382 results on '"Blood Coagulation immunology"'
Search Results
2. Immunological role of Gas6/TAM signaling in hemostasis and thrombosis.
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Li F, Xu L, Li C, Hu F, and Su Y
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- Humans, Animals, Receptor Protein-Tyrosine Kinases immunology, Receptor Protein-Tyrosine Kinases metabolism, Blood Coagulation immunology, Signal Transduction, Thrombosis immunology, Intercellular Signaling Peptides and Proteins metabolism, Hemostasis
- Abstract
The immune system is an emerging regulator of hemostasis and thrombosis. The concept of immunothrombosis redefines the relationship between coagulation and immunomodulation, and the Gas6/Tyro3-Axl-MerTK (TAM) signaling pathway builds the bridge across them. During coagulation, Gas6/TAM signaling pathway not only activates platelets, but also promotes thrombosis through endothelial cells and vascular smooth muscle cells involved in inflammatory responses. Thrombosis appears to be a common result of a Gas6/TAM signaling pathway-mediated immune dysregulation. TAM TK and its ligands have been found to be involved in coagulation through the PI3K/AKT or JAK/STAT pathway in various systemic diseases, providing new perspectives in the understanding of immunothrombosis. Gas6/TAM signaling pathway serves as a breakthrough target for novel therapeutic strategies to improve disease management. Many preclinical and clinical studies of TAM receptor inhibitors are in process, confirming the pivotal role of Gas6/TAM signaling pathway in immunothrombosis. Therapeutics targeting the TAM receptor show potential both in anticoagulation management and immunotherapy. Here, we review the immunological functions of the Gas6/TAM signaling pathway in coagulation and its multiple mechanisms in diseases identified to date, and discuss the new clinical strategies that may generated by these roles., Competing Interests: Declaration of competing interest None declared., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2024
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3. Complement(ing) long-COVID thromboinflammation and pathogenesis.
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Lee JD and Woodruff TM
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- Humans, Thromboinflammation immunology, Blood Coagulation immunology, Post-Acute COVID-19 Syndrome, Complement Activation immunology, Antibodies, Viral immunology, COVID-19 immunology, SARS-CoV-2 immunology, Complement System Proteins immunology, Complement System Proteins metabolism
- Abstract
The persistence or recurrence of symptoms after acute SARS-CoV-2 infection, termed 'long COVID', presents a formidable challenge to global healthcare systems. Recent research by Cervia-Hasler and colleagues delves into the intricate immunological landscape in patients with long COVID, demonstrating an interplay between complement and coagulation, driven by antiviral antibodies and tissue damage., Competing Interests: Declaration of interests Both authors have previously consulted for pharmaceutical companies that are developing complement inhibitors commercially., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
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- 2024
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4. Immune damage in Long Covid.
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Ruf W
- Subjects
- Humans, Blood Coagulation immunology, Complement System Proteins analysis, Complement System Proteins immunology, Post-Acute COVID-19 Syndrome blood, Post-Acute COVID-19 Syndrome immunology
- Abstract
Links between the complement and coagulation systems could lead to Long Covid therapies.
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- 2024
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5. A study of fibrinolytic system components in donor groups depending on various titers of circulating anti-SARS-CoV-2 IgG in the bloodstream.
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Rachkovska A, Krenytska D, Karbovskyy V, Raksha N, Halenova T, Vovk T, Savchuk O, and Ostapchenko L
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- Humans, SARS-CoV-2, Blood Coagulation immunology, Blood Coagulation physiology, Antibodies, Viral blood, Antibodies, Viral immunology, COVID-19 blood, COVID-19 immunology, Fibrinolysis immunology, Fibrinolysis physiology, Immunoglobulin G blood, Immunoglobulin G immunology, Tissue Plasminogen Activator
- Abstract
The fibrinolytic system plays an important role in controlling blood coagulation at each stage, from thrombin generation to fibrin clot cleavage. Currently, long-term multiorgan dysfunction post-coronavirus disease 2019 (COVID-19) may include coagulation disorders. Little information is available about the potential causes of post-COVID-19 coagulopathy, but one of them may be subpopulation IgG produced by the immune system against SARS-CoV-2. This article describes the changes in the main parameters of the fibrinolytic system in donors with various titers of anti-SARS-CoV-2 IgG, which is part of a complex study of the hemostasis system in these donor groups. We determined the most significant parameters of the fibrinolytic system, such as potential activity and amount of plasminogen and tissue plasminogen activator (tPA), amount of plasminogen activator inhibitor-1 (PAI-1), inhibitory potentials of α-2-antiplasmin, α-1-antitrypsin, α-2-macroglobulin in the blood plasma of donor groups. The obtained results represent the maximum and minimum values of measurement parameters among donor groups with titers of anti-SARS-CoV-2 IgG at least 10 ± 3 Index (S/C), and their statistical differences from the reference point [donor group with titer of anti-SARS-CoV-2 IgG 0 Index (S/C)]. We established the changes in fibrinolytic parameters depending on the titers of anti-SARS-CoV-2 IgG. One conclusion can be drawn from this: anti-SARS-CoV-2 IgG population may influence coagulation in the post-COVID-19 period. Further research in-vitro and in-vivo experimental models using selected and purified IgG may confirm our previous findings., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2023
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6. Why Does the Severity of COVID-19 Differ With Age?: Understanding the Mechanisms Underlying the Age Gradient in Outcome Following SARS-CoV-2 Infection.
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Zimmermann P and Curtis N
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- Adult, Angiotensin-Converting Enzyme 2 metabolism, Blood Coagulation immunology, Child, Cross Protection, Cross Reactions, Endothelium immunology, Humans, Patient Acuity, Serine Endopeptidases metabolism, Viral Load immunology, Adaptive Immunity, Age Factors, COVID-19 immunology, Immunity, Heterologous, Immunity, Innate, SARS-CoV-2 immunology
- Abstract
Although there are many hypotheses for the age-related difference in the severity of COVID-19, differences in innate, adaptive and heterologous immunity, together with differences in endothelial and clotting function, are the most likely mechanisms underlying the marked age gradient. Children have a faster and stronger innate immune response to SARS-CoV-2, especially in the nasal mucosa, which rapidly controls the virus. In contrast, adults can have an overactive, dysregulated and less effective innate response that leads to uncontrolled pro-inflammatory cytokine production and tissue injury. More recent exposure to other viruses and routine vaccines in children might be associated with protective cross-reactive antibodies and T cells against SARS-CoV-2. There is less evidence to support other mechanisms that have been proposed to explain the age-related difference in outcome following SARS-CoV-2 infection, including pre-existing immunity from exposure to common circulating coronaviruses, differences in the distribution and expression of the entry receptors ACE2 and TMPRSS2, and difference in viral load., Competing Interests: Disclosures: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2022
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7. Interplay between coagulation and inflammation in cancer: Limitations and therapeutic opportunities.
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Bauer AT, Gorzelanny C, Gebhardt C, Pantel K, and Schneider SW
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- Anticoagulants therapeutic use, Blood Coagulation drug effects, Humans, Inflammation immunology, Inflammation pathology, Neoplasms immunology, Thrombosis blood, Thrombosis drug therapy, Thrombosis pathology, Tumor Escape drug effects, Blood Coagulation immunology, Heparin, Low-Molecular-Weight therapeutic use, Immune Checkpoint Inhibitors therapeutic use, Inflammation blood, Neoplasms blood, Neoplasms drug therapy
- Abstract
Advances in understanding the molecular mechanisms of tumor progression have achieved impressive progress in the treatment of cancer and so-called immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. Indeed, antibody-based drugs blocking immune escape of tumor cells by modulation of T cell responses are increasingly utilized for a wide range of tumor entities. Nonetheless, response rates remain limited, and the development of secondary resistance is a common problem. In addition, by increasing the immune response a variety of severe side effects are provoked. Next to autoimmune responses, activation of the complement system and skin toxicity, an increased incidence for thrombotic complications has been observed associated with an increased mortality rate. Based on this, it can be postulated that the interplay of coagulation with inflammation in the tumor microenvironment is relevant for each step in the tumor life cycle. This review focuses on the coagulation as central player fostering mechanisms associated with tumor progression. Thus, a better understanding of the molecular pathways involved in the complex interaction of circulating tumor cells, the plasmatic coagulation and immune cells may help to improve therapeutic concepts reducing mortality and morbidity associated with cancer., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2022
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8. Roles of the tissue-type plasminogen activator in immune response.
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Seillier C, Hélie P, Petit G, Vivien D, Clemente D, Le Mauff B, Docagne F, and Toutirais O
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- Antigen-Presenting Cells immunology, COVID-19 epidemiology, COVID-19 virology, Endothelial Cells immunology, Endothelial Cells metabolism, Humans, Models, Immunological, Pandemics, SARS-CoV-2 physiology, T-Lymphocytes immunology, Tissue Plasminogen Activator metabolism, Blood Coagulation immunology, COVID-19 immunology, Fibrinolysis immunology, Immunity immunology, SARS-CoV-2 immunology, Tissue Plasminogen Activator immunology
- Abstract
The COVID-19 pandemic has once again brought to the forefront the existence of a tight link between the coagulation/fibrinolytic system and the immunologic processes. Tissue-type plasminogen activator (tPA) is a serine protease with a key role in fibrinolysis by converting plasminogen into plasmin that can finally degrade fibrin clots. tPA is released in the blood by endothelial cells and hepatocytes but is also produced by various types of immune cells including T cells and monocytes. Beyond its role on hemostasis, tPA is also a potent modulator of inflammation and is involved in the regulation of several inflammatory diseases. Here, after a brief description of tPA structure, we review its new functions in adaptive immunity focusing on T cells and antigen presenting cells. We intend to synthesize the recent knowledge on proteolysis- and receptor-mediated effects of tPA on immune response in physiological and pathological context., (Copyright © 2021 Elsevier Inc. All rights reserved.)
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- 2022
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9. The characteristics of clinical laboratory indicators in anticardiolipin antibody positive cerebral infarction patients.
