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1.
Circ Res ; 116(7): 1182-92, 2015 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-25547404

RESUMO

RATIONALE: Mechanisms of coronary occlusion in ST-elevation acute coronary syndrome are poorly understood. We have previously reported that neutrophil (polymorphonuclear cells [PMNs]) accumulation in culprit lesion site (CLS) thrombus is a predictor of cardiovascular outcomes. OBJECTIVE: The goal of this study was to characterize PMN activation at the CLS. We examined the relationships between CLS neutrophil extracellular traps (NETs), bacterial components as triggers of NETosis, activity of endogenous deoxyribonuclease, ST-segment resolution, and infarct size. METHODS AND RESULTS: We analyzed coronary thrombectomies from 111 patients with ST-elevation acute coronary syndrome undergoing primary percutaneous coronary intervention. Thrombi were characterized by immunostaining, flow cytometry, bacterial profiling, and immunometric and enzymatic assays. Compared with femoral PMNs, CLS PMNs were highly activated and formed aggregates with platelets. Nucleosomes, double-stranded DNA, neutrophil elastase, myeloperoxidase, and myeloid-related protein 8/14 were increased in CLS plasma, and NETs contributed to the scaffolds of particulate coronary thrombi. Copy numbers of Streptococcus species correlated positively with dsDNA. Thrombus NET burden correlated positively with infarct size and negatively with ST-segment resolution, whereas CLS deoxyribonuclease activity correlated negatively with infarct size and positively with ST-segment resolution. Recombinant deoxyribonuclease accelerated the lysis of coronary thrombi ex vivo. CONCLUSIONS: PMNs are highly activated in ST-elevation acute coronary syndrome and undergo NETosis at the CLS. Coronary NET burden and deoxyribonuclease activity are predictors of ST-segment resolution and myocardial infarct size.


Assuntos
Síndrome Coronariana Aguda/patologia , Trombose Coronária/patologia , Desoxirribonucleases/fisiologia , Armadilhas Extracelulares/fisiologia , Infarto do Miocárdio/patologia , Infiltração de Neutrófilos , Síndrome Coronariana Aguda/enzimologia , Síndrome Coronariana Aguda/microbiologia , Síndrome Coronariana Aguda/fisiopatologia , Síndrome Coronariana Aguda/terapia , Adulto , Idoso , Antígenos CD/análise , Terapia Combinada , Trombose Coronária/enzimologia , Trombose Coronária/microbiologia , Trombose Coronária/cirurgia , DNA Bacteriano/análise , Desoxirribonucleases/uso terapêutico , Eletrocardiografia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/etiologia , Intervenção Coronária Percutânea , Agregação Plaquetária , Streptococcus/genética , Streptococcus/isolamento & purificação , Trombectomia , Terapia Trombolítica , Receptor 2 Toll-Like/análise , Receptor 4 Toll-Like/análise
2.
J Am Heart Assoc ; 3(1): e000772, 2014 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-24584745

RESUMO

BACKGROUND: Splenectomy is a clinical risk factor for complicated thrombosis. We hypothesized that the loss of the mechanical filtering function of the spleen may enrich for thrombogenic phospholipids in the circulation, thereby affecting the vascular remodeling of thrombosis. METHODS AND RESULTS: We investigated the effects of splenectomy both in chronic thromboembolic pulmonary hypertension (CTEPH), a human model disease for thrombus nonresolution, and in a mouse model of stagnant flow venous thrombosis mimicking deep vein thrombosis. Surgically excised thrombi from rare cases of CTEPH patients who had undergone previous splenectomy were enriched for anionic phospholipids like phosphatidylserine. Similar to human thrombi, phosphatidylserine accumulated in thrombi after splenectomy in the mouse model. A postsplenectomy state was associated with larger and more persistent thrombi. Higher counts of procoagulant platelet microparticles and increased leukocyte-platelet aggregates were observed in mice after splenectomy. Histological inspection revealed a decreased number of thrombus vessels. Phosphatidylserine-enriched phospholipids specifically inhibited endothelial proliferation and sprouting. CONCLUSIONS: After splenectomy, an increase in circulating microparticles and negatively charged phospholipids is enhanced by experimental thrombus induction. The initial increase in thrombus volume after splenectomy is due to platelet activation, and the subsequent delay of thrombus resolution is due to inhibition of thrombus angiogenesis. The data illustrate a potential mechanism of disease in CTEPH.


Assuntos
Hipertensão Pulmonar/etiologia , Embolia Pulmonar/etiologia , Esplenectomia/efeitos adversos , Trombose Venosa/etiologia , Idoso , Animais , Coagulação Sanguínea , Estudos de Casos e Controles , Proliferação de Células , Micropartículas Derivadas de Células/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Endarterectomia , Feminino , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/cirurgia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Neovascularização Patológica , Fosfatidilserinas/sangue , Ativação Plaquetária , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Embolia Pulmonar/sangue , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/cirurgia , Fatores de Risco , Fatores de Tempo , Veia Cava Inferior/metabolismo , Veia Cava Inferior/patologia , Trombose Venosa/sangue , Trombose Venosa/diagnóstico
3.
Arterioscler Thromb Vasc Biol ; 34(4): 810-819, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24526692

