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  1. Article ; Online: Platelet-leukocyte interactions in COVID-19: Contributions to hypercoagulability, inflammation, and disease severity.

    Hottz, Eugenio D / Bozza, Patrícia T

    Research and practice in thrombosis and haemostasis

    2022  Volume 6, Issue 3, Page(s) e12709

    Abstract: A State of the Art lecture titled "Platelet-leukocyte interactions in COVID-19: Contributions to hypercoagulability, inflammation and disease severity" was presented at the International Society for Thrombosis and Hemostasis (ISTH) congress in 2021. ... ...

    Abstract A State of the Art lecture titled "Platelet-leukocyte interactions in COVID-19: Contributions to hypercoagulability, inflammation and disease severity" was presented at the International Society for Thrombosis and Hemostasis (ISTH) congress in 2021. Severe coronavirus disease 2019 (COVID-19) has been associated with a high incidence of coagulopathy and thromboembolic events that contributes to disease severity and poor outcomes. Therefore, understanding the mechanisms of COVID-19-associated hypercoagulability and thromboinflammation has gained great interest. Here, we review the mechanisms involved in platelet activation and platelet interactions with leukocytes during COVID-19. We highlight recent evidence that platelet activation, platelet-monocyte, and platelet-neutrophil interactions in COVID-19 support pathological thromboinflammation, including in driving tissue factor expression and NETosis, which have been associated with thromboembolic complication and poor outcomes in critically ill patients. The contributions of platelet-leukocyte interactions to COVID-19 immunoregulation, inflammation, and hypercoagulability, as well as their potential implications in disease severity and therapeutic strategies, will be discussed. Finally, we summarize relevant new data on this topic presented during the 2021 ISTH Congress.
    Language English
    Publishing date 2022-05-02
    Publishing country United States
    Document type Journal Article
    ISSN 2475-0379
    ISSN (online) 2475-0379
    DOI 10.1002/rth2.12709
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  2. Article ; Online: Acute to post-acute COVID-19 thromboinflammation persistence: Mechanisms and potential consequences.

    Martins-Gonçalves, Remy / Hottz, Eugenio D / Bozza, Patricia T

    Current research in immunology

    2023  Volume 4, Page(s) 100058

    Abstract: Concerns for the long-term effects of COVID-19 infection have grown due to frequently reported persisting symptoms that can affect multiple systems for longer than 4 weeks after initial infection, a condition known as long-COVID-19 or post-acute COVID-19 ...

    Abstract Concerns for the long-term effects of COVID-19 infection have grown due to frequently reported persisting symptoms that can affect multiple systems for longer than 4 weeks after initial infection, a condition known as long-COVID-19 or post-acute COVID-19 syndrome (PACS). Even nonhospitalized survivors have an elevated risk for the development of thromboinflammatory-associated events, such as ischemic stroke and heart failure, pulmonary embolism and deep vein thrombosis. Recent findings point to the persistence of many mechanisms of hypercoagulability identified to be associated with disease severity and mortality in the acute phase of the disease, such as sustained inflammation and endotheliopathy, accompanied by abnormal fibrin generation and impaired fibrinolysis. Platelets seem to be central to the sustained hypercoagulable state, displaying hyperreactivity to stimuli and increased adhesive capacity. Platelets also contribute to elevated levels of thromboinflammatory mediators and pro-coagulant extracellular vesicles in individuals with ongoing PACS. Despite new advances in the understanding of mechanisms sustaining thromboinflammation in PACS, little is known about what triggers this persistence. In this graphical review, we provide a schematic representation of the known mechanisms and consequences of persisting thromboinflammation in COVID-19 survivors and summarize the hypothesized triggers maintaining this prothrombotic state.
    Language English
    Publishing date 2023-04-10
    Publishing country Netherlands
    Document type Journal Article ; Review
    ISSN 2590-2555
    ISSN (online) 2590-2555
    DOI 10.1016/j.crimmu.2023.100058
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  3. Article ; Online: Editorial: Host Innate Immune Response and Its Impact on Pulmonary Pathogenesis During Influenza Virus Infection.

