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1.
Blood Adv ; 4(1): 207-216, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31935292

RESUMO

The intrinsic tenase complex (FIXa-FVIIIa) of the intrinsic coagulation pathway and, to a lesser extent, thrombin-mediated activation of FXI, are necessary to amplify tissue factor (TF)-FVIIa-initiated thrombin generation. In this study, we determined the contribution of murine FIX and FXI to TF-dependent thrombin generation in vitro. We further investigated TF-dependent FIX activation in mice and the contribution of this pathway to hemostasis. Thrombin generation was decreased in FIX- but not in FXI-deficient mouse plasma. Furthermore, injection of TF increased levels of FIXa-antithrombin complexes in both wild-type and FXI-/- mice. Genetic studies were used to determine the effect of complete deficiencies of either FIX or FXI on the survival of mice expressing low levels of TF. Low-TF;FIX-/y male mice were born at the expected frequency, but none survived to wean. In contrast, low-TF;FXI-/- mice were generated at the expected frequency at wean and had a 6-month survival equivalent to that of low-TF mice. Surprisingly, a deficiency of FXI, but not FIX, exacerbated the size of blood pools in low-TF placentas and led to acute hemorrhage and death of some pregnant dams. Our data indicate that FIX, but not FXI, is essential for survival of low-TF mice after birth. This finding suggests that TF-FVIIa-mediated activation of FIX plays a critical role in murine hemostasis. In contrast, FXI deficiency, but not FIX deficiency, exacerbated blood pooling in low-TF placentas, indicating a tissue-specific requirement for FXI in the murine placenta under conditions of low TF.

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.
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.
Platelets ; : 1-7, 2019 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-31608756

RESUMO

The ferric chloride models of arterial thrombosis are useful tools with which to investigate the cellular and molecular mechanisms that contribute to arterial thrombosis. Recent insights have, however, revealed the complex and multifaceted mechanism by which ferric chloride induces thrombus formation. Here, we discuss the strengths and weaknesses of the ferric chloride models of arterial thrombosis. Particular focus is given to the phenotypes of different knockout mice in the ferric chloride models and how these compare to other models with independent modes of initiation. Further, we discuss the relevance of the ferric chloride models to the human pathology of atherothrombotic disease.

5.
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
6.
J Exp Med ; 216(6): 1291-1300, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31048328

RESUMO

Macrophages resident in different organs express distinct genes, but understanding how this diversity fits into tissue-specific features is limited. Here, we show that selective expression of coagulation factor V (FV) by resident peritoneal macrophages in mice promotes bacterial clearance in the peritoneal cavity and serves to facilitate the well-known but poorly understood "macrophage disappearance reaction." Intravital imaging revealed that resident macrophages were nonadherent in peritoneal fluid during homeostasis. Bacterial entry into the peritoneum acutely induced macrophage adherence and associated bacterial phagocytosis. However, optimal control of bacterial expansion in the peritoneum also required expression of FV by the macrophages to form local clots that effectively brought macrophages and bacteria in proximity and out of the fluid phase. Thus, acute cellular adhesion and resident macrophage-induced coagulation operate independently and cooperatively to meet the challenges of a unique, open tissue environment. These events collectively account for the macrophage disappearance reaction in the peritoneal cavity.

7.
J Thromb Haemost ; 17(4): 699-707, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30927321

RESUMO

Murine models are widely used valuable tools to study deep vein thrombosis (VT). Leading experts in VT research came together through the American Venous Forum to develop a consensus on maximizing the utility and application of available mouse models of VT. In this work, we provide an algorithm for model selection, with discussion of the advantages, disadvantages, and applications of the main mouse models of VT. Additionally, we provide a detailed surgical description of the models with guidelines to validate surgical technique.

8.
Arterioscler Thromb Vasc Biol ; 39(3): 311-318, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30786739

RESUMO

Murine models are widely used valuable tools to study deep vein thrombosis. Leading experts in venous thrombosis research came together through the American Venous Forum to develop a consensus on maximizing the utility and application of available mouse models of venous thrombosis. In this work, we provide an algorithm for model selection, with discussion of the advantages, disadvantages, and applications of the main mouse models of venous thrombosis. Additionally, we provide a detailed surgical description of the models with guidelines to validate surgical technique.