RESUMO

OBJECTIVE: Restoration of patency is a natural target of vascular remodeling after venous thrombosis that involves vascular endothelial cells and smooth muscle cells, as well as leukocytes. Acute pulmonary emboli usually resolve <6 months. However, in some instances, thrombi transform into fibrous vascular obstructions, resulting in occlusion of the deep veins, or in chronic thromboembolic pulmonary hypertension (CTEPH). We proposed that dysregulated thrombus angiogenesis may contribute to thrombus persistence. APPROACH AND RESULTS: Mice with an endothelial cell-specific conditional deletion of vascular endothelial growth factor receptor 2/kinase insert domain protein receptor were used in a model of stagnant flow venous thrombosis closely resembling human deep vein thrombosis. Biochemical and functional analyses were performed on pulmonary endarterectomy specimens from patients with CTEPH, a human model of nonresolving venous thromboembolism. Endothelial cell-specific deletion of kinase insert domain protein receptor and subsequent ablation of thrombus vascularization delayed thrombus resolution. In accordance with these findings, organized human CTEPH thrombi were largely devoid of vascular structures. Several vessel-specific genes, such as kinase insert domain protein receptor, vascular endothelial cadherin, and podoplanin, were expressed at lower levels in white CTEPH thrombi than in organizing deep vein thrombi and organizing thrombi from aortic aneurysms. In addition, red CTEPH thrombi attenuated the angiogenic response induced by vascular endothelial growth factor. CONCLUSIONS: In the present work, we propose a mechanism of thrombus nonresolution demonstrating that endothelial cell-specific deletion of kinase insert domain protein receptor abates thrombus vessel formation, misguiding thrombus resolution. Medical conditions associated with the development of CTEPH may be compromising early thrombus angiogenesis.


Assuntos
Hipertensão Pulmonar/etiologia , Neovascularização Fisiológica , Tromboembolia Venosa/complicações , Trombose Venosa/complicações , Idoso , Proteínas Angiogênicas/genética , Proteínas Angiogênicas/metabolismo , Animais , Células Cultivadas , Doença Crônica , Modelos Animais de Doenças , Endarterectomia , Feminino , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/cirurgia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Neovascularização Fisiológica/genética , Fatores de Tempo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/deficiência , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Tromboembolia Venosa/sangue , Tromboembolia Venosa/genética , Tromboembolia Venosa/cirurgia , Trombose Venosa/sangue , Trombose Venosa/genética , Trombose Venosa/cirurgia
4.
Blood ; 122(19): 3376-84, 2013 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-24081660

RESUMO

Platelet endothelial cell adhesion molecule 1 (PECAM-1) is involved in leukocyte migration and angiogenesis, which are key components of venous thrombus resolution. This study investigated the effect of PECAM-1 deficiency on thrombus resolution in FVB/n mice and the extent to which levels of soluble PECAM-1 (sPECAM-1) correlate with delayed thrombus resolution in humans after acute symptomatic deep vein thrombosis (DVT). In a mouse stagnant flow venous thrombosis model Pecam-1(-/-) thrombi were larger, persisted for longer periods of time, and displayed attenuated macrophage invasion and decreased vessel formation in the presence of increased fibrosis. In humans, higher levels of truncated plasma sPECAM-1 possibly cleaved from cell surfaces, were found in patients with delayed thrombus resolution (assessed via duplex-based thrombus scoring) relative to those whose thrombi resolved (median, 25th/75th percentile): 92.5 (87.7/103.4) ng/mL vs 71.5 (51.1/81.0) ng/mL; P < .001. Furthermore, unresolved human deep vein thrombus specimens stained positively with antibodies specific for the extracellular, but not the cytoplasmic domain of PECAM-1, consistent with accumulation of cleaved PECAM-1. Our data suggest a regulatory role of PECAM-1 in venous thrombus resolution and suggest a predictive value of sPECAM-1 for postthrombotic syndrome (PTS) after acute DVT.


Assuntos
Molécula-1 de Adesão Celular Endotelial a Plaquetas/sangue , Síndrome Pós-Trombótica/sangue , Veias/metabolismo , Trombose Venosa/sangue , Idoso , Animais , Movimento Celular , Feminino , Fibrinólise/fisiologia , Deleção de Genes , Expressão Gênica , Humanos , Macrófagos/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Síndrome Pós-Trombótica/genética , Síndrome Pós-Trombótica/patologia , Estrutura Terciária de Proteína , Proteólise , Veias/patologia , Trombose Venosa/genética , Trombose Venosa/patologia
5.
Pulm Circ ; 3(4): 728-38, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25006391

RESUMO

Venous thromboembolism comprises deep-vein thrombosis, thrombus in transit, acute pulmonary embolism, and chronic thromboembolic pulmonary hypertension (CTEPH). Pulmonary thromboemboli commonly resolve, with restoration of normal pulmonary hemodynamics. When they fail to resorb, permanent occlusion of the deep veins and/or CTEPH are the consequences. Apart from endogenous fibrinolysis, venous thrombi resolve by a process of mechanical fragmentation, through organization of the thromboembolus by invasion of endothelial cells, leukocytes, and fibroblasts leading to recanalization. Recent data utilizing various models have contributed to a better understanding of venous thrombosis and the resolution process that is directed at maintaining vascular patency. This review summarizes the plasmatic and cellular components of venous thrombus formation and resolution.

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