    Tan, Yee-Joo / Huber, Victor C / Hottz, Eugenio D

    Frontiers in cellular and infection microbiology

    2021  Volume 11, Page(s) 779411

    Language English
    Publishing date 2021-11-09
    Publishing country Switzerland
    Document type Editorial
    ZDB-ID 2619676-1
    ISSN 2235-2988 ; 2235-2988
    ISSN (online) 2235-2988
    ISSN 2235-2988
    DOI 10.3389/fcimb.2021.779411
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  4. Article ; Online: Acute to post-acute COVID-19 thromboinflammation persistence

    Remy Martins-Gonçalves / Eugenio D. Hottz / Patricia T. Bozza

    Current Research in Immunology, Vol 4, Iss , Pp 100058- (2023)

    Mechanisms and potential consequences

    2023  

    Abstract: Concerns for the long-term effects of COVID-19 infection have grown due to frequently reported persisting symptoms that can affect multiple systems for longer than 4 weeks after initial infection, a condition known as long-COVID-19 or post-acute COVID-19 ...

    Abstract Concerns for the long-term effects of COVID-19 infection have grown due to frequently reported persisting symptoms that can affect multiple systems for longer than 4 weeks after initial infection, a condition known as long-COVID-19 or post-acute COVID-19 syndrome (PACS). Even nonhospitalized survivors have an elevated risk for the development of thromboinflammatory-associated events, such as ischemic stroke and heart failure, pulmonary embolism and deep vein thrombosis. Recent findings point to the persistence of many mechanisms of hypercoagulability identified to be associated with disease severity and mortality in the acute phase of the disease, such as sustained inflammation and endotheliopathy, accompanied by abnormal fibrin generation and impaired fibrinolysis. Platelets seem to be central to the sustained hypercoagulable state, displaying hyperreactivity to stimuli and increased adhesive capacity. Platelets also contribute to elevated levels of thromboinflammatory mediators and pro-coagulant extracellular vesicles in individuals with ongoing PACS. Despite new advances in the understanding of mechanisms sustaining thromboinflammation in PACS, little is known about what triggers this persistence. In this graphical review, we provide a schematic representation of the known mechanisms and consequences of persisting thromboinflammation in COVID-19 survivors and summarize the hypothesized triggers maintaining this prothrombotic state.
    Keywords Post-acute COVID-19 syndrome (PACS) ; Platelet activation ; Hypercoagulability ; Thromboinflammation ; Specialties of internal medicine ; RC581-951
    Language English
    Publishing date 2023-01-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article: Fundamentals in Covid-19-Associated Thrombosis: Molecular and Cellular Aspects.

    Mizurini, Daniella M / Hottz, Eugenio D / Bozza, Patrícia T / Monteiro, Robson Q

    Frontiers in cardiovascular medicine

    2021  Volume 8, Page(s) 785738

    Abstract: ... increased D-dimer levels are the most common laboratory finding and have been repeatedly reported ...

    Abstract The novel coronavirus disease (COVID-19) is associated with a high incidence of coagulopathy and venous thromboembolism that may contribute to the worsening of the clinical outcome in affected patients. Marked increased D-dimer levels are the most common laboratory finding and have been repeatedly reported in critically ill COVID-19 patients. The infection caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is followed by a massive release of pro-inflammatory cytokines, which mediate the activation of endothelial cells, platelets, monocytes, and neutrophils in the vasculature. In this context, COVID-19-associated thrombosis is a complex process that seems to engage vascular cells along with soluble plasma factors, including the coagulation cascade, and complement system that contribute to the establishment of the prothrombotic state. In this review, we summarize the main findings concerning the cellular mechanisms proposed for the establishment of COVID-19-associated thrombosis.
    Language English
    Publishing date 2021-12-17
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2781496-8
    ISSN 2297-055X
    ISSN 2297-055X
    DOI 10.3389/fcvm.2021.785738
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  6. Article ; Online: Isolation of Microvesicles from Plasma Samples Avoiding Lipoprotein Contamination.

    Merij, Laura B / Andrade, Fernanda B / Silva, Adriana R / Hottz, Eugenio D

    Methods in molecular biology (Clifton, N.J.)

    2021  Volume 2409, Page(s) 245–255

    Abstract: Dengue is an infectious disease caused by Dengue Virus, mainly transmitted by Aedes aegypti mosquitoes. Severe dengue is a potentially fatal syndrome in consequence of overwhelmed inflammation, in which thrombocytopenia and increased vascular ... ...

