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1.
J Biomed Sci ; 29(1): 52, 2022 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-35820906

RESUMO

BACKGROUND: Coronavirus-induced disease 19 (COVID-19) infects more than three hundred and sixty million patients worldwide, and people with severe symptoms frequently die of acute respiratory distress syndrome (ARDS). Recent studies indicated that excessive neutrophil extracellular traps (NETs) contributed to immunothrombosis, thereby leading to extensive intravascular coagulopathy and multiple organ dysfunction. Thus, understanding the mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced NET formation would be helpful to reduce thrombosis and prevent ARDS in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: We incubated SARS-CoV-2 with neutrophils in the presence or absence of platelets to observe NET formation. We further isolated extracellular vesicles from COVID-19 patients' sera (COVID-19-EVs) to examine their ability to induce NET formation. RESULTS: We demonstrated that antagonistic mAbs against anti-CLEC5A mAb and anti-TLR2 mAb can inhibit COVID-19-EVs-induced NET formation, and generated clec5a-/-/tlr2-/- mice to confirm the critical roles of CLEC5A and TLR2 in SARS-CoV-2-induced lung inflammation in vivo. We found that virus-free extracellular COVID-19 EVs induced robust NET formation via Syk-coupled C-type lectin member 5A (CLEC5A) and TLR2. Blockade of CLEC5A inhibited COVID-19 EVs-induced NETosis, and simultaneous blockade of CLEC5A and TLR2 further suppressed SARS-CoV-2-induced NETosis in vitro. Moreover, thromboinflammation was attenuated dramatically in clec5a-/-/tlr2-/- mice. CONCLUSIONS: This study demonstrates that SARS-CoV-2-activated platelets produce EVs to enhance thromboinflammation via CLEC5A and TLR2, and highlight the importance of CLEC5A and TLR2 as therapeutic targets to reduce the risk of ARDS in COVID-19 patients.


Assuntos
COVID-19 , Lectinas Tipo C , Neutrófilos , Pneumonia , Síndrome do Desconforto Respiratório , SARS-CoV-2 , Trombose , Animais , Plaquetas/imunologia , Plaquetas/patologia , Plaquetas/virologia , COVID-19/sangue , COVID-19/imunologia , Humanos , Lectinas Tipo C/imunologia , Camundongos , Neutrófilos/imunologia , Neutrófilos/patologia , Neutrófilos/virologia , Pneumonia/imunologia , Pneumonia/patologia , Pneumonia/virologia , Receptores de Superfície Celular , Síndrome do Desconforto Respiratório/imunologia , Síndrome do Desconforto Respiratório/virologia , SARS-CoV-2/imunologia , Trombose/sangue , Trombose/imunologia , Trombose/virologia , Receptor 2 Toll-Like/imunologia
2.
Int J Mol Sci ; 23(3)2022 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-35163180

RESUMO

Spontaneous venous thrombosis is often the first clinical sign of cancer, and it is linked to a worsened survival rate. Traditionally, tumor-cell induced platelet activation has been the main actor studied in cancer-associated-thrombosis. However, platelet involvement alone does not seem to be sufficient to explain this heightened pro-thrombotic state. Neutrophils are emerging as key players in both thrombus generation and cancer progression. Neutrophils can impact thrombosis through the release of pro-inflammatory cytokines and expression of molecules like P-selectin and Tissue Factor (TF) on their membrane and on neutrophil-derived microvesicles. Their role in cancer progression is evidenced by the fact that patients with high blood-neutrophil counts have a worsened prognosis. Tumors can attract neutrophils to the cancer site via pro-inflammatory cytokine secretions and induce a switch to pro-tumoral (or N2) neutrophils, which support metastatic spread and have an immunosuppressive role. They can also expel their nuclear contents to entrap pathogens forming Neutrophil Extracellular Traps (NETs) and can also capture coagulation factors, enhancing the thrombus formation. These NETs are also known to have pro-tumoral effects by supporting the metastatic process. Here, we strived to do a comprehensive literature review of the role of neutrophils as drivers of both cancer-associated thrombosis (CAT) and cancer progression.