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Chen C, Fang M, Zheng H, Xie S, Wang Y, Tong Y, Ma X, Guo L, and Lu R
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- Aged, Aged, 80 and over, Blood Coagulation immunology, Blood Platelets immunology, Blood Platelets metabolism, Cerebral Infarction complications, Cerebral Infarction diagnosis, Clinical Laboratory Techniques, Creatine Kinase blood, Creatine Kinase immunology, Diabetes Complications immunology, Diabetes Mellitus immunology, Female, Folic Acid blood, Folic Acid immunology, Homocysteine blood, Homocysteine immunology, Humans, Hypertension complications, Hypertension immunology, Immunity, L-Lactate Dehydrogenase blood, L-Lactate Dehydrogenase immunology, Lipids blood, Lipids immunology, Male, Middle Aged, Thyroid Hormones blood, Thyroid Hormones immunology, Vitamin B 12 blood, Vitamin B 12 immunology, Antibodies, Anticardiolipin blood, Cerebral Infarction blood, Cerebral Infarction immunology
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- 2022
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10. Time-course analysis reveals that corticosteroids resuscitate diminished CD8+ T cells in COVID-19: a retrospective cohort study.
- Author
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Ye F, Liu J, Chen L, Zhu B, Yu L, Liang B, Xu L, Li S, Lu S, Fan L, Yang D, and Zheng X
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- Adult, Aged, Aged, 80 and over, Blood Coagulation drug effects, Blood Coagulation immunology, CD8-Positive T-Lymphocytes immunology, COVID-19 blood, COVID-19 diagnosis, COVID-19 immunology, Dose-Response Relationship, Drug, Female, Fibrin Fibrinogen Degradation Products analysis, Fibrin Fibrinogen Degradation Products immunology, Heparin administration & dosage, Humans, Inflammation blood, Inflammation diagnosis, Inflammation immunology, Linear Models, Longitudinal Studies, Lymphocyte Count, Male, Methylprednisolone administration & dosage, Middle Aged, Models, Biological, Retrospective Studies, SARS-CoV-2 immunology, SARS-CoV-2 isolation & purification, Severity of Illness Index, Time Factors, Time-to-Treatment, Young Adult, CD8-Positive T-Lymphocytes drug effects, Glucocorticoids administration & dosage, Inflammation drug therapy, COVID-19 Drug Treatment
- Abstract
Objective: To illustrate the effect of corticosteroids and heparin, respectively, on coronavirus disease 2019 (COVID-19) patients' CD8+ T cells and D-dimer., Methods: In this retrospective cohort study involving 866 participants diagnosed with COVID-19, patients were grouped by severity. Generalized additive models were established to explore the time-course association of representative parameters of coagulation, inflammation and immunity. Segmented regression was performed to examine the influence of corticosteroids and heparin upon CD8+ T cell and D-dimer, respectively., Results: There were 541 moderate, 169 severe and 156 critically ill patients involved in the study. Synchronous changes of levels of NLR, D-dimer and CD8+ T cell in critically ill patients were observed. Administration of methylprednisolone before 14 DFS compared with those after 14 DFS ( β = 0.154%, 95% CI=(0, 0.302), p =.048) or a dose lower than 40 mg per day compared with those equals to 40 mg per day ( β = 0.163%, 95% CI=(0.027, 0.295), p =.020) significantly increased the rising rate of CD8+ T cell in 14-56 DFS., Conclusions: The parameters of coagulation, inflammation and immunity were longitudinally correlated, and an early low-dose corticosteroid treatment accelerated the regaining of CD8+ T cell to help battle against SARS-Cov-2 in critical cases of COVID-19.
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- 2021
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11. Haemocyte-mediated immunity in insects: Cells, processes and associated components in the fight against pathogens and parasites.
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Eleftherianos I, Heryanto C, Bassal T, Zhang W, Tettamanti G, and Mohamed A
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- Animals, Blood Coagulation immunology, Hemocytes metabolism, Hemolymph cytology, Host-Pathogen Interactions immunology, Immunity, Humoral, Insecta microbiology, Wound Healing immunology, Hemocytes immunology, Hemolymph immunology, Immunity, Cellular, Insecta immunology
- Abstract
The host defence of insects includes a combination of cellular and humoral responses. The cellular arm of the insect innate immune system includes mechanisms that are directly mediated by haemocytes (e.g., phagocytosis, nodulation and encapsulation). In addition, melanization accompanying coagulation, clot formation and wound healing, nodulation and encapsulation processes leads to the formation of cytotoxic redox-cycling melanin precursors and reactive oxygen and nitrogen species. However, demarcation between cellular and humoral immune reactions as two distinct categories is not straightforward. This is because many humoral factors affect haemocyte functions and haemocytes themselves are an important source of many humoral molecules. There is also a considerable overlap between cellular and humoral immune functions that span from recognition of foreign intruders to clot formation. Here, we review these immune reactions starting with the cellular mechanisms that limit haemolymph loss and participate in wound healing and clot formation and advancing to cellular functions that are critical in restricting pathogen movement and replication. This information is important because it highlights that insect cellular immunity is controlled by a multilayered system, different components of which are activated by different pathogens or during the different stages of the infection., (© 2021 John Wiley & Sons Ltd.)
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- 2021
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12. Platelets: Underestimated Regulators of Autoinflammation in Psoriasis.
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Herster F, Karbach S, Chatterjee M, and Weber ANR
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- Animals, Blood Coagulation immunology, Cardiovascular Diseases blood, Cardiovascular Diseases epidemiology, Cell Communication immunology, Comorbidity, Dermatitis blood, Dermatitis epidemiology, Dermatitis pathology, Disease Models, Animal, Humans, Neutrophils immunology, Psoriasis blood, Psoriasis epidemiology, Psoriasis pathology, Skin immunology, Blood Platelets immunology, Cardiovascular Diseases immunology, Dermatitis immunology, Psoriasis immunology, Skin pathology
- Abstract
Platelets have long been known as mediators of hemostasis and, more recently, as mediators of thromboinflammation, although their physiopathological role has mostly been investigated in the context of disease of internal organs, such as liver and kidney, or systemic disorders. Of late, exciting recent data suggest that platelets may also play a role in inflammation at distal sites such as the skin: recent studies show that platelets, by engaging polymorphonuclear neutrophils (PMNs), contribute to local inflammation in the frequent skin disorder, psoriasis. In an experimental model, systemic depletion of platelets drastically attenuated skin inflammation by preventing PMN infiltration of the skin. A broader role of platelets in different types of skin inflammation is therefore likely, and in this paper, we specifically review recent advances in psoriasis. Special emphasis is given to the crosstalk with systemic platelet effects, which may be of interest in psoriasis-related cardiovascular comorbidities. Furthermore, we discuss the potential for platelet-centered interventions in the therapy for psoriasis., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2021
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13. A Review of Pathophysiology, Clinical Features, and Management Options of COVID-19 Associated Coagulopathy.
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Goswami J, MacArthur TA, Sridharan M, Pruthi RK, McBane RD 2nd, Witzig TE, and Park MS
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- Humans, Ischemic Stroke complications, Ischemic Stroke metabolism, Ischemic Stroke pathology, Pulmonary Embolism etiology, Pulmonary Embolism immunology, Pulmonary Embolism pathology, Pulmonary Embolism therapy, Thrombosis etiology, Thrombosis immunology, Thrombosis pathology, Thrombosis therapy, Blood Coagulation immunology, Blood Coagulation Disorders etiology, Blood Coagulation Disorders immunology, Blood Coagulation Disorders pathology, Blood Coagulation Disorders therapy, COVID-19 complications, COVID-19 pathology, COVID-19 therapy, Immunity, Innate, SARS-CoV-2 immunology
- Abstract
Abstract: There is increasing evidence that novel coronavirus disease 2019 (COVID-19) leads to a significant coagulopathy, a phenomenon termed "COVID-19 associated coagulopathy." COVID-19 has been associated with increased rates of both venous and arterial thromboembolic events, a source of significant morbidity and mortality in this disease. Further evidence suggests a link between the inflammatory response and coagulopathy associated with COVID-19. This presents a unique set of challenges for diagnosis, prevention, and treatment of thrombotic complications. In this review, we summarize and discuss the current literature on laboratory coagulation disruptions associated with COVID-19 and the clinical effects of thromboembolic events including pulmonary embolism, deep vein thrombosis, peripheral arterial thrombosis, and acute ischemic stroke in COVID-19. Endothelial injury and augmented innate immune response are implicated in the development of diffuse macro- and microvascular thrombosis in COVID-19. The pathophysiology of COVID-19 associated coagulopathy is an important determinant of appropriate treatment and monitoring of these complications. We highlight the importance of diagnosis and management of dysregulated coagulation in COVID-19 to improve outcomes in COVID-19 patients with thromboembolic complications., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Shock Society.)
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- 2021
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14. C1 Esterase Inhibition: Targeting Multiple Systems in COVID-19.
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Adesanya TMA, Campbell CM, Cheng L, Ogbogu PU, and Kahwash R
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- Blood Coagulation drug effects, Blood Coagulation immunology, COVID-19 blood, COVID-19 virology, Complement Activation drug effects, Complement Activation immunology, Complement C1s metabolism, Complement Inactivating Agents pharmacology, Complement Inactivating Agents therapeutic use, Humans, Immunity, Innate drug effects, SARS-CoV-2 metabolism, Thrombosis blood, Thrombosis prevention & control, COVID-19 Drug Treatment, COVID-19 immunology, Complement C1 Inhibitor Protein metabolism, Complement C1s antagonists & inhibitors, SARS-CoV-2 immunology, Thrombosis immunology
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- 2021
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15. Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19.
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Bonaventura A, Vecchié A, Dagna L, Martinod K, Dixon DL, Van Tassell BW, Dentali F, Montecucco F, Massberg S, Levi M, and Abbate A
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- Blood Coagulation immunology, Blood Platelets immunology, Critical Illness therapy, Cytokine Release Syndrome immunology, Endothelium, Vascular pathology, Fibrinolytic Agents therapeutic use, Humans, Immunity, Innate immunology, Lung blood supply, Lung pathology, Lung virology, Monocytes immunology, Neutrophils immunology, SARS-CoV-2 immunology, SARS-CoV-2 pathogenicity, Venous Thrombosis prevention & control, COVID-19 immunology, COVID-19 pathology, Cytokine Release Syndrome pathology, Venous Thrombosis immunology, Venous Thrombosis pathology
- Abstract
Coronavirus disease 2019 (COVID-19) is a clinical syndrome caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients with severe disease show hyperactivation of the immune system, which can affect multiple organs besides the lungs. Here, we propose that SARS-CoV-2 infection induces a process known as immunothrombosis, in which activated neutrophils and monocytes interact with platelets and the coagulation cascade, leading to intravascular clot formation in small and larger vessels. Microthrombotic complications may contribute to acute respiratory distress syndrome (ARDS) and other organ dysfunctions. Therapeutic strategies aimed at reducing immunothrombosis may therefore be useful. Several antithrombotic and immunomodulating drugs have been proposed as candidates to treat patients with SARS-CoV-2 infection. The growing understanding of SARS-CoV-2 infection pathogenesis and how it contributes to critical illness and its complications may help to improve risk stratification and develop targeted therapies to reduce the acute and long-term consequences of this disease.