    Abstract Dengue is an infectious disease caused by Dengue Virus, mainly transmitted by Aedes aegypti mosquitoes. Severe dengue is a potentially fatal syndrome in consequence of overwhelmed inflammation, in which thrombocytopenia and increased vascular permeability are frequently observed. Several experimental evidences point to the participation of both microvesicles (MVs) and circulating lipoproteins in inflammatory amplification in dengue pathogenesis. On this regard, many protocols for isolating plasma MVs have shown lipoproteins as the main contaminant. This is a limitation to studies aiming at the functional characterization of MVs, since both MVs and lipoproteins can modulate inflammatory responses. Here, we describe a biphasic density-based gradient ultracentrifugation as a tool for concomitant isolation of MVs and lipoproteins without cross-contamination. Flow cytometry for MVs quantification and western blot for detection of apoB100 may be used to confirm the isolation and purity of the MVs.
    MeSH term(s) Animals ; Cell-Derived Microparticles ; Dengue ; Flow Cytometry ; Lipoproteins
    Chemical Substances Lipoproteins
    Language English
    Publishing date 2021-10-28
    Publishing country United States
    Document type Journal Article
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-0716-1879-0_17
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  7. Article ; Online: The Weight of Obesity in Immunity from Influenza to COVID-19.

    Andrade, Fernanda B / Gualberto, Ana / Rezende, Camila / Percegoni, Nathércia / Gameiro, Jacy / Hottz, Eugenio D

    Frontiers in cellular and infection microbiology

    2021  Volume 11, Page(s) 638852

    Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged in December 2019 and rapidly outspread worldwide endangering human health. The coronavirus disease 2019 (COVID-19) manifests itself through a wide spectrum of symptoms that can ... ...

    Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged in December 2019 and rapidly outspread worldwide endangering human health. The coronavirus disease 2019 (COVID-19) manifests itself through a wide spectrum of symptoms that can evolve to severe presentations as pneumonia and several non-respiratory complications. Increased susceptibility to COVID-19 hospitalization and mortality have been linked to associated comorbidities as diabetes, hypertension, cardiovascular diseases and, recently, to obesity. Similarly, individuals living with obesity are at greater risk to develop clinical complications and to have poor prognosis in severe influenza pneumonia. Immune and metabolic dysfunctions associated with the increased susceptibility to influenza infection are linked to obesity-associated low-grade inflammation, compromised immune and endocrine systems, and to high cardiovascular risk. These preexisting conditions may favor virological persistence, amplify immunopathological responses and worsen hemodynamic instability in severe COVID-19 as well. In this review we highlight the main factors and the current state of the art on obesity as risk factor for influenza and COVID-19 hospitalization, severe respiratory manifestations, extrapulmonary complications and even death. Finally, immunoregulatory mechanisms of severe influenza pneumonia in individuals with obesity are addressed as likely factors involved in COVID-19 pathophysiology.
    MeSH term(s) Adipokines ; Adipose Tissue ; Animals ; Body Weight ; COVID-19/immunology ; COVID-19/physiopathology ; Comorbidity ; Diabetes Mellitus ; Endotoxemia ; Heart Disease Risk Factors ; Hospitalization ; Humans ; Hyperglycemia ; Immunity ; Inflammation ; Influenza, Human/immunology ; Influenza, Human/physiopathology ; Metabolic Syndrome ; Obesity/complications ; Obesity/immunology ; Orthomyxoviridae Infections/immunology ; Risk Factors ; SARS-CoV-2
    Chemical Substances Adipokines
    Language English
    Publishing date 2021-03-17
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2619676-1
    ISSN 2235-2988 ; 2235-2988
    ISSN (online) 2235-2988
    ISSN 2235-2988
    DOI 10.3389/fcimb.2021.638852
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  8. Article: Platelets in Immune Response to Virus and Immunopathology of Viral Infections.

    Hottz, Eugenio D / Bozza, Fernando A / Bozza, Patrícia T

    Frontiers in medicine

    2018  Volume 5, Page(s) 121

    Abstract: Platelets are essential effector cells in hemostasis. Aside from their role in coagulation, platelets are now recognized as major inflammatory cells with key roles in the innate and adaptive arms of the immune system. Activated platelets have key ... ...

    Abstract Platelets are essential effector cells in hemostasis. Aside from their role in coagulation, platelets are now recognized as major inflammatory cells with key roles in the innate and adaptive arms of the immune system. Activated platelets have key thromboinflammatory functions linking coagulation to immune responses in various infections, including in response to virus. Recent studies have revealed that platelets exhibit several pattern recognition receptors (PRR) including those from the toll-like receptor, NOD-like receptor, and C-type lectin receptor family and are first-line sentinels in detecting and responding to pathogens in the vasculature. Here, we review the main mechanisms of platelets interaction with viruses, including their ability to sustain viral infection and replication, their expression of specialized PRR, and activation of thromboinflammatory responses against viruses. Finally, we discuss the role of platelet-derived mediators and platelet interaction with vascular and immune cells in protective and pathophysiologic responses to dengue, influenza, and human immunodeficiency virus 1 infections.
    Language English
    Publishing date 2018-04-30
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2775999-4
    ISSN 2296-858X
    ISSN 2296-858X
    DOI 10.3389/fmed.2018.00121
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  9. Article: TF/PAR2 Signaling Axis Supports the Protumor Effect of Neutrophil Extracellular Traps (NETs) on Human Breast Cancer Cells.