Assuntos
Neoplasias/metabolismo , Neutrófilos/metabolismo , Trombose/imunologia , Plaquetas/metabolismo , Armadilhas Extracelulares/metabolismo , Humanos , Neoplasias/imunologia , Neutrófilos/imunologia , Selectina-P/metabolismo , Ativação Plaquetária/imunologia , Ativação Plaquetária/fisiologia , Tromboplastina/metabolismo , Trombose/metabolismo , Trombose Venosa/metabolismo
3.
Rheumatology (Oxford) ; 61(3): 1243-1254, 2022 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-34015111

RESUMO

OBJECTIVE: Anti-ß-2 glycoprotein I (anti-ß2GPI) antibodies, defined as primary pathogenic antibody in antiphospholipid syndrome (APS). It has been reported that IgG Fc N-glycosylation affects IgG effector, we aim to investigate the association of Fc glycosylation profiles of purified anti-ß2GP1 IgG with clinical features of APS. METHODS: We purify anti-ß2GPI IgG and total IgG from 82 APS patients including nine catastrophic antiphospholipid syndrome (CAPS) patients, as well as total IgG from 103 healthy controls to quantitatively analyse all detectable Fc N-glycanforms of all IgG subclasses with Multiple Reaction Monitoring (MRM) method based on UPLC-ESI-QqQ mass spectrometry. RESULTS: Both purified anti-ß2GPI IgG and APS total IgG showed altered N-glycan profiles when compared with healthy control (HC) IgG. Anti-ß2GPI IgG presented with lower galactosylation, increased bisection and core fucosylation compared with APS total IgG and HC IgG. We found higher galactosylation of aß2GPI IgG2 in thrombotic APS compared with the obstetric APS, and lower galactosylation of aß2GPI IgG2 associated with late pregnancy morbidity. Moreover, low galactosylation of all anti-ß2GPI IgG subclasses, increased bisection and core fucosylation of anti-ß2GPI IgG1/2 were strongly associated with CAPS and triple positivity of antiphospholipid antibodies (aPLs). CONCLUSION: We comprehensively characterize the N-Glycans landscape of both anti-ß2GP1 and total IgG in APS. Altered N-glycan profiles of anti-ß2GPI IgG enables enabled the antibodies with proinflammatory properties. Furthermore, we associated levels of IgG Fc-glycosylation with clinical features antiphospholipid syndrome. These findings could increase our understanding of anti-ß2GPI antibody mediated mechanisms in APS and be used to develop diagnostics and new target treatments.


Assuntos
Anticorpos Antifosfolipídeos/imunologia , Síndrome Antifosfolipídica/imunologia , Imunoglobulina G/imunologia , Complicações na Gravidez/imunologia , Trombose/imunologia , beta 2-Glicoproteína I/imunologia , Feminino , Humanos , Gravidez
4.
Crit Care Med ; 50(1): e80-e86, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34259661

RESUMO

OBJECTIVES: Vaccine-induced immune thrombotic thrombocytopenia is an unexpected consequence of the coronavirus disease 2019 pandemic era. We reviewed the pathogenesis, clinical presentation, diagnosis, and treatment of this rare side effect. DATA SOURCES: Online search of published medical literature through PubMed, Scopus, Web of Science, and Google Scholar using the terms "COVID-19," "vaccine," "thrombosis" was performed. STUDY SELECTION: Articles were chosen for inclusion based on their relevance to coronavirus disease 2019, vaccine, and thrombosis. DATA SYNTHESIS: Vaccine-induced immune thrombotic thrombocytopenia manifests most often as unusual thromboses (cerebral venous sinus thrombosis, splanchnic vein thrombosis) but sometimes also "usual" thromboses (arterial stroke, pulmonary embolism, deep-vein thrombosis), with oftentimes severe thrombocytopenia, that becomes clinically evident 5-30 days after adenovirus-vectored coronavirus disease 2019 vaccine administration. Most patients have disseminated intravascular coagulation. These features are the result of vaccine-triggered formation of anti-platelet factor 4 immunoglobulin G that activate platelets, clinically mimicking autoimmune heparin-induced thrombocytopenia. Early recognition based on thrombosis (sometimes, hemorrhage), thrombocytopenia, and d-dimer elevation within the day 5-30 postvaccine "window" is important given treatment with high-dose IV immunoglobulin plus nonheparin anticoagulation. CONCLUSIONS: Vaccine-induced immune thrombotic thrombocytopenia is a serious complication of vaccination that is not feasible to anticipate or prevent. When the patient presents with sustained headache, neurologic symptoms/signs, abdominal pain, dyspnea, or limb pain/swelling beginning 5-30 days post vaccination, platelet count and d-dimer must be measured, and imaging for thrombosis performed. Confirmation of vaccine-induced immune thrombotic thrombocytopenia diagnosis should be ordered (platelet factor 4/polyanion enzyme-linked immunosorbent assay; platelet factor 4-enhanced platelet activation testing) as treatment is initiated (nonheparin anticoagulation, IV immunoglobulin).


