only subpopulation positively associated with primary outcome was PS-TF+PMV, with adjusted hazard ratio of 1.86 (1.04-3.31, p = 0.036) by Cox regression. Unexpectedly, several MV subpopulations tended to be associated with reduced risk of poor long-term outcome. Our results suggest that PS+TF+PMV may be a promising marker for cerebral ischemia, and that the in vivo generation of PS-MV after IS/TIA warrants further study. Future MV studies should ideally enumerate PS+ and PS-MV subpopulations separately.

2.
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.

3.
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.

4.
Lakartidningen ; 1162019 May 21.
Artigo em Sueco | MEDLINE | ID: mdl-31192424

RESUMO

Neutrophil extracellular traps (NETs) were first described over a decade ago as part of our innate immune system. Through the extracellular release of web-like structures composed of DNA and histones coated with antimicrobial peptides, the neutrophil was shown to entrap and disarm invading microorganisms. Recent data now propose a central role of NETs in a variety of non-infectious conditions - such as autoimmunity, thrombosis, and cancer - revealing that NETs may not only be beneficial, but also harmful if uncontrolled. Continued investigations into the clinical relevance of NETs will shed further light on the utility of biomarkers associated with NETs, and may open for new therapeutic options in several disease settings.


Assuntos
Armadilhas Extracelulares , Doenças Autoimunes/imunologia , Armadilhas Extracelulares/imunologia , Armadilhas Extracelulares/fisiologia , Humanos , Imunidade Inata , Neoplasias/imunologia , Trombose/imunologia
5.
J Thromb Thrombolysis ; 48(1): 111-118, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30739306

RESUMO

The association between venous thromboembolism (VTE) and occult cancer is well established. However, the benefit of cancer screening in all VTE patients remains controversial. The Registro Informatizado Enfermedad TromboEmbólica (RIETE) score is a recently proposed risk score to identify VTE patients at high risk of occult cancer. We evaluated the performance of the RIETE score in a routine clinical setting comprising patients presenting with VTE between January 1 and December 31, 2014, at Danderyd University hospital. Out of 488 VTE patients, 47 (9.6%) patients received a new cancer diagnosis during a 24-month follow-up. After exclusion of patients with cancer diagnosed at baseline (≤ 10 days after VTE, n = 16), 472 patients were considered eligible for cancer screening. Among these 472 patients, 31 (6.6%) received a cancer diagnosis during follow-up. The cumulative incidence was high after both unprovoked (8.5%) and provoked (4.8%) VTE. The RIETE score was evaluated in 467 of these patients. Interestingly, a high RIETE score was not significantly associated with cancer diagnosis during follow-up (OR 1.78; 95% CI 0.85-3.63), which was mainly due to a poor performance in women (OR 1.04; 95% CI 0.30-2.83). In summary, we observed a relatively high incidence of occult cancer in both unprovoked and provoked VTE. The RIETE score performed poorly in identifying patients at high risk of occult cancer in our VTE population. Additional risk assessment models are warranted to identify VTE patients who would benefit from extensive cancer screening.


Assuntos
Detecção Precoce de Câncer/métodos , Neoplasias Primárias Desconhecidas/etiologia , Medição de Risco/métodos , Tromboembolia Venosa/complicações , Detecção Precoce de Câncer/estatística & dados numéricos , Humanos , Masculino , Neoplasias Primárias Desconhecidas/diagnóstico , Valor Preditivo dos Testes , Medição de Risco/normas , Fatores Sexuais
6.
Sci Rep ; 8(1): 12641, 2018 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-30140006

RESUMO

Early diagnosis of sepsis is crucial since prompt interventions decrease mortality. Citrullinated histone H3 (H3Cit), released from neutrophil extracellular traps (NETs) upon binding of platelets to neutrophils following endotoxin stimulation, has recently been proposed a promising blood biomarker in sepsis. Moreover, microvesicles (MVs), which are released during cell activation and apoptosis and carry a variety of proteins from their parental cells, have also been shown to be elevated in sepsis. In a randomized and placebo-controlled human model of endotoxemia (lipopolysaccharide injection; LPS), we now report significant LPS-induced elevations of circulating H3Cit in 22 healthy individuals. We detected elevations of circulating H3Cit by enzyme-linked immunosorbent assay (ELISA), as well as bound to MVs quantified by flow cytometry. H3Cit-bearing MVs expressed neutrophil and/or platelet surface markers, indicating platelet-neutrophil interactions. In addition, in vitro experiments revealed that H3Cit can bind to phosphatidylserine exposed on platelet derived MVs. Taken together; our results demonstrate that NETs can be detected in peripheral blood during endotoxemia by two distinct H3Cit-specific methods. Furthermore, we propose a previously unrecognized mechanism by which H3Cit may be disseminated throughout the vasculature by the binding to MVs.