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- 2021
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16. COVID-19 and Kounis Syndrome: Deciphering Their Relationship.
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Kounis NG, Koniari I, and de Gregorio C
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- Anaphylaxis immunology, Anaphylaxis physiopathology, Humans, Mast Cells, SARS-CoV-2, Thrombosis immunology, Blood Coagulation immunology, COVID-19 immunology, COVID-19 physiopathology, Cytokine Release Syndrome etiology, Cytokine Release Syndrome immunology, Hypersensitivity immunology, Kounis Syndrome immunology, Kounis Syndrome physiopathology
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- 2021
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17. Epidemiological and Clinical Characteristics of 217 Cases of COVID-19 in Jiangsu Province, China.
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Zhou J, Chen B, Wang Y, and Wu F
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- Adult, Aged, Aged, 80 and over, Blood Coagulation immunology, COVID-19 blood, COVID-19 complications, COVID-19 epidemiology, China epidemiology, Comorbidity, Cough blood, Cough immunology, Cough virology, Female, Fever blood, Fever immunology, Fever virology, Humans, Inflammation blood, Inflammation diagnosis, Inflammation immunology, Inflammation virology, Male, Middle Aged, Retrospective Studies, Risk Factors, SARS-CoV-2 isolation & purification, T-Lymphocyte Subsets immunology, Young Adult, COVID-19 diagnosis, Cough epidemiology, Fever epidemiology, SARS-CoV-2 immunology, Severity of Illness Index
- Abstract
BACKGROUND COVID-19 has become a worldwide epidemic disease and is a public health crisis. We aim to provide evidence for clinical diagnosis and assessment of severity by analyzing patients' clinical data and early laboratory results and exploring the correlation between laboratory results and clinical classification. MATERIAL AND METHODS We enrolled 283 cases of suspected and diagnosed COVID-19 from 16 hospitals in Jiangsu Province from January to April 2020. The routine laboratory blood examinations, T lymphocyte subsets, and biochemical and coagulation function among different populations were contrasted by t test and chi-square (χ²) test. RESULTS Cough, fever, and dyspnea could be helpful to diagnose COVID-19 infection (P<0.05). Patients who were older or had comorbidities tended to become severe and critical cases. Among all the patients, the most obvious abnormal laboratory results were higher neutrophil count, CRP, total bilirubin, BUN, CRE, APTT, PT, and D-dimer, and lower blood platelet and lymphocyte count. CD3⁺ T cell, CD4⁺ T cell, and CD8⁺ T cell counts gradually decreased with exacerbation of the disease (P<0.05). CONCLUSIONS Cough and fever were the most common symptom. Patients with comorbidities were in more serious condition. The detection of inflammatory indexes, coagulation function, lymphocyte subsets, and renal function can help diagnose and assess the severity of COVID-19.
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- 2021
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18. Crosstalk between coagulation and complement activation promotes cardiac dysfunction in arrhythmogenic right ventricular cardiomyopathy.
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Ren J, Tsilafakis K, Chen L, Lekkos K, Kostavasili I, Varela A, Cokkinos DV, Davos CH, Sun X, Song J, and Mavroidis M
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- Adult, Animals, Arrhythmogenic Right Ventricular Dysplasia immunology, Autoantibodies immunology, Female, Hirudins immunology, Humans, Male, Mice, Knockout, Middle Aged, Recombinant Proteins immunology, Thrombin immunology, Mice, Blood Coagulation immunology, Complement Activation immunology, Heart Ventricles immunology, Myocardium immunology
- Abstract
Aims: We previously found that complement components are upregulated in the myocardium of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), and inhibiting the complement receptor C5aR reduces disease severity in desmin knockout ( Des
-/- ) mice, a model for ARVC. Here, we examined the mechanism underlying complement activation in ARVC, revealing a potential new therapeutic target. Methods: First, immunostaining, RT-PCR and western blot were used to detect the expression levels of complement and coagulation factors. Second, we knocked out the central complement component C3 in Des-/- mice (ARVC model) by crossing Des-/- mice with C3-/- mice to explore whether complement system activation occurs independently of the conventional pathway. Then, we evaluated whether a targeted intervention to coagulation system is effective to reduce myocardium injury. Finally, the plasma sC5b9 level was assessed to investigate the role in predicting adverse cardiac events in the ARVC cohort. Results: The complement system is activated in the myocardium in ARVC. Autoantibodies against myocardial proteins provided a possible mechanism underlying. Moreover, we found increased levels of myocardial C5 and the serum C5a in Des-/- C3-/- mice compared to wild-type mice, indicating that C5 is activated independently from the conventional pathway, presumably via the coagulation system. Crosstalk between the complement and coagulation systems exacerbated the myocardial injury in ARVC mice, and this injury was reduced by using the thrombin inhibitor lepirudin. In addition, we found significantly elevated plasma levels of sC5b9 and thrombin in patients, and this increase was correlated with all-cause mortality. Conclusions: These results suggest that crosstalk between the coagulation and complement systems plays a pathogenic role in cardiac dysfunction in ARVC. Thus, understanding this crosstalk may have important clinical implications with respect to diagnosing and treating ARVC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)- Published
- 2021
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19. Thrombotic Complications in Patients with COVID-19: Pathophysiological Mechanisms, Diagnosis, and Treatment.
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Gąsecka A, Borovac JA, Guerreiro RA, Giustozzi M, Parker W, Caldeira D, and Chiva-Blanch G
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- Blood Coagulation Tests methods, Humans, Prognosis, Anticoagulants pharmacology, Blood Coagulation drug effects, Blood Coagulation immunology, COVID-19 blood, COVID-19 immunology, COVID-19 physiopathology, COVID-19 therapy, Patient Care Management methods, Thrombosis etiology, Thrombosis physiopathology, Thrombosis prevention & control, Thrombosis therapy
- Abstract
Introduction: Emerging evidence points to an association between severe clinical presentation of COVID-19 and increased risk of thromboembolism. One-third of patients hospitalized due to severe COVID-19 develops macrovascular thrombotic complications, including venous thromboembolism, myocardial injury/infarction and stroke. Concurrently, the autopsy series indicate multiorgan damage pattern consistent with microvascular injury., Prophylaxis, Diagnosis and Treatment: COVID-19 associated coagulopathy has distinct features, including markedly elevated D-dimers concentration with nearly normal activated partial thromboplastin time, prothrombin time and platelet count. The diagnosis may be challenging due to overlapping features between pulmonary embolism and severe COVID-19 disease, such as dyspnoea, high concentration of D-dimers, right ventricle with dysfunction or enlargement, and acute respiratory distress syndrome. Both macro- and microvascular complications are associated with an increased risk of in-hospital mortality. Therefore, early recognition of coagulation abnormalities among hospitalized COVID-19 patients are critical measures to identify patients with poor prognosis, guide antithrombotic prophylaxis or treatment, and improve patients' clinical outcomes., Recommendations for Clinicians: Most of the guidelines and consensus documents published on behalf of professional societies focused on thrombosis and hemostasis advocate the use of anticoagulants in all patients hospitalized with COVID-19, as well as 2-6 weeks post hospital discharge in the absence of contraindications. However, since there is no guidance for deciding the intensity and duration of anticoagulation, the decision-making process should be made in individual-case basis., Conclusions: Here, we review the mechanistic relationships between inflammation and thrombosis, discuss the macrovascular and microvascular complications and summarize the prophylaxis, diagnosis and treatment of thromboembolism in patients affected by COVID-19.
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- 2021
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20. Circulating Histones in Sepsis: Potential Outcome Predictors and Therapeutic Targets.
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Li Y, Wan D, Luo X, Song T, Wang Y, Yu Q, Jiang L, Liao R, Zhao W, and Su B
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- Alarmins antagonists & inhibitors, Alarmins metabolism, Animals, Anti-Inflammatory Agents therapeutic use, Biomarkers blood, Biomarkers metabolism, Blood Coagulation drug effects, Blood Coagulation immunology, Disease Models, Animal, Endothelium, Vascular drug effects, Endothelium, Vascular immunology, Endothelium, Vascular pathology, Extracellular Traps drug effects, Extracellular Traps immunology, Extracellular Traps metabolism, Heparin pharmacology, Heparin therapeutic use, Histones antagonists & inhibitors, Histones metabolism, Humans, Molecular Targeted Therapy methods, Prognosis, Protein C pharmacology, Protein C therapeutic use, Recombinant Proteins pharmacology, Recombinant Proteins therapeutic use, Sepsis blood, Sepsis drug therapy, Sepsis immunology, Severity of Illness Index, Signal Transduction immunology, Thrombomodulin therapeutic use, Alarmins blood, Anti-Inflammatory Agents pharmacology, Histones blood, Sepsis diagnosis
- Abstract
Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection and is associated with high morbidity and mortality. Circulating histones (CHs), a group of damage-associated molecular pattern molecules mainly derived from neutrophil extracellular traps, play a crucial role in sepsis by mediating inflammation response, organ injury and death through Toll-like receptors or inflammasome pathways. Herein, we first elucidate the molecular mechanisms of histone-induced inflammation amplification, endothelium injury and cascade coagulation activation, and discuss the close correlation between elevated level of CHs and disease severity as well as mortality in patients with sepsis. Furthermore, current state-of-the-art on anti-histone therapy with antibodies, histone-binding proteins (namely recombinant thrombomodulin and activated protein C), and heparin is summarized to propose promising approaches for sepsis treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Wan, Luo, Song, Wang, Yu, Jiang, Liao, Zhao and Su.)
- Published
- 2021
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21. Inflammasome-Dependent Coagulation Activation in Sepsis.
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Wu R, Wang N, Comish PB, Tang D, and Kang R
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- Animals, HMGB1 Protein immunology, Humans, Membrane Proteins immunology, Thromboplastin immunology, Blood Coagulation immunology, Inflammasomes immunology, Macrophage Activation, Macrophages immunology, Monocytes immunology, Sepsis immunology
- Abstract
Sepsis is a potentially life-threatening, pathological condition caused by a dysregulated host response to infection. Pathologically, systemic inflammation can initiate coagulation activation, leading to organ dysfunction, and ultimately to multiple organ failure and septic death. The inflammasomes are cytosolic multiprotein signaling complexes that control the host response to diverse pathogen-associated molecular patterns (PAMPs) from microorganisms as well as damage-associated molecular patterns (DAMPs) from dead or dying host cells. Recent studies highlight that the activation of canonical and non-canonical inflammasomes not only mediate the maturation and secretion of interleukin-1 (IL1) family cytokines, but also trigger the release of coagulation factor III, tissue factor (F3, best known as TF) in activated macrophages and monocytes. These emerging functions of inflammasomes in immunocoagulation are further positively regulated by stimulator of interferon response cGAMP interactor 1 (STING1, also known as STING or TMEM173, a hub of the innate immune signaling network) and high mobility group box 1 (HMGB1, a nuclear DAMP). This mini-review will discuss the regulation and function of inflammasome-dependent coagulation activation in sepsis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wu, Wang, Comish, Tang and Kang.)