Assuntos
Vacinas contra COVID-19/efeitos adversos , Trombocitopenia/induzido quimicamente , Trombose/induzido quimicamente , Fatores Etários , COVID-19/prevenção & controle , Vacinas contra COVID-19/administração & dosagem , Ensaio de Imunoadsorção Enzimática , Humanos , SARS-CoV-2 , Fatores Sexuais , Trombocitopenia/imunologia , Trombose/imunologia
5.
Hepatol Commun ; 6(2): 255-269, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34658172

RESUMO

Liver injury, characterized predominantly by elevated aspartate aminotransferase and alanine aminotransferase, is a common feature of coronavirus disease 2019 (COVID-19) symptoms caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). Additionally, SARS-CoV-2 infection is associated with acute-on-chronic liver failure in patients with cirrhosis and has a notably elevated mortality in patients with alcohol-related liver disease compared to other etiologies. Direct viral infection of the liver with SARS-CoV-2 remains controversial, and alternative pathophysiologic explanations for its hepatic effects are an area of active investigation. In this review, we discuss the effects of SARS-CoV-2 and the inflammatory environment it creates on endothelial cells and platelets more generally and then with a hepatic focus. In doing this, we present vascular inflammation and thrombosis as a potential mechanism of liver injury and liver-related complications in COVID-19.


Assuntos
Transtornos Plaquetários/virologia , COVID-19/fisiopatologia , Endotélio Vascular/virologia , Inflamação/virologia , Hepatopatias/virologia , Trombose/virologia , Transtornos Plaquetários/imunologia , Transtornos Plaquetários/fisiopatologia , COVID-19/imunologia , Endotélio Vascular/imunologia , Endotélio Vascular/fisiopatologia , Humanos , Inflamação/imunologia , Inflamação/fisiopatologia , Hepatopatias/imunologia , Hepatopatias/fisiopatologia , Trombose/imunologia , Trombose/fisiopatologia
6.
Am J Surg Pathol ; 46(1): 89-96, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34081038

RESUMO

Approximately 20% of patients with symptomatic syndrome-associated coronavirus-2 (SARS-CoV-2) infection have gastrointestinal bleeding and/or diarrhea. Most are managed without endoscopic evaluation because the risk of practitioner infection outweighs the value of biopsy analysis unless symptoms are life-threatening. As a result, much of what is known about the gastrointestinal manifestations of coronavirus disease-2019 (COVID-19) has been gleaned from surgical and autopsy cases that suffer from extensive ischemic injury and/or poor preservation. There are no detailed reports describing any other gastrointestinal effects of SARS-CoV-2 even though >3,000,000 people have died from COVID-19 worldwide. The purpose of this study is to report the intestinal findings related to SARS-CoV-2 infection by way of a small case series including one with evidence of direct viral cytopathic effect and 2 with secondary injury attributed to viral infection. Infection can be confirmed by immunohistochemical stains directed against SARS-CoV-2 spike protein, in situ hybridization for spike protein-encoding RNA, and ultrastructural visualization of viruses within the epithelium. It induces cytoplasmic blebs and tufted epithelial cells without inflammation and may not cause symptoms. In contrast, SARS-CoV-2 infection can cause gastrointestinal symptoms after the virus is no longer detected, reflecting systemic activation of cytokine and complement cascades rather than direct viral injury. Reversible mucosal ischemia features microvascular injury with hemorrhage, small vessel thrombosis, and platelet-rich thrombi. Systemic cytokine elaboration and dysbiosis likely explain epithelial cell injury that accompanies diarrheal symptoms. These observations are consistent with clinical and in vitro data and contribute to our understanding of the protean manifestations of COVID-19.


Assuntos
COVID-19/patologia , Enteropatias/patologia , Enteropatias/virologia , Intestinos/patologia , Intestinos/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Biópsia , COVID-19/diagnóstico , COVID-19/imunologia , Citocinas/metabolismo , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/imunologia , Hemorragia Gastrointestinal/patologia , Hemorragia Gastrointestinal/virologia , Humanos , Enteropatias/diagnóstico , Enteropatias/imunologia , Intestinos/imunologia , Isquemia/diagnóstico , Isquemia/imunologia , Isquemia/patologia , Isquemia/virologia , Masculino , Trombose/diagnóstico , Trombose/imunologia , Trombose/patologia , Trombose/virologia
7.
Front Immunol ; 12: 775168, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34868042