Assuntos
Modelos Animais de Doenças , Camundongos , Trombose Venosa , Algoritmos , Animais , Cloretos/toxicidade , Eletrólise , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/patologia , Compostos Férricos/toxicidade , Radicais Livres , Hemorreologia , Ligadura , Recidiva , Projetos de Pesquisa , Veias/cirurgia , Trombose Venosa/induzido quimicamente , Trombose Venosa/etiologia , Trombose Venosa/fisiopatologia , Vênulas
9.
Arterioscler Thromb Vasc Biol ; 39(3): 331-338, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30700128

RESUMO

Activation of the intrinsic pathway of coagulation contributes to the pathogenesis of arterial and venous thrombosis. Critical insights into the involvement of intrinsic pathway factors have been derived from the study of gene-specific knockout animals and targeted inhibitors. Importantly, preclinical studies have indicated that targeting components of this pathway, including FXI (factor XI), FXII, and PKK (prekallikrein), reduces thrombosis with no significant effect on protective hemostatic pathways. This review highlights the advances made from studying the intrinsic pathway using gene-specific knockout animals and inhibitors in models of arterial and venous thrombosis. Development of inhibitors of activated FXI and FXII may reduce thrombosis with minimal increases in bleeding compared with current anticoagulant drugs.


Assuntos
Coagulação Sanguínea/fisiologia , Trombose/fisiopatologia , Animais , Anticoagulantes/efeitos adversos , Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Tempo de Sangramento , Coagulação Sanguínea/efeitos dos fármacos , Fatores de Coagulação Sanguínea/antagonistas & inibidores , Fatores de Coagulação Sanguínea/genética , Fatores de Coagulação Sanguínea/fisiologia , Modelos Animais de Doenças , Desenho de Drogas , Ativação Enzimática , Hemorragia/induzido quimicamente , Humanos , Camundongos Knockout , Primatas , Coelhos , Ratos , Trombose/tratamento farmacológico , Trombose/epidemiologia , Trombose/prevenção & controle
10.
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
12.
J Mol Cell Cardiol ; 122: 80-87, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30098988

RESUMO

OBJECTIVE: The anti-cancer anthracycline drug Doxorubicin (Dox) causes cardiotoxicity. We investigated the role of protease-activated receptor 1 (PAR-1) in Dox-induced cardiotoxicity. METHODS AND RESULTS: In vitro experiments revealed that PAR-1 enhanced Dox-induced mitochondrial dysfunction, reactive oxygen species and cell death of cardiac myocytes and cardiac fibroblasts. The contribution of PAR-1 to Dox-induced cardiotoxicity was investigated by subjecting PAR-1-/- mice and PAR-1+/+ mice to acute and chronic exposure to Dox. Heart function was measured by echocardiography. PAR-1-/- mice exhibited significant less cardiac injury and dysfunction compared to PAR-1+/+ mice after acute and chronic Dox administration. PAR-1-/- mice had reduced levels of nitrotyrosine, apoptosis and inflammation in their heart compared to PAR-1+/+ mice. Furthermore, inhibition of PAR-1 in wild-type mice with vorapaxar significantly reduced the acute Dox-induced cardiotoxicity. CONCLUSION: Our results indicate that activation of PAR-1 contributes to Dox-induced cardiotoxicity. Inhibition of PAR-1 may be a new approach to reduce Dox-induced cardiotoxicity in cancer patients.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Cardiotoxicidade/etiologia , Cardiotoxicidade/metabolismo , Doxorrubicina/efeitos adversos , Receptor PAR-1/metabolismo , Análise de Variância , Animais , Apoptose/efeitos dos fármacos , Permeabilidade da Membrana Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ecocardiografia , Fibroblastos/metabolismo , Traumatismos Cardíacos/metabolismo , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/citologia , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo
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
15.
Arterioscler Thromb Vasc Biol ; 38(4): 709-725, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29437578

RESUMO

Tissue factor (TF) is the high-affinity receptor and cofactor for factor (F)VII/VIIa. The TF-FVIIa complex is the primary initiator of blood coagulation and plays an essential role in hemostasis. TF is expressed on perivascular cells and epithelial cells at organ and body surfaces where it forms a hemostatic barrier. TF also provides additional hemostatic protection to vital organs, such as the brain, lung, and heart. Under pathological conditions, TF can trigger both arterial and venous thrombosis. For instance, atherosclerotic plaques contain high levels of TF on macrophage foam cells and microvesicles that drives thrombus formation after plaque rupture. In sepsis, inducible TF expression on monocytes leads to disseminated intravascular coagulation. In cancer patients, tumors release TF-positive microvesicles into the circulation that may contribute to venous thrombosis. TF also has nonhemostatic roles. For instance, TF-dependent activation of the coagulation cascade generates coagulation proteases, such as FVIIa, FXa, and thrombin, which induce signaling in a variety of cells by cleavage of protease-activated receptors. This review will focus on the roles of TF in protective hemostasis and pathological thrombosis.