Assuntos
Micropartículas Derivadas de Células/metabolismo , Endotoxemia/metabolismo , Histonas/metabolismo , Adulto , Estudos Cross-Over , Método Duplo-Cego , Endotoxemia/induzido quimicamente , Ensaio de Imunoadsorção Enzimática , Armadilhas Extracelulares/metabolismo , Feminino , Humanos , Lipopolissacarídeos/toxicidade , Masculino , Neutrófilos/metabolismo , Sepse/metabolismo , Adulto Jovem
7.
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
8.
PLoS One ; 13(1): e0191231, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29324871

RESUMO

Citrullinated histone H3 (H3Cit) is a central player in the neutrophil release of nuclear chromatin, known as neutrophil extracellular traps (NETs). NETs have been shown to elicit harmful effects on the host, and were recently proposed to promote tumor progression and spread. Here we report significant elevations of plasma H3Cit in patients with advanced cancer compared with age-matched healthy individuals. These elevations were specific to cancer patients as no increase was observed in severely ill and hospitalized patients with a higher non-malignant comorbidity. The analysis of neutrophils from cancer patients showed a higher proportion of neutrophils positive for intracellular H3Cit compared to severely ill patients. Moreover, the presence of plasma H3Cit in cancer patients strongly correlated with neutrophil activation markers neutrophil elastase (NE) and myeloperoxidase (MPO), and the inflammatory cytokines interleukin-6 and -8, known to induce NETosis. In addition, we show that high levels of circulating H3Cit strongly predicted poor clinical outcome in our cohort of cancer patients with a 2-fold increased risk for short-term mortality. Our results also corroborate the association of NE, interleukin-6 and -8 with poor clinical outcome. Taken together, our results are the first to unveil H3Cit as a potential diagnostic and prognostic blood marker associated with an exacerbated inflammatory response in patients with advanced cancer.


Assuntos
Biomarcadores Tumorais/sangue , Histonas/sangue , Neoplasias/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/química , Estudos de Casos e Controles , Citrulinação , Armadilhas Extracelulares/imunologia , Armadilhas Extracelulares/metabolismo , Feminino , Histonas/química , Humanos , Interleucina-6/sangue , Interleucina-8/sangue , Masculino , Pessoa de Meia-Idade , Neoplasias/imunologia , Neoplasias/mortalidade , Ativação de Neutrófilo , Neutrófilos/imunologia , Neutrófilos/metabolismo , Prognóstico
9.
Immunol Res ; 65(3): 706-712, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28161762

RESUMO

There is an emerging interest in the diverse functions of neutrophil extracellular traps (NETs) in a variety of disease settings. However, data on circulating NETs rely largely upon surrogate NET markers such as cell-free DNA, nucleosomes, and NET-associated enzymes. Citrullination of histone H3 by peptidyl arginine deiminase 4 (PAD4) is central for NET formation, and citrullinated histone H3 (H3Cit) is considered a NET-specific biomarker. We therefore aimed to optimize and validate a new enzyme-linked immunosorbent assay (ELISA) to quantify the levels of H3Cit in human plasma. A standard curve made of in vitro PAD4-citrullinated histones H3 allows for the quantification of H3Cit in plasma using an anti-histone antibody as capture antibody and an anti-histone H3 citrulline antibody for detection. The assay was evaluated for linearity, stability, specificity, and precision on plasma samples obtained from a human model of inflammation before and after lipopolysaccharide injection. The results revealed linearity and high specificity demonstrated by the inability of detecting non-citrullinated histone H3. Coefficients of variation for intra- and inter-assay variability ranged from 2.1 to 5.1% and from 5.8 to 13.5%, respectively, allowing for a high precision. Furthermore, our results support an inflammatory induction of a systemic NET burden by showing, for the first time, clear intra-individual elevations of plasma H3Cit in a human model of lipopolysaccharide-induced inflammation. Taken together, our work demonstrates the development of a new method for the quantification of H3Cit by ELISA that can reliably be used for the detection of NETs in human plasma.


Assuntos
Ensaio de Imunoadsorção Enzimática/métodos , Armadilhas Extracelulares/metabolismo , Histonas/metabolismo , Inflamação/diagnóstico , Neutrófilos/imunologia , Plasma/metabolismo , Biomarcadores/metabolismo , Citrulinação , Estudos de Viabilidade , Humanos , Lipopolissacarídeos/imunologia , Variações Dependentes do Observador , Desiminases de Arginina em Proteínas/metabolismo , Sensibilidade e Especificidade
10.
Thromb Res ; 139: 56-64, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26916297