RESUMO

COVID-19 is characterized by virus-induced injury leading to multi-organ failure, together with inflammatory reaction, endothelial cell (EC) injury, and prothrombotic coagulopathy with thrombotic events. Complement system (C) via its cross-talk with the contact and coagulation systems contributes significantly to the severity and pathological consequences due to SARS-CoV-2 infection. These immunopathological mechanisms overlap in COVID-19 and pre-eclampsia (PE). Thus, mothers contracting SARS-CoV-2 infection during pregnancy are more vulnerable to developing PE. SARS-CoV-2 infection of ECs, via its receptor ACE2 and co-receptor TMPRSS2, can provoke endothelial dysfunction and disruption of vascular integrity, causing hyperinflammation and hypercoagulability. This is aggravated by bradykinin increase due to inhibition of ACE2 activity by the virus. C is important for the progression of normal pregnancy, and its dysregulation can impact in the form of PE-like syndrome as a consequence of SARS-CoV-2 infection. Thus, there is also an overlap between treatment regimens of COVID-19 and PE. C inhibitors, especially those targeting C3 or MASP-2, are exciting options for treating COVID-19 and consequent PE. In this review, we examine the role of C, contact and coagulation systems as well as endothelial hyperactivation with respect to SARS-CoV-2 infection during pregnancy and likely development of PE.


Assuntos
COVID-19/imunologia , Proteínas do Sistema Complemento/imunologia , Pré-Eclâmpsia/imunologia , Complicações Infecciosas na Gravidez/imunologia , COVID-19/tratamento farmacológico , COVID-19/fisiopatologia , Proteínas Inativadoras do Complemento/uso terapêutico , Endotélio/imunologia , Feminino , Humanos , Pré-Eclâmpsia/fisiopatologia , Pré-Eclâmpsia/prevenção & controle , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Complicações Infecciosas na Gravidez/fisiopatologia , SARS-CoV-2 , Trombose/imunologia
8.
Med Sci Monit ; 27: e935134, 2021 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-34961758

RESUMO

The pathogenesis of the aortic aneurysm (AA) includes several mechanisms, such as chronic sterile inflammation and homeostasis imbalance, with arteriosclerosis, hemodynamic forces, and genetic factors. In addition to the roles of these processes in the development of AA, neutrophilic activity may play a pivotal role (mostly in inflammation and thrombus formation). Neutrophils, which play a crucial role in innate immunity, can release neutrophil extracellular traps (NETs), one of the mechanisms against fighting pathogens, beside phagocytosis and degranulation. NETs are structures composed of nuclear elements (eg, chromatin and modified histones) and granular and cytoplasmic components, which can lead to inflammation and coagulation changes. In addition, the exacerbation of NETosis (the process of NET formation) can be noticed in vascular diseases, including in the development of AA and myocardial infarction and in diabetes, hypertension, and COPD, which are the risk factors of the presence of AA. The discharge of NETs, which are extracellular materials formed by citrullinated histones (Cit-H), cell-free DNA fibers (cf-DNA), and granular and cytoplasmic molecules, is a newly identified method of neutrophil activation that can be activated by endogenous inflammatory stimuli, which contribute to AA development. Cit-H and cf-DNA can be used as biomarkers of AA growth. By understanding the neutrophilic influence of NET release, a new pathway of screening AA growth (by measurement of biomarkers of NETosis) and pharmacological assessment (by repression of NET formation) can be developed. This review summarizes the current knowledge about the influence of NETs on AA growth in human and animal studies.


Assuntos
Aneurisma Aórtico/imunologia , Aterosclerose/imunologia , Armadilhas Extracelulares/imunologia , Inflamação/imunologia , Neutrófilos/imunologia , Trombose/imunologia , Animais , Aterosclerose/fisiopatologia , Endotélio Vascular/fisiopatologia , Humanos , Inflamação/fisiopatologia , Trombose/fisiopatologia
9.
OMICS ; 25(12): 770-781, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34807729