Assuntos
Hemostasia , Tromboplastina/metabolismo , Trombose/sangue , Animais , Aterosclerose/sangue , Aterosclerose/complicações , Coagulação Sanguínea , Fator IX/metabolismo , Fator VIIa/metabolismo , Fator X/metabolismo , Fibrinolíticos/uso terapêutico , Regulação da Expressão Gênica , Hemostasia/efeitos dos fármacos , Humanos , Neoplasias/sangue , Neoplasias/complicações , Fatores de Risco , Sepse/sangue , Sepse/complicações , Transdução de Sinais , Tromboplastina/antagonistas & inibidores , Tromboplastina/genética , Trombose/tratamento farmacológico , Trombose/etiologia , Trombose/genética
17.
J Biol Chem ; 292(22): 9063-9074, 2017 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-28364042

RESUMO

Thiol isomerases such as protein-disulfide isomerase (PDI) direct disulfide rearrangements required for proper folding of nascent proteins synthesized in the endoplasmic reticulum. Identifying PDI substrates is challenging because PDI catalyzes conformational changes that cannot be easily monitored (e.g. compared with proteolytic cleavage or amino acid phosphorylation); PDI has multiple substrates; and it can catalyze either oxidation, reduction, or isomerization of substrates. Kinetic-based substrate trapping wherein the active site motif CGHC is modified to CGHA to stabilize a PDI-substrate intermediate is effective in identifying some substrates. A limitation of this approach, however, is that it captures only substrates that are reduced by PDI, whereas many substrates are oxidized by PDI. By manipulating the highly conserved -GH- residues in the CGHC active site of PDI, we created PDI variants with a slowed reaction rate toward substrates. The prolonged intermediate state allowed us to identify protein substrates that have biased affinities for either oxidation or reduction by PDI. Because extracellular PDI is critical for thrombus formation but its extracellular substrates are not known, we evaluated the ability of these bidirectional trapping PDI variants to trap proteins released from platelets and on the platelet surface. Trapped proteins were identified by mass spectroscopy. Of the trapped substrate proteins identified by mass spectroscopy, five proteins, cathepsin G, glutaredoxin-1, thioredoxin, GP1b, and fibrinogen, showed a bias for oxidation, whereas annexin V, heparanase, ERp57, kallekrein-14, serpin B6, tetranectin, and collagen VI showed a bias for reduction. These bidirectional trapping variants will enable more comprehensive identification of thiol isomerase substrates and better elucidation of their cellular functions.


Assuntos
Plaquetas/enzimologia , Isomerases de Dissulfetos de Proteínas/química , Domínio Catalítico , Humanos , Cinética , Isomerases de Dissulfetos de Proteínas/metabolismo , Especificidade por Substrato
18.
Arterioscler Thromb Vasc Biol ; 36(2): 245-52, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26681755

RESUMO

Deep vein thrombosis and common complications, including pulmonary embolism and post-thrombotic syndrome, represent a major source of morbidity and mortality worldwide. Experimental models of venous thrombosis have provided considerable insight into the cellular and molecular mechanisms that regulate thrombus formation and subsequent resolution. Here, we critically appraise the ex vivo and in vivo techniques used to assess venous thrombosis in these models. Particular attention is paid to imaging modalities, including magnetic resonance imaging, micro-computed tomography, and high-frequency ultrasound that facilitate longitudinal assessment of thrombus size and composition.