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- 2021
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22. Lipid presentation by the protein C receptor links coagulation with autoimmunity.
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Müller-Calleja N, Hollerbach A, Royce J, Ritter S, Pedrosa D, Madhusudhan T, Teifel S, Meineck M, Häuser F, Canisius A, Nguyen TS, Braun J, Bruns K, Etzold A, Zechner U, Strand S, Radsak M, Strand D, Gu JM, Weinmann-Menke J, Esmon CT, Teyton L, Lackner KJ, and Ruf W
- Subjects
- Animals, Antibodies, Antiphospholipid biosynthesis, Autoantibodies biosynthesis, Disease Models, Animal, Embryo Loss immunology, Endosomes immunology, Endothelial Protein C Receptor genetics, Humans, Immunity, Innate, Lupus Erythematosus, Systemic blood, Mice, Mice, Mutant Strains, Sphingomyelin Phosphodiesterase metabolism, Thrombosis immunology, Toll-Like Receptor 7 immunology, Antigen Presentation, Autoimmunity, Blood Coagulation immunology, Endothelial Protein C Receptor immunology, Lupus Erythematosus, Systemic immunology, Lysophospholipids immunology, Monoglycerides immunology
- Abstract
Antiphospholipid antibodies (aPLs) cause severe autoimmune disease characterized by vascular pathologies and pregnancy complications. Here, we identify endosomal lysobisphosphatidic acid (LBPA) presented by the CD1d-like endothelial protein C receptor (EPCR) as a pathogenic cell surface antigen recognized by aPLs for induction of thrombosis and endosomal inflammatory signaling. The engagement of aPLs with EPCR-LBPA expressed on innate immune cells sustains interferon- and toll-like receptor 7-dependent B1a cell expansion and autoantibody production. Specific pharmacological interruption of EPCR-LBPA signaling attenuates major aPL-elicited pathologies and the development of autoimmunity in a mouse model of systemic lupus erythematosus. Thus, aPLs recognize a single cell surface lipid-protein receptor complex to perpetuate a self-amplifying autoimmune signaling loop dependent on the cooperation with the innate immune complement and coagulation pathways., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
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- 2021
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23. Rogue antibodies could be driving severe COVID-19.
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Khamsi R
- Subjects
- Aging immunology, Annexin A2 immunology, Autoantibodies isolation & purification, Autoimmune Diseases microbiology, Autoimmune Diseases virology, B-Lymphocytes immunology, B-Lymphocytes pathology, Blood Coagulation immunology, Blood Vessels immunology, Blood Vessels pathology, Brain immunology, Brain pathology, COVID-19 etiology, COVID-19 immunology, COVID-19 pathology, COVID-19 virology, Critical Illness, Cytokine Release Syndrome complications, Cytokine Release Syndrome immunology, Cytokine Release Syndrome pathology, Cytokine Release Syndrome physiopathology, Female, HLA-DRB1 Chains immunology, Helicobacter pylori immunology, Helicobacter pylori pathogenicity, Herpesvirus 4, Human immunology, Herpesvirus 4, Human pathogenicity, Humans, Interferon Type I antagonists & inhibitors, Interferon Type I immunology, Male, Myocardium immunology, Myocardium pathology, Phospholipids immunology, Racial Groups, SARS-CoV-2 immunology, SARS-CoV-2 isolation & purification, Sex Characteristics, Streptococcus pyogenes immunology, Streptococcus pyogenes pathogenicity, Time Factors, Post-Acute COVID-19 Syndrome, Autoantibodies adverse effects, Autoantibodies immunology, Autoimmune Diseases etiology, Autoimmune Diseases immunology, COVID-19 complications, COVID-19 physiopathology, Models, Immunological, SARS-CoV-2 pathogenicity
- Published
- 2021
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24. Immune storm and coagulation storm in the pathogenesis of amniotic fluid embolism.
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Yang RL, Lang MZ, Li H, and Qiao XM
- Subjects
- Embolism, Amniotic Fluid pathology, Female, Humans, Pregnancy, Blood Coagulation immunology, Embolism, Amniotic Fluid immunology
- Abstract
Amniotic fluid embolism (AFE) is a rare but severe obstetric complication with high mortality. To date, the pathogenesis of AFE has evolved from a simple theory of mechanical obstruction to an immunological theory. However, it is not yet fully understood. Here we elaborate on the immune storm and coagulation storm induced by the amniotic fluid entering the maternal circulation. These two storms contribute to a better understanding of the pathogenesis of typical and atypical AFE. Our theory needs to be confirmed by further clinical studies and basic research.
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- 2021
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25. Anti-coagulation for COVID-19 treatment: both anti-thrombotic and anti-inflammatory?
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Paar V, Wernly B, Zhou Z, Motloch LJ, Hoppe UC, Egle A, and Lichtenauer M
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- COVID-19 blood, COVID-19 immunology, Cells, Cultured, Chemokines immunology, Dose-Response Relationship, Drug, Fibrinolytic Agents pharmacology, Heparin pharmacology, Humans, Immunization, Passive, Leukocytes, Mononuclear drug effects, SARS-CoV-2, COVID-19 Serotherapy, COVID-19 Drug Treatment, Blood Coagulation drug effects, Blood Coagulation immunology, COVID-19 therapy, Cytokine Release Syndrome blood, Cytokine Release Syndrome drug therapy, Cytokine Release Syndrome etiology, Fibrin immunology, Fibrin pharmacology, Inflammation blood, Inflammation therapy
- Abstract
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has been linked to a higher risk of mortality compared to influenza, which is mainly due to severe secondary diseases, such as acute respiratory distress syndrome (ARDS). In turn, ARDS is characterized by an acute inflammation and an excessive activity of the coagulation cascade, rising the vulnerability for venous thromboembolic events. In order to investigate the relation of inflammation and the influence of coagulation factors on their release, human peripheral mononuclear blood cells (PBMCs) were treated with autologous serum, heparinized plasma and different doses of fibrin. Thereafter, the concentration of pro-inflammatory cytokines and chemokines in the secretome of PBMCs was measured by enzyme-linked immunosorbent assay. Our analyses revealed autologous serum to significantly increase the secretion of cytokines and chemokines after 24 h of incubation time. Furthermore, the addition of fibrin markedly increased the secretion of cytokines and chemokines by PBMCs in a dose-dependent manner. Consequently, in accordance with previous studies, our study outlines that anti-coagulation may constitute a promising tool for the treatment of SARS-CoV-2, reducing both, the cytokine storm, as well as the risk for thrombotic complications.
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- 2021
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26. Microkinetic coagulation assays for human and zebrafish plasma.
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Iyer N and Jagadeeswaran P
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- Animals, Humans, Male, Zebrafish, Blood Coagulation immunology, Blood Coagulation Tests instrumentation, Microchemistry methods, Partial Thromboplastin Time methods, Plasma metabolism, Prothrombin Time methods
- Abstract
Coagulation assays, prothrombin time (PT), and partial thromboplastin time (PTT) are tests to measure the clotting ability of plasma and used in evaluating patients suffering from bleeding disorders. These assays require 100 μl of human plasma. In zebrafish, dilute plasma with exogenously added human fibrinogen was used. Our objective is to create a microkinetic coagulation assay for human and zebrafish plasmas using 1 μl plasma under conditions similar to PT and PTTs. Here, we developed an assay using the Take3 plate with wells holding up to 6 μl, which can be loaded in a microplate reader for measuring the absorbance of fibrin formation. In this assay, we used 1 μl of citrated zebrafish or human plasma followed by the addition of either thromboplastin or Dade ACTIN or factor X activator from Russell viper venom as an activating agent and CaCl2. We found 4 or 3 μl of the final volume of reaction was optimal. Our results showed both zebrafish and human plasmas yielded kinetic PT, kinetic PTT, and kinetic Russel's viper venom time curves similar to previously established curves using dilute plasma. This kinetic coagulation was inhibited by heparin and was reduced significantly in coagulation factor deficient plasmas. These results validated our microkinetic coagulation assays. Moreover, we derived clotting times from these kinetic curves, which were identical to human PT, PTT, and Russel's viper venom time. In conclusion, we established a microkinetic assay that could measure blood coagulation activity in models like zebrafish and human blood samples obtained from a finger prick in adults or heel prick in infants., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.)
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- 2021
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27. Intrahepatic metastases may be specific to hepatocellular carcinoma due to the coagulation and fibrinolytic systems (Review).
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Li X, Gu B, Wang B, Feng Z, Ma Y, Li H, Lucas A, and Chen H
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- Anoikis drug effects, Anoikis immunology, Biomarkers metabolism, Blood Coagulation drug effects, Carcinogenesis drug effects, Carcinogenesis immunology, Carcinogenesis pathology, Carcinoma, Hepatocellular blood, Carcinoma, Hepatocellular drug therapy, Carcinoma, Hepatocellular immunology, Humans, Liver immunology, Liver Neoplasms drug therapy, Liver Neoplasms immunology, Protease Inhibitors pharmacology, Protease Inhibitors therapeutic use, Protein Precursors metabolism, Prothrombin metabolism, Tumor Escape drug effects, Tumor Microenvironment drug effects, Tumor Microenvironment immunology, Urokinase-Type Plasminogen Activator antagonists & inhibitors, Urokinase-Type Plasminogen Activator metabolism, Blood Coagulation immunology, Carcinoma, Hepatocellular secondary, Liver pathology, Liver Neoplasms pathology, Liver Neoplasms secondary
- Abstract
Hepatocellular carcinoma (HCC) is different from other solid tumors because it is commonly associated with the occurrence of intrahepatic metastasis. Additionally, the liver, unlike other organs, is the main site of coagulation and fibrinolytic factor production. Therefore, it was speculated that coagulation and fibrinolytic factors could be associated with intrahepatic metastasis of HCC. Do the coagulation and fibrinolytic systems protect HCC cells against anoikis during infiltration and metastasis? Conversely, do the coagulation and fibrinolytic systems lead to immune escape of HCC cells by affecting the immune microenvironment of patients? The current review aimed to present a number of novel hypotheses for the treatment of HCC by exploring the mechanisms of coagulation and fibrinolytic factors in the regulation of cancer growth.