RESUMO

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a systemic disease affecting not only the lungs but also multiple organ systems. Clinical studies implicate that SARS-CoV-2 infection causes imbalance of cellular homeostasis and immune response that trigger cytokine storm, oxidative stress, thrombosis, and insulin resistance. Mathematical modeling can offer in-depth understanding of the SARS-CoV-2 infection and illuminate how subcellular mechanisms and feedback loops underpin disease progression and multiorgan failure. We report here a mathematical model of SARS-CoV-2 infection pathway network with cytokine storm, oxidative stress, thrombosis, insulin resistance, and nitric oxide (NO) pathways. The biochemical systems theory model shows autocrine loops with positive feedback enabling excessive immune response, cytokines, transcription factors, and interferons, which can imbalance homeostasis of the system. The simulations suggest that changes in immune response led to uncontrolled release of cytokines and chemokines, including interleukin (IL)-1ß, IL-6, and tumor necrosis factor α (TNFα), and affect insulin, coagulation, and NO signaling pathways. Increased production of NETs (neutrophil extracellular traps), thrombin, PAI-1 (plasminogen activator inhibitor-1), and other procoagulant factors led to thrombosis. By analyzing complex biochemical reactions, this model forecasts the key intermediates, potential biomarkers, and risk factors at different stages of COVID-19. These insights can be useful for drug discovery and development, as well as precision treatment of multiorgan implications of COVID-19 as seen in systems medicine.


Assuntos
COVID-19/imunologia , Síndrome da Liberação de Citocina/imunologia , Resistência à Insulina/imunologia , Óxido Nítrico/imunologia , Estresse Oxidativo/imunologia , SARS-CoV-2/imunologia , Trombose/imunologia , COVID-19/virologia , Síndrome da Liberação de Citocina/virologia , Citocinas/imunologia , Humanos , Modelos Teóricos , Transdução de Sinais/imunologia , Trombose/virologia
10.
Viruses ; 13(10)2021 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-34696334

RESUMO

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) commonly complicates with coagulopathy. A syndrome called Long-COVID-19 is emerging recently in COVID-19 survivors, characterized, in addition to the persistence of symptoms typical of the acute phase, by alterations in inflammatory and coagulation parameters due to endothelial damage. The related disseminated intravascular coagulation (DIC) can be associated with high death rates in COVID-19 patients. It is possible to find a prothrombotic state also in Long-COVID-19. Early administration of anticoagulants in COVID-19 was suggested in order to improve patient outcomes, although exact criteria for their application were not well-established. Low-molecular-weight heparin (LMWH) was commonly adopted for counteracting DIC and venous thromboembolism (VTE), due to its pharmacodynamics and anti-inflammatory properties. However, the efficacy of anticoagulant therapy for COVID-19-associated DIC is still a matter of debate. Thrombin and Factor Xa (FXa) are well-known components of the coagulation cascade. The FXa is known to strongly promote inflammation as the consequence of increased cytokine expression. Endothelial cells and mononuclear leucocytes release cytokines, growth factors, and adhesion molecules due to thrombin activation. On the other hand, cytokines can activate coagulation. The cross-talk between coagulation and inflammation is mediated via protease-activated receptors (PARs). These receptors might become potential targets to be considered for counteracting the clinical expressions of COVID-19. SARS-CoV-2 is effectively able to activate local and circulating coagulation factors, thus inducing the generation of disseminated coagula. LMWH may be considered as the new frontier in the treatment of COVID-19 and Long-COVID-19. Indeed, direct oral anticoagulants (DOACs) may be an alternative option for both early and later treatment of COVID-19 patients due to their ability to inhibit PARs. The aim of this report was to evaluate the role of anticoagulants-and DOACs in particular in COVID-19 and Long-COVID-19 patients. We report the case of a COVID-19 patient who, after administration of enoxaparin developed DIC secondary to virosis and positivity for platelet factor 4 (PF4) and a case of Long-COVID with high residual cardiovascular risk and persistence of blood chemistry of inflammation and procoagulative state.


Assuntos
COVID-19/complicações , Síndrome de Resposta Inflamatória Sistêmica/fisiopatologia , Trombose/fisiopatologia , Anticoagulantes/uso terapêutico , Coagulação Sanguínea/efeitos dos fármacos , Transtornos da Coagulação Sanguínea/tratamento farmacológico , COVID-19/tratamento farmacológico , Células Endoteliais , Inibidores do Fator Xa/uso terapêutico , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Inflamação/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/patogenicidade , Síndrome de Resposta Inflamatória Sistêmica/tratamento farmacológico , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Trombose/tratamento farmacológico , Trombose/imunologia
11.
Int J Mol Sci ; 22(19)2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34639132