Assuntos
Veias , Trombose Venosa/diagnóstico , Animais , Biomarcadores/metabolismo , Velocidade do Fluxo Sanguíneo , Diagnóstico por Imagem/métodos , Valor Preditivo dos Testes , Prognóstico , Fluxo Sanguíneo Regional , Veias/metabolismo , Veias/patologia , Veias/fisiopatologia , Trombose Venosa/metabolismo , Trombose Venosa/patologia , Trombose Venosa/fisiopatologia
19.
Thromb Res ; 136(6): 1285-90, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26489729

RESUMO

INTRODUCTION: The assessment of thrombus size following treatments directed at preventing thrombosis or enhancing its resolution has generally relied on physical or histological methods. This cross-sectional design imposes the need for increased numbers of animals for experiments. Micro-computed tomography (microCT) has been used to detect the presence of venous thrombus in experimental models but has yet to be used in a quantitative manner. In this study, we investigate the use of contrast-enhanced microCT for the longitudinal assessment of experimental venous thrombus resolution. MATERIALS AND METHODS: Thrombi induced by stenosis of the inferior vena cava in mice were imaged by contrast-enhanced microCT at 1, 7 and 14 days post-induction (n=18). Thrombus volumes were determined longitudinally by segmentation and 3D volume reconstruction of microCT scans and by standard end-point histological analysis at day 14. An additional group of thrombi were analysed solely by histology at 1, 7 and 14 days post-induction (n=15). RESULTS: IVC resident thrombus was readily detectable by contrast-enhanced microCT. MicroCT-derived measurements of thrombus volume correlated well with time-matched histological analyses (ICC=0.75, P<0.01). Thrombus volumes measured by microCT were significantly greater than those derived from histological analysis (P<0.001). Intra- and inter-observer analyses were highly correlated (ICC=0.99 and 0.91 respectively, P<0.0001). Further histological analysis revealed noticeable levels of contrast agent extravasation into the thrombus that was associated with the presence of neovascular channels, macrophages and intracellular iron deposits. CONCLUSION: Contrast-enhanced microCT represents a reliable and reproducible method for the longitudinal assessment of venous thrombus resolution providing powerful paired data.


Assuntos
Ouro/química , Nanopartículas Metálicas/química , Trombose Venosa/diagnóstico por imagem , Microtomografia por Raio-X/métodos , Animais , Meios de Contraste/química , Estudos Transversais , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Ferro/química , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Animais , Neovascularização Fisiológica , Variações Dependentes do Observador , Reprodutibilidade dos Testes , Trombose/imunologia , Veia Cava Inferior/patologia
20.
Semin Thromb Hemost ; 41(6): 615-20, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26276933

RESUMO

Surgery is associated with an increased risk of venous thromboembolic events (VTE) including deep vein thrombosis and pulmonary embolism. Although the current treatment regiments such as mechanical manipulation and administration of pharmacological prophylaxis significantly reduced the incidence of postsurgical VTE, they remain a major cause of postoperative morbidity and mortality worldwide. The pathophysiology of venous thrombosis traditionally emphasizes the series of factors that constitute Virchow triad of factors. However, inflammation can also be a part of this by giving rise to a hypercoagulable state and endothelial damage. The inflammatory response after surgery, which is initiated by a cytokine "storm" and occurs within hours of surgery, creates a prothrombotic environment that is further accentuated by several cellular processes including neutrophil extracellular traps formation, platelet activation, and the generation of tissue factor-bearing microparticles. Although such inflammatory markers are elevated in undergoing surgery, the precise mechanism by which they give rise to venous thrombosis is poorly understood. Here, we discuss the potential mechanisms linking inflammation to thrombosis, and highlight strategies that may minimize surgical inflammation and reduce the incidence of postoperative VTE.


Assuntos
Inflamação/sangue , Complicações Pós-Operatórias/sangue , Tromboembolia Venosa/etiologia , Anticoagulantes/uso terapêutico , Micropartículas Derivadas de Células , Citocinas/sangue , Endotélio Vascular/fisiopatologia , Armadilhas Extracelulares/imunologia , Previsões , Humanos , Inflamação/etiologia , Mediadores da Inflamação/metabolismo , Procedimentos Cirúrgicos Minimamente Invasivos , Ativação Plaquetária , Complicações Pós-Operatórias/imunologia , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/terapia , Meias de Compressão , Trombofilia/etiologia , Tromboembolia Venosa/sangue , Tromboembolia Venosa/imunologia , Tromboembolia Venosa/prevenção & controle , Tromboembolia Venosa/terapia
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