    Martins-Cardoso, Karina / Maçao, Aquiles / Souza, Juliana L / Silva, Alexander G / König, Sandra / Martins-Gonçalves, Remy / Hottz, Eugenio D / Rondon, Araci M R / Versteeg, Henri H / Bozza, Patrícia T / Almeida, Vitor H / Monteiro, Robson Q

    Cancers

    2023  Volume 16, Issue 1

    Abstract: Neutrophil extracellular traps (NETs) have been implicated in several hallmarks of cancer. Among the protumor effects, NETs promote epithelial-mesenchymal transition (EMT) in different cancer models. EMT has been linked to an enhanced expression of the ... ...

    Abstract Neutrophil extracellular traps (NETs) have been implicated in several hallmarks of cancer. Among the protumor effects, NETs promote epithelial-mesenchymal transition (EMT) in different cancer models. EMT has been linked to an enhanced expression of the clotting-initiating protein, tissue factor (TF), thus favoring the metastatic potential. TF may also exert protumor effects by facilitating the activation of protease-activated receptor 2 (PAR2). Herein, we evaluated whether NETs could induce TF expression in breast cancer cells and further promote procoagulant and intracellular signaling effects via the TF/PAR2 axis. T-47D and MCF7 cell lines were treated with isolated NETs, and samples were obtained for real-time PCR, flow cytometry, Western blotting, and plasma coagulation assays. In silico analyses were performed employing RNA-seq data from breast cancer patients deposited in The Cancer Genome Atlas (TCGA) database. A positive correlation was observed between neutrophil/NETs gene signatures and TF gene expression. Neutrophils/NETs gene signatures and PAR2 gene expression also showed a significant positive correlation in the bioinformatics model. In vitro analysis showed that treatment with NETs upregulated TF gene and protein expression in breast cancer cell lines. The inhibition of ERK/JNK reduced the TF gene expression induced by NETs. Remarkably, the pharmacological or genetic inhibition of the TF/PAR2 signaling axis attenuated the NETs-induced expression of several protumor genes. Also, treatment of NETs with a neutrophil elastase inhibitor reduced the expression of metastasis-related genes. Our results suggest that the TF/PAR2 signaling axis contributes to the pro-cancer effects of NETs in human breast cancer cells.
    Language English
    Publishing date 2023-12-19
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers16010005
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  10. Article ; Online: Platelet-leukocyte interactions in the pathogenesis of viral infections.

    Hottz, Eugenio D / Quirino-Teixeira, Anna Cecíllia / Merij, Laura Botelho / Pinheiro, Mariana Brandi Mendonça / Rozini, Stephane Vicente / Bozza, Fernando A / Bozza, Patrícia T

    Platelets

    2021  Volume 33, Issue 2, Page(s) 200–207

    Abstract: Evolving evidence demonstrates that platelets have major roles in viral syndromes through previously unrecognized viral sensing and effector functions. Activated platelets and increased platelet-leukocyte aggregates are observed in clinical and ... ...

    Abstract Evolving evidence demonstrates that platelets have major roles in viral syndromes through previously unrecognized viral sensing and effector functions. Activated platelets and increased platelet-leukocyte aggregates are observed in clinical and experimental viral infections. The mechanisms and outcomes of platelet-leukocyte interactions depend on the interacting leukocyte as well as on the pathogen and pathological conditions. In this review, we discuss the mechanisms involved in platelet interactions with leukocytes and its functions during viral infections. We focus on the contributions of human platelet-leukocyte interactions to pathophysiological and protective responses during viral infections of major global health relevance, including acquired immunodeficiency syndrome (AIDS), dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), influenza pneumonia, and COVID-19.
    MeSH term(s) Blood Platelets/metabolism ; Humans ; Leukocytes/metabolism ; Virus Diseases/blood
    Language English
    Publishing date 2021-07-14
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1034283-7
    ISSN 1369-1635 ; 0953-7104
    ISSN (online) 1369-1635
    ISSN 0953-7104
    DOI 10.1080/09537104.2021.1952179
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