RESUMO

Novel coronavirus SARS-CoV-2 has resulted in a global pandemic with worldwide 6-digit infection rates and thousands of death tolls daily. Enormous efforts are undertaken to achieve high coverage of immunization to reach herd immunity in order to stop the spread of SARS-CoV-2 infection. Several SARS-CoV-2 vaccines based on mRNA, viral vectors, or inactivated SARS-CoV-2 virus have been approved and are being applied worldwide. However, the recent increased numbers of normally very rare types of thromboses associated with thrombocytopenia have been reported, particularly in the context of the adenoviral vector vaccine ChAdOx1 nCoV-19 from Astra Zeneca. The statistical prevalence of these side effects seems to correlate with this particular vaccine type, i.e., adenoviral vector-based vaccines, but the exact molecular mechanisms are still not clear. The present review summarizes current data and hypotheses for molecular and cellular mechanisms into one integrated hypothesis indicating that coagulopathies, including thromboses, thrombocytopenia, and other related side effects, are correlated to an interplay of the two components in the vaccine, i.e., the spike antigen and the adenoviral vector, with the innate and immune systems, which under certain circumstances can imitate the picture of a limited COVID-19 pathological picture.


Assuntos
Vacinas contra COVID-19/efeitos adversos , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Trombocitopenia/etiologia , Trombose/etiologia , Adenoviridae/imunologia , Animais , COVID-19/imunologia , Vacinas contra COVID-19/imunologia , Vetores Genéticos/efeitos adversos , Vetores Genéticos/imunologia , Humanos , Púrpura Trombocitopênica Idiopática/etiologia , Púrpura Trombocitopênica Idiopática/imunologia , Glicoproteína da Espícula de Coronavírus/efeitos adversos , Trombocitopenia/imunologia , Trombose/imunologia , Vacinação/efeitos adversos
13.
Front Immunol ; 12: 752612, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34616409

RESUMO

Background: Lymphopenia and the neutrophil/lymphocyte ratio may have prognostic value in COVID-19 severity. Objective: We investigated neutrophil subsets and functions in blood and bronchoalveolar lavage (BAL) of COVID-19 patients on the basis of patients' clinical characteristics. Methods: We used a multiparametric cytometry profiling based to mature and immature neutrophil markers in 146 critical or severe COVID-19 patients. Results: The Discovery study (38 patients, first pandemic wave) showed that 80% of Intensive Care Unit (ICU) patients develop strong myelemia with CD10-CD64+ immature neutrophils (ImNs). Cellular profiling revealed three distinct neutrophil subsets expressing either the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), the interleukin-3 receptor alpha (CD123), or programmed death-ligand 1 (PD-L1) overrepresented in ICU patients compared to non-ICU patients. The proportion of LOX-1- or CD123-expressing ImNs is positively correlated with clinical severity, cytokine storm (IL-1ß, IL-6, IL-8, TNFα), acute respiratory distress syndrome (ARDS), and thrombosis. BALs of patients with ARDS were highly enriched in LOX-1-expressing ImN subsets and in antimicrobial neutrophil factors. A validation study (118 patients, second pandemic wave) confirmed and strengthened the association of the proportion of ImN subsets with disease severity, invasive ventilation, and death. Only high proportions of LOX-1-expressing ImNs remained strongly associated with a high risk of severe thrombosis independently of the plasma antimicrobial neutrophil factors, suggesting an independent association of ImN markers with their functions. Conclusion: LOX-1-expressing ImNs may help identifying COVID-19 patients at high risk of severity and thrombosis complications.


Assuntos
COVID-19/complicações , Neutrófilos/imunologia , Receptores Depuradores Classe E/genética , Trombose/etiologia , Adulto , Idoso , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Líquido da Lavagem Broncoalveolar/imunologia , COVID-19/genética , COVID-19/imunologia , COVID-19/virologia , Estado Terminal , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-3/genética , Subunidade alfa de Receptor de Interleucina-3/imunologia , Interleucina-8/genética , Interleucina-8/imunologia , Masculino , Pessoa de Meia-Idade , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/genética , Síndrome do Desconforto Respiratório/imunologia , SARS-CoV-2/fisiologia , Receptores Depuradores Classe E/imunologia , Trombose/genética , Trombose/imunologia
14.
Front Immunol ; 12: 716361, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34491250