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- 2020
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28. Coagulopathy and Thrombosis as a Result of Severe COVID-19 Infection: A Microvascular Focus.
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Katneni UK, Alexaki A, Hunt RC, Schiller T, DiCuccio M, Buehler PW, Ibla JC, and Kimchi-Sarfaty C
- Subjects
- ADAMTS13 Protein metabolism, Animals, Blood Coagulation immunology, Humans, von Willebrand Factor metabolism, COVID-19 complications, Disseminated Intravascular Coagulation etiology, Microvessels pathology, SARS-CoV-2 physiology, Thrombosis etiology
- Abstract
Coronavirus disease of 2019 (COVID-19) is the clinical manifestation of the respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While primarily recognized as a respiratory disease, it is clear that COVID-19 is systemic illness impacting multiple organ systems. One defining clinical feature of COVID-19 has been the high incidence of thrombotic events. The underlying processes and risk factors for the occurrence of thrombotic events in COVID-19 remain inadequately understood. While severe bacterial, viral, or fungal infections are well recognized to activate the coagulation system, COVID-19-associated coagulopathy is likely to have unique mechanistic features. Inflammatory-driven processes are likely primary drivers of coagulopathy in COVID-19, but the exact mechanisms linking inflammation to dysregulated hemostasis and thrombosis are yet to be delineated. Cumulative findings of microvascular thrombosis has raised question if the endothelium and microvasculature should be a point of investigative focus. von Willebrand factor (VWF) and its protease, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13), play important role in the maintenance of microvascular hemostasis. In inflammatory conditions, imbalanced VWF-ADAMTS-13 characterized by elevated VWF levels and inhibited and/or reduced activity of ADAMTS-13 has been reported. Also, an imbalance between ADAMTS-13 activity and VWF antigen is associated with organ dysfunction and death in patients with systemic inflammation. A thorough understanding of VWF-ADAMTS-13 interactions during early and advanced phases of COVID-19 could help better define the pathophysiology, guide thromboprophylaxis and treatment, and improve clinical prognosis., Competing Interests: None declared., (Thieme. All rights reserved.)
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- 2020
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29. A novel immune-related genes prognosis biomarker for hepatocellular carcinoma.
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Wang K, Chen X, Jin C, Mo J, Jiang H, Yi B, and Chen X
- Subjects
- Adipokines, Biomarkers, Blood Coagulation genetics, Blood Coagulation immunology, Carcinoma, Hepatocellular immunology, Carcinoma, Hepatocellular pathology, Complement Activation genetics, Complement Activation immunology, Databases, Genetic, Female, Gene Expression Profiling, Humans, Insulin, Liver Neoplasms immunology, Liver Neoplasms pathology, Male, Middle Aged, Neoplasm Invasiveness, Neoplasm Staging, Neoplasm, Residual, Peroxisomes, Prognosis, Proportional Hazards Models, Reproducibility of Results, Signal Transduction genetics, Signal Transduction immunology, Survival Rate, Carcinoma, Hepatocellular genetics, Liver Neoplasms genetics
- Abstract
Background: Hepatocellular carcinoma (HCC) is closely associated with the immune microenvironment. To identify the effective population before administering treatment, the establishment of prognostic immune biomarkers is crucial for early HCC diagnosis and treatment., Results: A total of 335 IRGs identified from 788 overlapping IRGs were associated with the survival of HCC. A prognostic immunoscore model was identified. The Kaplan-Meier survival curves and time-dependent ROC analysis revealed a powerful prognostic performance of immunoscore signature via multi validation. Besides, the immunoscore signature exhibited a better predictive power compared to other prognostic signatures. Gene set enrichment analysis showed multiple signaling differences between the high and low immunoscore group. Furthermore, immunoscore was significantly associated with multiple immune cells and immune infiltration in the tumor microenvironment., Conclusions: We identified the immunoscore as a robust marker for predicting HCC patient survival., Methods: Three sets of immune-related genes (IRGs) were integrated to identify the overlapping IRGs. Weighted gene co-expression network analysis was performed to obtain the survival-related IRGs. Further, the prognostic immunoscore model was constructed via LASSO-penalized Cox regression analysis. Then the prognostic performance of immunoscore was evaluated. In addition, ESTIMATE and CIBERSORT algorithms were applied to explore the relationship between immunoscore and tumor immune microenvironment.
- Published
- 2020
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30. Platelet-Reactive Antibodies in Patients after Ischaemic Stroke-An Epiphenomenon or a Natural Protective Mechanism.
- Author
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Park YE, Penumarthy R, Sun PP, Kang CY, Morel-Kopp MC, Downing J, Green TN, Immanuel T, Ward CM, Young D, During MJ, Barber PA, and Kalev-Zylinska ML
- Subjects
- Aged, Autoimmunity immunology, Blood Coagulation immunology, Female, Humans, Male, Platelet Aggregation immunology, Platelet Count methods, Thrombosis immunology, Autoantibodies immunology, Blood Platelets immunology, Brain Ischemia immunology, Ischemic Stroke immunology
- Abstract
Ischaemic brain damage induces autoimmune responses, including the production of autoantibodies with potential neuroprotective effects. Platelets share unexplained similarities with neurons, and the formation of anti-platelet antibodies has been documented in neurological disorders. The aim of this study was to investigate the presence of anti-platelet antibodies in the peripheral blood of patients after ischaemic stroke and determine any clinical correlations. Using a flow cytometry-based platelet immunofluorescence method, we detected platelet-reactive antibodies in 15 of 48 (31%) stroke patients and two of 50 (4%) controls ( p < 0.001). Western blotting revealed heterogeneous reactivities with platelet proteins, some of which overlapped with brain proteins. Stroke patients who carried anti-platelet antibodies presented with larger infarcts and more severe neurological dysfunction, which manifested as higher scores on the National Institutes of Health Stroke Scale (NIHSS; p = 0.009), but they had a greater recovery in the NIHSS by the time of hospital discharge (day 7 ± 2) compared with antibody-negative patients ( p = 0.043). Antibodies from stroke sera reacted more strongly with activated platelets ( p = 0.031) and inhibited platelet aggregation by up to 30.1 ± 2.8% ( p < 0.001), suggesting the potential to interfere with thrombus formation. In conclusion, platelet-reactive antibodies can be found in patients soon after ischaemic stroke and correlate with better short-term outcomes, suggesting a potential novel mechanism limiting thrombosis.
- Published
- 2020
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31. Sphingosine-1-phosphate in anti-neutrophil cytoplasmic antibody-associated vasculitis: coagulation-related clinical indicators and complications.
- Author
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Wu KL, Liang QH, Ding N, Li BW, and Hao J
- Subjects
- Aged, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis blood, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis complications, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis immunology, Biomarkers blood, Blood Coagulation immunology, Case-Control Studies, Cerebral Hemorrhage blood, Cerebral Hemorrhage immunology, Feasibility Studies, Female, Fibrin Fibrinogen Degradation Products analysis, Humans, Male, Middle Aged, Platelet Count, Risk Assessment methods, Sphingosine blood, Thromboembolism blood, Thromboembolism immunology, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis diagnosis, Cerebral Hemorrhage epidemiology, Lysophospholipids blood, Severity of Illness Index, Sphingosine analogs & derivatives, Thromboembolism epidemiology
- Abstract
Background: Sphingosine-1-phosphate (S1P) plays a significant role in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV)., Methods: We collected the plasma samples from 40 patients with AAV and 10 healthy volunteers. The plasma levels of S1P were tested by enzyme-linked immunosorbent assay (ELISA). The levels of serum creatinine (Scr) were tested by rate method, and then the estimated glomerular filtration rate (eGFR) of the patients was calculated from the Scr, age, and gender. Prothrombin time (PT), partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (FIB), fibrinogen reduction product (FDP), D-dimer and C-reactive protein (CRP) were tested by turbidimetric inhibition immunoassays. Platelets (PLTs) were tested by fluorescently labeled electrical impedance method., Results: The plasma levels of S1P were significantly higher in AAV patients than in healthy volunteers. Correlation analysis showed that plasma levels of S1P were negatively correlated with glomerular filtration (P=0.022, r = -0.306), and positively correlated with circulating levels of Birmingham vasculitis activity score (BVAS), PLT and D-dimer, (P=0.004, r = 0.443; P<0.001, r = 0.654; P=0.006, r = 0.427). The 40 patients with AAV were classified into three groups: the thromboembolism group (with complications of cerebral infarction and myocardial infarction, n=6), cerebral ischemia group (n=4), and cerebral hemorrhage group (n=2). The plasma levels of S1P were highest in the thromboembolism group and lowest in the cerebral hemorrhage group (P=0.003)., Conclusions: Plasma levels of S1P were associated with circulating levels of D-dimer, PLT and BVAS in the patients with AAV. Hence, plasma S1P level can be used as a biomarker to predict coagulation-related complications in AAV., (© 2020 The Author(s).)
- Published
- 2020
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32. Coagulation/Complement Activation and Cerebral Hypoperfusion in Relapsing-Remitting Multiple Sclerosis.