RESUMO

INTRODUCTION: Large elevations of high sensitive Troponin T (hsTnT) in ischemic stroke patients is associated with a poor outcome. In a pilot study we found a high prevalence of malignancies among these patients. Since neutrophil extracellular traps (NETs) have been linked to cancer-associated thrombosis, we hypothesized that the concomitant cerebral and myocardial ischemia could be the result of a NET-induced hypercoagulable state. MATERIALS AND METHODS: Clinical assessments, plasma analyses and autopsies with histopathology (in cases of in-hospital mortality) were performed on ischemic stroke patients with high elevations of hsTnT (N=12) and normal hsTnT (N=19). RESULTS: Patients with hsTnT elevation had an unexpectedly higher prevalence of cancer (p=0.002), half of which were diagnosed post-mortem. Autopsies of these patients revealed widespread myocardial, cerebral and pulmonary microthrombosis with H3Cit in thrombi. A pro-coagulant state and an increase of the NET specific marker citrullinated histone H3 (H3Cit) was found in plasma of patients with elevated hsTnT compared to patients with normal levels (p<0.001). Plasma analyses in cancer patients showed even higher H3Cit levels (p<0.001), and an increase in granulocyte colony-stimulating factor, known to prime neutrophils towards NETosis. H3Cit correlated positively with thrombin-antithrombin complex (p=0.004) and soluble P-selectin (p<0.001), further linking NETosis to the pro-thrombotic state. CONCLUSIONS: The high prevalence of known or occult cancer in our study suggests that cancer-associated arterial microthrombosis may be underestimated. By linking the thrombosis to NETs, we suggest markers of NETosis that could aid in revealing cancer in arterial microthrombosis as well as arterial microthrombosis in cancer.


Assuntos
Isquemia Encefálica/complicações , Isquemia Miocárdica/complicações , Neoplasias/complicações , Trombose/complicações , Troponina T/sangue , Idoso , Idoso de 80 Anos ou mais , Encéfalo/metabolismo , Encéfalo/patologia , Isquemia Encefálica/sangue , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Estudos de Casos e Controles , Armadilhas Extracelulares/metabolismo , Feminino , Fator Estimulador de Colônias de Granulócitos/sangue , Fator Estimulador de Colônias de Granulócitos/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/sangue , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Neoplasias/sangue , Neoplasias/metabolismo , Neoplasias/patologia , Ativação Plaquetária , Trombose/sangue , Trombose/metabolismo , Trombose/patologia , Troponina T/metabolismo
11.
J Stroke Cerebrovasc Dis ; 24(10): 2390-6, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26236002

RESUMO

BACKGROUND: Elevated plasma levels of troponin in acute stroke patients are common and have in several studies been shown to predict in-hospital and short-term mortality. Little is, however, known about the long-term prognosis of these patients. The aim of this study was to determine patient characteristics and 5-year mortality in patients with acute stroke and troponin elevation on admission. METHODS: A retrospective cohort study of all consecutive patients with acute stroke and a plasma troponin I (TnI) analyzed on admission to Danderyd Hospital between January 1, 2005, and January 1, 2006 (n = 247). Patient characteristics were obtained from the Swedish National Stroke Register, Riksstroke, as well as hospital records. Mortality data were obtained from the Swedish Cause of Death Register. RESULTS: There were 133 patients (54%) with TnI less than .03 µg/L (normal), 74 patients (30%) with TnI .03-.11 µg/L (low elevation), and 40 patients (16%) with TnI greater than .11 µg/L (high elevation). TnI elevations were associated with a higher age, prior ischemic stroke, chronic heart failure, renal insufficiency, stroke severity, and ST segment elevation or depression on admission. The rate of hyperlipidemia decreased with increasing TnI. Adjusted for age and comorbidity, elevated TnI values on admission had a significantly and sustained increased mortality over the 5-year follow-up, with a hazard ratio of 1.90 (95% confidence interval, 1.33-2.70). CONCLUSIONS: Troponin elevation in patients with acute stroke, even when adjusted for several possible confounders, is associated with an almost 2-fold increased risk of 5-year mortality.


Assuntos
Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/mortalidade , Troponina/sangue , Idoso , Idoso de 80 Anos ou mais , Proteína C-Reativa/metabolismo , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Acidente Vascular Cerebral/epidemiologia , Suécia/epidemiologia
12.
J Investig Med High Impact Case Rep ; 2(2): 2324709614539283, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-26425612

RESUMO

Trousseau's syndrome is a well-known malignancy associated hypercoagulative state leading to venous or arterial thrombosis. The pathophysiology is however poorly understood, although multiple mechanisms are believed to be involved. We report a case of Trousseau's syndrome resulting in concomitant cerebral and myocardial microthrombosis, presenting with acute ischemic stroke and markedly elevated plasma troponin T levels suggesting myocardial injury. Without any previous medical history, the patient developed multiple cerebral infarctions and died within 11 days of admission. The patient was postmortem diagnosed with an advanced metastatic adenocarcinoma of the prostate with disseminated cerebral, pulmonary, and myocardial microthrombosis. Further analyses revealed, to the best of our knowledge for the first time in stroke patients, circulating microvesicles positive for the epithelial tumor marker CK18 and citrullinated histone H3 in thrombi, markers of the recently described cancer-associated procoagulant DNA-based neutrophil extracellular traps. We also found tissue factor, the main in vivo initiator of coagulation, both in thrombi and in metastases. Troponin elevation in acute ischemic stroke is common and has repeatedly been associated with an increased risk of mortality. The underlying pathophysiology is however not fully clarified, although a number of possible explanations have been proposed. We now suggest that unexplainable high levels of troponin in acute ischemic stroke deserve special attention in terms of possible occult malignancy.

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