RESUMO

Background: COVID-19 pathology is associated with exuberant inflammation, vascular damage, and activation of coagulation. In addition, complement activation has been described and is linked to disease pathology. However, few studies have been conducted in cancer patients. Objective: This study examined complement activation in response to COVID-19 in the setting of cancer associated thromboinflammation. Methods: Markers of complement activation (C3a, C5a, sC5b-9) and complement inhibitors (Factor H, C1-Inhibitor) were evaluated in plasma of cancer patients with (n=43) and without (n=43) COVID-19 and stratified based on elevated plasma D-dimer levels (>1.0 µg/ml FEU). Markers of vascular endothelial cell dysfunction and platelet activation (ICAM-1, thrombomodulin, P-selectin) as well as systemic inflammation (pentraxin-3, serum amyloid A, soluble urokinase plasminogen activator receptor) were analyzed to further evaluate the inflammatory response. Results: Increases in circulating markers of endothelial cell dysfunction, platelet activation, and systemic inflammation were noted in cancer patients with COVID-19. In contrast, complement activation increased in cancer patients with COVID-19 and elevated D-dimers. This was accompanied by decreased C1-Inhibitor levels in patients with D-dimers > 5 ug/ml FEU. Conclusion: Complement activation in cancer patients with COVID-19 is significantly increased in the setting of thromboinflammation. These findings support a link between coagulation and complement cascades in the setting of inflammation.


Assuntos
COVID-19/imunologia , Ativação do Complemento/imunologia , Inflamação/imunologia , Neoplasias/imunologia , SARS-CoV-2/imunologia , Trombose/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , COVID-19/sangue , COVID-19/virologia , Inativadores do Complemento/sangue , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Humanos , Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Ativação Plaquetária/imunologia , Estudos Retrospectivos , SARS-CoV-2/fisiologia , Trombose/sangue , Adulto Jovem
15.
Eur J Pharmacol ; 910: 174490, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34492283

RESUMO

Stent-induced vascular injury is manifested by removal of the endothelium and phenotypic changes in the underlying medial smooth muscle cells layer. This results in pathological vascular remodelling primarily contributed to smooth muscle cell proliferation and leads to vessel re-narrowing; neointimal hyperplasia. Current drug-eluting stents release non-selective anti-proliferative drugs such as paclitaxel from the stent surface that not only inhibit growth of smooth muscle cells but also delay endothelial healing, potentially leading to stent thrombosis. This highlights the need for novel bioactive stent coating candidates with the ability to target key events in the pathogenesis of in-stent restenosis. Citric acid, a molecule with anti-coagulant properties, was investigated against L-ascorbic acid, an antioxidant molecule reported to preferentially promote endothelial growth, and paclitaxel, a typically used anti-proliferative stent coating. Citric acid was found to exhibit growth supporting properties on endothelial cells across a range of concentrations that were significantly better than the model stent coating drug paclitaxel and better than the ascorbic acid which inhibited endothelial proliferation at concentrations ≥100 µg/ml. It was demonstrated that a citric acid-paclitaxel combination treatment significantly improves cell viability in comparison to paclitaxel only treated cells, with endothelial cells exhibiting greater cell recovery over smooth muscle cells. Furthermore, cell treatment with citric acid was found to reduce inflammation in a lipopolysaccharide (LPS)-induced in vitro inflammation model by significantly reducing interleukin 6 expression. Thus, this study demonstrates that citric acid is a promising candidate for use as a coating in stents and other endovascular devices.


Assuntos
Ácido Cítrico/administração & dosagem , Stents Farmacológicos/efeitos adversos , Trombose/prevenção & controle , Animais , Anti-Inflamatórios/administração & dosagem , Antioxidantes/administração & dosagem , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/imunologia , Células Endoteliais/patologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Humanos , Camundongos , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/imunologia , Miócitos de Músculo Liso/patologia , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Trombose/induzido quimicamente , Trombose/imunologia , Trombose/patologia , Remodelação Vascular/efeitos dos fármacos
16.
Clin Appl Thromb Hemost ; 27: 10760296211040110, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34541935

RESUMO

Since the outbreak of Covid-19 in December, 2019, scientists worldwide have been committed to developing COVID-19 vaccines. Only when most people have immunity to SARS-CoV-2, COVID-19 can reduce even wholly overcome. So far, nine kinds of COVID-19 vaccines have passed the phase III clinical trials and have approved for use. At the same time, adverse reactions after COVID-19 vaccination have also reported. This paper focuses on the adverse effects of thrombosis and thrombocytopenia caused by the COVID-19 vaccine, especially the adenovirus-vector vaccine from AstraZeneca and Pfizer, and discusses its mechanism and possible countermeasures.