- Author
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Koudriavtseva T, Stefanile A, Fiorelli M, Lapucci C, Lorenzano S, Zannino S, Conti L, D'Agosto G, Pimpinelli F, Di Domenico EG, Mandoj C, Giannarelli D, Donzelli S, Blandino G, Salvetti M, and Inglese M
- Subjects
- Biomarkers, Blood Coagulation Factors metabolism, Complement System Proteins immunology, Complement System Proteins metabolism, Disease Susceptibility, Gene Expression Profiling, Humans, Magnetic Resonance Imaging methods, Multiple Sclerosis, Relapsing-Remitting etiology, Blood Coagulation immunology, Cerebrovascular Circulation, Clinical Protocols, Complement Activation immunology, Multiple Sclerosis, Relapsing-Remitting blood, Multiple Sclerosis, Relapsing-Remitting diagnosis
- Abstract
Introduction: Multiple sclerosis (MS) is a demyelinating disease of the central nervous system with an underlying immune-mediated and inflammatory pathogenesis. Innate immunity, in addition to the adaptive immune system, plays a relevant role in MS pathogenesis. It represents the immediate non-specific defense against infections through the intrinsic effector mechanism "immunothrombosis" linking inflammation and coagulation. Moreover, decreased cerebral blood volume (CBV), cerebral blood flow (CBF), and prolonged mean transit time (MTT) have been widely demonstrated by MRI in MS patients. We hypothesized that coagulation/complement and platelet activation during MS relapse, likely during viral infections, could be related to CBF decrease. Our specific aims are to evaluate whether there are differences in serum/plasma levels of coagulation/complement factors between relapsing-remitting (RR) MS patients (RRMS) in relapse and those in remission and healthy controls as well as to assess whether brain hemodynamic changes detected by MRI occur in relapse compared with remission. This will allow us to correlate coagulation status with perfusion and demographic/clinical features in MS patients., Materials and Methods: This is a multi-center, prospective, controlled study. RRMS patients (1° group: 30 patients in relapse; 2° group: 30 patients in remission) and age/sex-matched controls (3° group: 30 subjects) will be enrolled in the study. Patients and controls will be tested for either coagulation/complement (C3, C4, C4a, C9, PT, aPTT, fibrinogen, factor II, VIII, and X, D-dimer, antithrombin, protein C, protein S, von-Willebrand factor), soluble markers of endothelial damage (thrombomodulin, Endothelial Protein C Receptor), antiphospholipid antibodies, lupus anticoagulant, complete blood count, viral serological assays, or microRNA microarray. Patients will undergo dynamic susceptibility contrast-enhanced MRI using a 3.0-T scanner to evaluate CBF, CBV, MTT, lesion number, and volume., Statistical Analysis: ANOVA and unpaired t-tests will be used. The level of significance was set at p ≤ 0.05., Discussion: Identifying a link between activation of coagulation/complement system and cerebral hypoperfusion could improve the identification of novel molecular and/or imaging biomarkers and targets, leading to the development of new effective therapeutic strategies in MS., Clinical Trial Registration: Clinicaltrials.gov, identifier NCT04380220., (Copyright © 2020 Koudriavtseva, Stefanile, Fiorelli, Lapucci, Lorenzano, Zannino, Conti, D’Agosto, Pimpinelli, Di Domenico, Mandoj, Giannarelli, Donzelli, Blandino, Salvetti and Inglese.)
- Published
- 2020
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33. Heparin affects the induction of regulatory T cells independent of anti-coagulant activity and suppresses allogeneic immune responses.
- Author
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Kashiwakura Y, Kojima H, Kanno Y, Hashiguchi M, and Kobata T
- Subjects
- Animals, Anticoagulants adverse effects, Disease Models, Animal, Fibrinolytic Agents adverse effects, Heparin, Mice, Mice, Inbred BALB C, T-Lymphocytes, Regulatory pathology, Anticoagulants pharmacology, Blood Coagulation drug effects, Blood Coagulation immunology, Fibrinolytic Agents pharmacology, Graft vs Host Disease immunology, T-Lymphocytes, Regulatory immunology
- Abstract
Heparin is a widely used anti-coagulant that enhances anti-thrombin (AT) activity. However, heparin also suppresses immune and inflammatory responses in various rodent models and clinical trials, respectively. The mechanism by which heparin suppresses immune responses is unclear. The effect of heparin on regulatory T cells (T
regs ) in allogeneic immune responses was analysed using an acute graft-versus-host disease (aGVHD) mouse model and mixed lymphocyte reactions (MLRs). In-vitro culture systems were utilized to study the effects of heparin on Tregs . Heparin administration reduced mortality rates and increased the proportion of Tregs in the early post-transplantation period of aGVHD mice. In both murine and human MLRs, heparin increased Tregs and inhibited responder T cell proliferation. Heparin promoted functional CD4+ CD25+ forkhead box protein 3 (FoxP3)+ Treg generation from naive CD4+ T cells, increased interleukin (IL)-2 production and enhanced the activation of pre-existing Tregs with IL-2. Heparin-induced Treg increases were not associated with anti-coagulant activity through AT, but required negatively charged sulphation of heparin. Importantly, N-acetyl heparin, a chemically modified heparin without anti-coagulant activity, induced Tregs and decreased mortality in aGVHD mice. Our results indicate that heparin contributes to Treg -mediated immunosuppression through IL-2 production and suggest that heparin derivatives may be useful for immunopathological control by efficient Treg induction., (© 2020 British Society for Immunology.)- Published
- 2020
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34. The need to manage the risk of thromboembolism in COVID-19 patients.
- Author
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Khan IH, Savarimuthu S, Leung MST, and Harky A
- Subjects
- Age Factors, Blood Coagulation immunology, COVID-19, Comorbidity, Coronavirus Infections diagnosis, Coronavirus Infections epidemiology, Coronavirus Infections virology, Cytokine Release Syndrome immunology, Cytokine Release Syndrome virology, Fibrin Fibrinogen Degradation Products analysis, Humans, Pandemics, Pneumonia, Viral diagnosis, Pneumonia, Viral epidemiology, Pneumonia, Viral virology, Risk Factors, SARS-CoV-2, Severity of Illness Index, Sex Factors, Thromboembolism blood, Thromboembolism diagnosis, Thromboembolism etiology, Anticoagulants administration & dosage, Betacoronavirus immunology, Coronavirus Infections complications, Cytokine Release Syndrome complications, Pneumonia, Viral complications, Thromboembolism prevention & control
- Abstract
COVID-19 first appeared in Wuhan, Hubei Province, China, in December 2019. Thought to be of zoonotic origin, it has been named SARS-CoV-2 (COVID-19) and has spread rapidly. As of April 20, 2020, there have been >2.4 million cases recorded worldwide. The inflammatory process, cytokine storm, and lung injury that are associated with COVID-19 can put patients at an increased risk of thrombosis. The total incidence of thrombotic events in COVID-19 patients is currently uncertain. Those with more severe disease and with other risk factors, including increasing age, male sex, obesity, cancer, comorbidities, and intensive care unit admission, are at higher risk of these events. However, there is little international guidance on managing these risks in COVID-19 patients. In this paper, we explore the current evidence and theories surrounding thrombosis in these unique patients and reflect on experience from our center., (Copyright © 2020 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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35. Is Acetylsalicylic Acid a Safe and Potentially Useful Choice for Adult Patients with COVID-19 ?
- Author
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Bianconi V, Violi F, Fallarino F, Pignatelli P, Sahebkar A, and Pirro M
- Subjects
- Anti-Inflammatory Agents pharmacology, COVID-19, Humans, Risk Assessment, SARS-CoV-2, Treatment Outcome, Aspirin pharmacology, Betacoronavirus drug effects, Betacoronavirus physiology, Blood Coagulation drug effects, Blood Coagulation immunology, Coronavirus Infections drug therapy, Coronavirus Infections immunology, Inflammation blood, Inflammation drug therapy, Pandemics, Pneumonia, Viral drug therapy, Pneumonia, Viral immunology
- Abstract
Severe Acute Respiratory Syndrome-Coronavirus-2 is responsible for the current pandemic that has led to more than 10 million confirmed cases of Coronavirus Disease-19 (COVID-19) and over 500,000 deaths worldwide (4 July 2020). Virus-mediated injury to multiple organs, mainly the respiratory tract, activation of immune response with the release of pro-inflammatory cytokines, and overactivation of the coagulation cascade and platelet aggregation leading to micro- and macrovascular thrombosis are the main pathological features of COVID-19. Empirical multidrug therapeutic approaches to treat COVID-19 are currently used with extremely uncertain outcomes, and many others are being tested in clinical trials. Acetylsalicylic acid (ASA) has both anti-inflammatory and antithrombotic effects. In addition, a significant ASA-mediated antiviral activity against DNA and RNA viruses, including different human coronaviruses, has been documented. The use of ASA in patients with different types of infections has been associated with reduced thrombo-inflammation and lower rates of clinical complications and in-hospital mortality. However, safety issues related both to the risk of bleeding and to that of developing rare but serious liver and brain damage mostly among children (i.e., Reye's syndrome) should be considered. Hence, whether ASA might be a safe and reasonable therapeutic candidate to be tested in clinical trials involving adults with COVID-19 deserves further attention. In this review we provide a critical appraisal of current evidence on the anti-inflammatory, antithrombotic, and antiviral effects of ASA, from both a pre-clinical and a clinical perspective. In addition, the potential benefits and risks of use of ASA have been put in the context of the adult-restricted COVID-19 population.
- Published
- 2020
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36. Complement C1q Enhances Primary Hemostasis.
- Author
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Donat C, Kölm R, Csorba K, Tuncer E, Tsakiris DA, and Trendelenburg M
- Subjects
- Animals, Biomarkers, Blood Cell Count, Blood Coagulation genetics, Blood Coagulation immunology, Blood Coagulation Tests, Blood Platelets immunology, Blood Platelets metabolism, Complement C1q genetics, Hemostasis genetics, Mice, Mice, Knockout, Platelet Activation immunology, Platelet Aggregation genetics, Platelet Aggregation immunology, von Willebrand Factor metabolism, Complement C1q immunology, Hemostasis immunology
- Abstract
The cross-talk between the inflammatory complement system and hemostasis is becoming increasingly recognized. The interaction between complement C1q, initiation molecule of the classical pathway, and von Willebrand factor (vWF), initiator molecule of primary hemostasis, has been shown to induce platelet rolling and adhesion in vitro . As vWF disorders result in prolonged bleeding, a lack of C1q as binding partner for vWF might also lead to an impaired hemostasis. Therefore, this study aimed to investigate the in vivo relevance of C1q-dependent binding of vWF in hemostasis. For this purpose, we analyzed parameters of primary and secondary hemostasis and performed bleeding experiments in wild type (WT) and C1q-deficient ( C1qa
-/- ) mice, with reconstitution experiments of C1q in the latter. Bleeding tendency was examined by quantification of bleeding time and blood loss. First, we found that complete blood counts and plasma vWF levels do not differ between C1qa-/- mice and WT mice. Moreover, platelet aggregation tests indicated that the platelets of both strains of mice are functional. Second, while the prothrombin time was comparable between both groups, the activated partial thromboplastin time was shorter in C1qa-/- mice. In contrast, tail bleeding times of C1qa-/- mice were prolonged accompanied by an increased blood loss. Upon reconstitution of C1qa-/- mice with C1q, parameters of increased bleeding could be reversed. In conclusion, our data indicate that C1q, a molecule of the first-line of immune defense, actively participates in primary hemostasis by promoting arrest of bleeding. This observation might be of relevance for the understanding of thromboembolic complications in inflammatory disorders, where excess of C1q deposition is observed., (Copyright © 2020 Donat, Kölm, Csorba, Tuncer, Tsakiris and Trendelenburg.)- Published
- 2020
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37. Complement in Hemolysis- and Thrombosis- Related Diseases.
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Luo S, Hu D, Wang M, Zipfel PF, and Hu Y
- Subjects
- Animals, Blood Coagulation immunology, Blood Platelets immunology, Blood Platelets metabolism, Cell Communication, Complement Activation immunology, Hemostasis immunology, Humans, Thrombosis diagnosis, Complement System Proteins immunology, Disease Susceptibility immunology, Hemolysis immunology, Thrombosis blood, Thrombosis immunology
- Abstract
The complement system, originally classified as part of innate immunity, is a tightly self-regulated system consisting of liquid phase, cell surface, and intracellular proteins. In the blood circulation, the complement system, platelets, coagulation system, and fibrinolysis system form a close and complex network. They activate and regulate each other and jointly mediate immune monitoring and tissue homeostasis. The dysregulation of each cascade system results in clinical manifestations and the progression of different diseases, such as sepsis, atypical hemolytic uremic syndrome, C3 glomerulonephritis, systemic lupus erythematosus, or ischemia-reperfusion injury. In this review, we summarize the crosstalk between the complement system, platelets, and coagulation, provide integrative insights into how complement dysfunction leads to hemopathic progression, and further discuss the therapeutic relevance of complement in hemolytic and thrombotic diseases., (Copyright © 2020 Luo, Hu, Wang, Zipfel and Hu.)
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- 2020
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38. COVID-19 cytokine storm: the interplay between inflammation and coagulation.
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Jose RJ and Manuel A
- Subjects
- Blood Coagulation immunology, COVID-19, Coronavirus Infections immunology, Cytokines immunology, Humans, Inflammation virology, Pandemics, Pneumonia, Viral immunology, SARS-CoV-2, Betacoronavirus immunology, Coronavirus Infections blood, Cytokines blood, Pneumonia, Viral blood
- Published
- 2020
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39. Serious disseminated intravascular coagulation associated with combination therapy of nivolumab and ipilimumab in advanced melanoma.
- Author
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Kuriyama H, Fukushima S, Nakahara S, Kanemaru H, Miyashita A, Aoi J, Tomita Y, Kawasaki T, Nosaka K, and Ihn H
- Subjects
- Blood Coagulation drug effects, Blood Coagulation immunology, Disseminated Intravascular Coagulation chemically induced, Disseminated Intravascular Coagulation drug therapy, Disseminated Intravascular Coagulation immunology, Drug Therapy, Combination methods, Humans, Lung Neoplasms immunology, Lung Neoplasms secondary, Lung Neoplasms therapy, Lymphocyte Activation drug effects, Male, Melanoma immunology, Melanoma secondary, Melanoma therapy, Middle Aged, Skin Neoplasms diagnosis, Skin Neoplasms immunology, Skin Neoplasms pathology, Skin Neoplasms therapy, T-Lymphocytes drug effects, T-Lymphocytes immunology, Antineoplastic Combined Chemotherapy Protocols adverse effects, Disseminated Intravascular Coagulation diagnosis, Immune Checkpoint Inhibitors adverse effects, Ipilimumab adverse effects, Nivolumab adverse effects
- Published
- 2020
- Full Text
- View/download PDF
40. In silico identification of new inhibitors for βeta-2-glycoprotein I as a major antigen in antiphospholipid antibody syndrome.
- Author
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Mahdian S, Zarrabi M, Moini A, Movahedi M, and Shahhoseini M
- Subjects
- Blood Coagulation immunology, Computer Simulation, Humans, Lactones pharmacology, Piperazines pharmacology, Protein Binding immunology, Pyridines pharmacology, Antigens immunology, Antiphospholipid Syndrome immunology, Autoantibodies immunology, Phospholipids immunology, beta 2-Glycoprotein I antagonists & inhibitors
- Abstract
Beta 2 glycoprotein I (β2GPI) is a major antigen for autoantibodies present in antiphospholipid antibody syndrome (APS). β2GPI is a single polypeptide with five repeated domains and different conformations. The activated J-shaped conformation of β2GPI binds to negatively charged phospholipids in the membrane via the fifth domain and causes blood clotting reactions. We applied a drug repurposing strategy using virtual screening and molecular dynamics to find the best FDA drugs against the fifth domain of β2GPI. In the first phase, FDA drugs that had the most favorable ΔG with the fifth domain of β2GPI were selected by virtual screening. Among these drugs that had the most favorable ΔG, Vorapaxar and Antrafenine were selected for molecular dynamics (MD) simulation studies. MD simulation was performed to evaluate the stability of Vorapaxar and Antrafenine complexes and the effect of the two drugs on protein conformation. Also, MD simulation was done to investigate the effect of Antrafenine and Vorapaxar on the binding of β2GPI to the platelet model membrane. According to the results, Vorapaxar and Antrafenine were bound to the protein with the favorable binding energy (Vorapaxar and Antrafenine binding energies are - 49.641 and - 38.803 kcal/mol, respectively). In this study, it was shown that unlike protein alone and protein in the Antrafenine complex, the protein in the Vorapaxar complex was completely separated from the model membrane after 350 ns. Moreover, Vorapaxar led to more changes in the activated J-shape of β2GPI. Thus, Vorapaxar can be a suitable candidate for further investigations on the treatment of APS.
- Published
- 2020
- Full Text
- View/download PDF
41. Traumatic-Induced Coagulopathy as a Systems Failure: A New Window into Hemostasis.
- Author
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Dobson GP, Morris JL, Davenport LM, and Letson HL
- Subjects
- Humans, Blood Coagulation immunology, Hemostasis immunology, Wounds and Injuries physiopathology
- Abstract
Traumatic-induced coagulopathy (TIC) is often associated with significant bleeding, transfusion requirements, inflammation, morbidity, and mortality. This review considers TIC as a systems failure, not as a single-event manifestation of trauma. After briefly reviewing the meaning of TIC and the bewildering array of fibrinolysis phenotypes, we will discuss the role of platelets and fibrinogen in coagulopathy. Next, we will review the different TIC hypotheses and drill down to a single mechanistic domain comprising (1) thrombin's differential binding to thrombomodulin, (2) the expression of annexin II-S100A10 complex, and (3) the functional integrity of the endothelial glycocalyx. This triad forms the basis of the "switch" hypothesis of TIC. We will next address the potential limitations of current practice in treating a coagulation or fibrinolytic defect, and the next defect, and so on down the line, which often leads to what U.S. surgeon William C. Shoemaker considered "an uncoordinated and sometimes contradictory therapeutic outcome." The treat-as-you-go approach using sequential, single-target treatments appears to be a by-product of decades of highly reductionist thinking and research. Lastly, we will present a unified systems hypothesis of TIC involving three pillars of physiology: the central nervous system (CNS)-cardiovascular system, the endothelial glycocalyx, and mitochondrial integrity. If CNS control of ventriculoarterial coupling is maintained close to unity following trauma, we hypothesize that the endothelium will be protected, mitochondrial energetics will be maintained, and TIC (and inflammation) will be minimized. The Systems Hypothesis of Trauma (SHOT) also helps to answer why certain groups of severely bleeding trauma patients are still dying despite receiving the best care. Currently, no drug therapy exists that targets the whole system., Competing Interests: Dr. Geoffrey Dobson is the sole inventor of the ALM concept for cardioplegia, surgery, infection, and trauma. All other authors have no conflicts to declare., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)
- Published
- 2020
- Full Text
- View/download PDF
42. Interactions of viruses and the humoral innate immune response.
- Author
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Maloney BE, Perera KD, Saunders DRD, Shadipeni N, and Fleming SD
- Subjects
- Animals, Humans, Immune Evasion immunology, Antibodies immunology, Blood Coagulation immunology, Complement Activation immunology, Immunity, Humoral immunology, Immunity, Innate immunology, Virus Diseases immunology, Viruses pathogenicity
- Abstract
The innate immune response is crucial for defense against virus infections where the complement system, coagulation cascade and natural antibodies play key roles. These immune components are interconnected in an intricate network and are tightly regulated to maintain homeostasis and avoid uncontrolled immune responses. Many viruses in turn have evolved to modulate these interactions through various strategies to evade innate immune activation. This review summarizes the current understanding on viral strategies to inhibit the activation of complement and coagulation cascades, evade natural antibody-mediated clearance and utilize complement regulatory mechanisms to their advantage., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
43. Platelets as key players in inflammation and infection.
- Author
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Nicolai L and Massberg S
- Subjects
- Animals, Blood Platelets pathology, Humans, Infections pathology, Infections therapy, Inflammation immunology, Inflammation pathology, Inflammation therapy, Leukocytes immunology, Leukocytes pathology, Thrombosis immunology, Thrombosis pathology, Thrombosis therapy, Blood Coagulation immunology, Blood Platelets immunology, Immunity, Innate, Infections immunology, Platelet Activation immunology
- Abstract
Purpose of Review: This review highlights recent insights into the role of platelets in acute inflammation and infection., Recent Findings: Platelets exhibit intravascular crawling behavior and can collect and bundle bacteria. In addition, platelets are key in promoting intravascular thrombus formation in infection, a process termed 'immunothrombosis', which contributes to pathogen containment, but also potentially damages the host. Platelets are at the nexus of leukocyte recruitment and activation, yet they are at the same time crucial in preventing inflammation-associated hemorrhage and tissue damage. This multitasking requires specific receptors and pathways, depending on stimulus, organ and effector function., Summary: New findings highlight the complex interplay of innate immunity, coagulation and platelets in inflammation and infection, and unravel novel molecular pathways and effector functions. These offer new potential therapeutic approaches, but require further extensive research to distinguish treatable proinflammatory from host-protective pathways.
- Published
- 2020
- Full Text
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44. Re-Evaluating Biologic Pharmacotherapies that Target the Host Response during Sepsis.