Assuntos
Adenoviridae/genética , Vacinas contra COVID-19/efeitos adversos , Vetores Genéticos , Trombocitopenia/induzido quimicamente , Trombose/induzido quimicamente , Vacinação/efeitos adversos , Anticorpos/sangue , Vacinas contra COVID-19/genética , Vacinas contra COVID-19/imunologia , Humanos , Fator Plaquetário 4/imunologia , Medição de Risco , Fatores de Risco , Trombocitopenia/sangue , Trombocitopenia/imunologia , Trombose/sangue , Trombose/imunologia
18.
Cells ; 10(9)2021 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-34571857

RESUMO

The enlightenment of the formation of neutrophil extracellular traps (NETs) as a part of the innate immune system shed new insights into the pathologies of various diseases. The initial idea that NETs are a pivotal defense structure was gradually amended due to several deleterious effects in consecutive investigations. NETs formation is now considered a double-edged sword. The harmful effects are not limited to the induction of inflammation by NETs remnants but also include occlusions caused by aggregated NETs (aggNETs). The latter carries the risk of occluding tubular structures like vessels or ducts and appear to be associated with the pathologies of various diseases. In addition to life-threatening vascular clogging, other occlusions include painful stone formation in the biliary system, the kidneys, the prostate, and the appendix. AggNETs are also prone to occlude the ductal system of exocrine glands, as seen in ocular glands, salivary glands, and others. Last, but not least, they also clog the pancreatic ducts in a murine model of neutrophilia. In this regard, elucidating the mechanism of NETs-dependent occlusions is of crucial importance for the development of new therapeutic approaches. Therefore, the purpose of this review is to address the putative mechanisms of NETs-associated occlusions in the pathogenesis of disease, as well as prospective treatment modalities.


Assuntos
Embolia/imunologia , Armadilhas Extracelulares/fisiologia , Trombose/imunologia , Animais , Líquidos Corporais/imunologia , Líquidos Corporais/fisiologia , Embolia/fisiopatologia , Armadilhas Extracelulares/imunologia , Armadilhas Extracelulares/metabolismo , Humanos , Inflamação/patologia , Neutrófilos/imunologia , Estudos Prospectivos , Trombose/fisiopatologia
19.
Sci Rep ; 11(1): 18025, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34504150

RESUMO

Neutrophil extracellular traps (NETs) are web-like structures consisting of DNA, histones and granule proteins, released from neutrophils in thrombus formation, inflammation, and cancer. We asked if plasma levels of the NET markers myeloperoxidase (MPO)-DNA and citrullinated histone H3 (H3Cit)-DNA, are elevated in liver cirrhosis and hepatocellular carcinoma (HCC) and if the levels correlate with clinical parameters. MPO-DNA, H3Cit-DNA, and thrombin-antithrombin (TAT) complex, as a marker of coagulation activity, were measured using ELISA in plasma from 82 patients with HCC, 95 patients with cirrhosis and 50 healthy controls. Correlations were made to clinical parameters and laboratory data and patients were followed for a median of 22.5 months regarding thrombosis development. H3Cit-DNA was significantly (p < 0.01) elevated in plasma from cirrhosis (66.4 ng/mL) and HCC (63.8 ng/mL) patients compared to healthy controls (31.8 ng/mL). TAT levels showed similar pattern (3.1, 3.7, and 0.0 µg/mL respectively, p < 0.01). MPO-DNA was significantly (p < 0.01) elevated in cirrhosis patients (0.53 O.D.) as compared to controls (0.33 O.D.). Levels of MPO-DNA and H3Cit-DNA correlated positively with Child-Pugh and MELD score. TAT was increased in all Child-Pugh and MELD groups. In multivariable logistic regression, Child B and C liver cirrhosis were independent predictors of elevated H3Cit-DNA in plasma. Levels of MPO-DNA and H3Cit-DNA were similar in patients with or without history of thrombosis, or thrombus formation during follow-up. In conclusion, plasma markers of NET formation are elevated in liver cirrhosis and correlate to the degree of liver dysfunction in patients with liver cirrhosis and/or HCC. The presence of HCC did not further increase the plasma levels of NET markers as compared to patients with cirrhosis only.


Assuntos
Carcinoma Hepatocelular/imunologia , Cirrose Hepática/imunologia , Neoplasias Hepáticas/imunologia , Fígado/imunologia , Neutrófilos/imunologia , Trombose/imunologia , Idoso , Antitrombina III/imunologia , Biomarcadores/sangue , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patologia , Estudos de Casos e Controles , Citrulinação , DNA/sangue , Armadilhas Extracelulares/imunologia , Feminino , Histonas/sangue , Humanos , Inflamação , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/sangue , Cirrose Hepática/diagnóstico , Cirrose Hepática/patologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/patologia , Peptídeo Hidrolases/sangue , Peptídeo Hidrolases/imunologia , Peroxidase/sangue , Trombose/sangue , Trombose/diagnóstico , Trombose/patologia
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