- Author
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Tuttle K, McDonald M, and Anderson E
- Subjects
- 1-Alkyl-2-acetylglycerophosphocholine Esterase therapeutic use, Alkaline Phosphatase therapeutic use, Blood Coagulation genetics, Blood Coagulation immunology, Clinical Trials as Topic, Cytokines antagonists & inhibitors, Cytokines genetics, Cytokines immunology, Gene Expression, Granulocyte-Macrophage Colony-Stimulating Factor therapeutic use, Humans, Immunoglobulins, Intravenous therapeutic use, Inflammation, Multiple Organ Failure genetics, Multiple Organ Failure immunology, Multiple Organ Failure pathology, Sepsis genetics, Sepsis immunology, Sepsis pathology, Anti-Inflammatory Agents therapeutic use, Biological Products therapeutic use, Blood Coagulation drug effects, Immunity, Innate drug effects, Multiple Organ Failure drug therapy, Sepsis drug therapy
- Abstract
Multiple organ dysfunction syndrome (MODS) caused by the systemic inflammatory response during sepsis is responsible for millions of deaths worldwide each year, and despite broad consensus concerning its pathophysiology, no specific or effective therapies exist. Recent efforts to treat and/or prevent MODS have included a variety of biologics, recombinant proteins targeting various components of the host response to the infection (e.g., inflammation, coagulation, etc.) Improvements in molecular biology and pharmaceutical engineering have enabled a wide range of utility for biologics to target various aspects of the systemic inflammatory response. The majority of clinical trials to date have failed to show clinical benefit, but some have demonstrated promising results in certain patient populations. In this review we summarize the underlying rationale and outcome of major clinical trials where biologics have been tested as a pharmacotherapy for MODS in sepsis. A brief description of the study design and overall outcome for each of the major trials are presented. Emphasis is placed on discussing targets and/or trials where promising results were observed. Post hoc analyses of trials where therapy demonstrated harm or additional risk to certain patient subgroups are highlighted, and details are provided about specific trials where more stringent inclusion/exclusion criteria are warranted., Competing Interests: The authors have no conflicts of interest to disclose.
- Published
- 2019
- Full Text
- View/download PDF
45. Is low-level HIV-1 viraemia associated with elevated levels of markers of immune activation, coagulation and cardiovascular disease?
- Author
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Elvstam O, Medstrand P, Jansson M, Isberg PE, Gisslén M, and Björkman P
- Subjects
- Adult, Biomarkers blood, C-Reactive Protein metabolism, CD4 Lymphocyte Count, Cardiovascular Diseases blood, Cardiovascular Diseases virology, Female, Fibrin Fibrinogen Degradation Products metabolism, GPI-Linked Proteins blood, Growth Differentiation Factor 15 blood, HIV Infections blood, HIV Infections physiopathology, Humans, Lipopolysaccharide Receptors blood, Male, Receptors, IgG blood, Retrospective Studies, Vascular Cell Adhesion Molecule-1 blood, Viral Load, Viremia physiopathology, Blood Coagulation immunology, Cardiovascular Diseases immunology, HIV Infections immunology, HIV-1 immunology, Viremia immunology
- Abstract
Objectives: The clinical significance of low-level viraemia (LLV) during antiretroviral therapy (ART) is debated. We retrospectively investigated longitudinal levels of plasma markers associated with inflammation, altered coagulation and cardiovascular disease in Swedish HIV-positive adults in relation to LLV or permanent virological suppression during long-term ART., Methods: Plasma levels of C-reactive protein (CRP), D-dimer, vascular cell adhesion molecule 1 (VCAM-1), suppression of tumorigenicity 2 (ST2), growth differentiation factor 15 (GDF-15), soluble CD14 (sCD14), soluble CD163 (sCD163), interferon-γ-induced protein 10 (IP-10) and β-2-microglobulin were measured in 34 individuals with LLV (viral load 50-999 HIV-1 RNA copies/mL) and in matched controls with persistent virological suppression. Biomarker levels were analysed in samples obtained during episodes of LLV and follow-up samples obtained 1 year later (with similar timing for controls). All biomarkers were analysed using an independent sample t-test and analysis of covariance (ANCOVA) after logarithmic transformation. Log-rank analysis was applied for markers with concentration values out of range., Results: Compared with controls, patients with LLV had significantly higher levels of GDF-15 [geometric mean 3416 (95% confidence interval (CI) 804-14 516) pg/mL versus 2002 (95% CI 355-11 295) pg/mL in controls; P = 0.026] and D-dimer [mean 1114 (95% CI 125-9917) ng/mL versus 756 (95% CI 157-3626) ng/mL; P = 0.038] after adjustment for age, CD4 count nadir and type of ART. In the unadjusted t-test, only GDF-15 was significantly higher and in the log-rank test, both GDF-15 and D-dimer were significantly elevated. No significant differences were observed for the other biomarkers analysed., Conclusions: Although levels of inflammation markers were similar in ART recipients with and without LLV, persons with LLV had significantly higher levels of GDF-15 and D-dimer. These findings suggest a potential link between LLV and cardiovascular outcomes., (© 2019 British HIV Association.)
- Published
- 2019
- Full Text
- View/download PDF
46. MASP-1 of the complement system alters fibrinolytic behaviour of blood clots.
- Author
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Jenny L, Noser D, Larsen JB, Dobó J, Gál P, Pál G, and Schroeder V
- Subjects
- Humans, Plasma immunology, Plasminogen immunology, Blood Coagulation immunology, Complement System Proteins immunology, Fibrin immunology, Fibrinolysis immunology, Mannose-Binding Protein-Associated Serine Proteases immunology, Thrombosis immunology
- Abstract
Background: The lectin pathway serine protease mannan-binding lectin-associated serine protease 1 (MASP-1) has been demonstrated to be a major link between complement and coagulation, yet little is known about its interactions with the fibrinolytic system. The aim of this work was to assess the effects of MASP-1 on fibrin clot lysis in different experimental settings., Methods: Rotational thrombelastometry was used to evaluate the effect of MASP-1 on the lysis of clots formed in whole blood under static conditions. Whole blood clots were also formed in the presence and absence of MASP-1 under flow conditions in the Chandler loop and their lysis was analysed separately by fluorescence release of incorporated labelled fibrin. Real-time observation by laser scanning confocal microscopy was used to investigate the lysis of plasma clots where MASP-1 was present either during clot formation or lysis. Cleavage of tPA or plasminogen by MASP-1 was analysed by gel electrophoresis. We performed a turbidimetric clot lysis assay in the presence and absence of the MASP-1 inhibitor SGMI-1 (Schistocerca gregaria protease inhibitor (SGPI)-based MASP inhibitor-1) to evaluate the effect of endogenous MASP-1 in normal plasma and plasma samples from sepsis patients., Results: In the thrombelastometric experiments, where MASP-1 was present during the entire clotting and lysis process, MASP-1 had a significant profibrinolytic effect and accelerated clot lysis. When clots were formed in the presence of MASP-1 under flow in the Chandler loop, the effects on fibrinolysis were heterogenous with impaired fibrinolysis in some individuals (n = 5) and no (n = 3) or even the opposite effect (n = 2) in others. In plasma clot lysis observed by confocal microscopy, lysis was prolonged when MASP-1 was added to the lysis solution, yet there was no difference in lysis time when MASP-1 was present during clot formation. When MASP-1 was incubated with tPA or plasminogen, respectively, cleavage of single-chain tPA into two-chain tPA and a slight reduction of plasminogen were observed. SGMI-1 significantly prolonged clot lysis in the turbidimetric clot lysis assay suggesting that MASP-1 accelerated lysis in plasma samples., Conclusion: MASP-1 is able to alter the susceptibility of blood clots to the fibrinolytic system. MASP-1 has complex, mostly promoting effects on fibrinolysis with high inter-individual variation. Interactions of MASP-1 with the fibrinolytic system may be relevant in the development and therapy of cardiovascular and thrombotic diseases., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
47. Monocyte procoagulant responses to anthrax peptidoglycan are reinforced by proinflammatory cytokine signaling.
- Author
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Popescu NI, Girton A, Burgett T, Lovelady K, and Coggeshall KM
- Subjects
- Biomarkers, Blood Coagulation drug effects, Brefeldin A pharmacology, Flow Cytometry, Host-Pathogen Interactions immunology, Humans, Leukocytes, Mononuclear immunology, Leukocytes, Mononuclear metabolism, Lipopolysaccharides immunology, Monocytes drug effects, Thromboplastin metabolism, Anthrax immunology, Blood Coagulation immunology, Cytokines metabolism, Inflammation Mediators metabolism, Monocytes immunology, Monocytes metabolism, Peptidoglycan immunology, Signal Transduction drug effects
- Abstract
Disseminated intravascular coagulation is a frequent manifestation during bacterial infections and is associated with negative clinical outcomes. Imbalanced expression and activity of intravascular tissue factor (TF) is central to the development of infection-associated coagulopathies. Recently, we showed that anthrax peptidoglycan (PGN) induces disseminated intravascular coagulation in a nonhuman primate model of anthrax sepsis. We hypothesized that immune recognition of PGN by monocytes is critical for procoagulant responses to PGN and investigated whether and how PGN induces TF expression in primary human monocytes. We found that PGN induced monocyte TF expression in a large cohort of healthy volunteers similar to lipopolysaccharide stimulation. Both immune and procoagulant responses to PGN involve intracellular recognition after PGN internalization, as well as surface signaling through immune Fcγ receptors (FcγRs). In line with our hypothesis, blocking immune receptor function, both signaling and FcγR-mediated phagocytosis, significantly reduced but did not abolish PGN-induced monocyte TF expression, indicating that FcγR-independent internalization contributes to intracellular recognition of PGN. Conversely, when intracellular PGN recognition is abolished, TF expression was sensitive to inhibitors of FcγR signaling, indicating that surface engagement of monocyte immune receptors can promote TF expression. The primary procoagulant responses to PGN were further amplified by proinflammatory cytokines through paracrine and autocrine signaling. Despite intersubject variability in the study cohort, dual neutralization of tumor necrosis factor-α and interleukin-1β provided the most robust inhibition of the procoagulant amplification loop and may prove useful for reducing coagulopathies in gram-positive sepsis., (© 2019 by The American Society of Hematology.)
- Published
- 2019
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- View/download PDF
48. Cholesterol Crystals Induce Coagulation Activation through Complement-Dependent Expression of Monocytic Tissue Factor.
- Author
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Gravastrand CS, Steinkjer B, Halvorsen B, Landsem A, Skjelland M, Jacobsen EA, Woodruff TM, Lambris JD, Mollnes TE, Brekke OL, Espevik T, and Rokstad AMA
- Subjects
- Carotid Artery Diseases immunology, Carotid Artery Diseases metabolism, Humans, Monocytes immunology, Monocytes metabolism, Thromboplastin immunology, Thrombosis immunology, Thrombosis metabolism, Blood Coagulation immunology, Cholesterol immunology, Complement Activation immunology, Receptor, Anaphylatoxin C5a metabolism, Thromboplastin biosynthesis
- Abstract
Cholesterol crystals (CC) are strong activators of complement and could potentially be involved in thromboinflammation through complement-coagulation cross-talk. To explore the coagulation-inducing potential of CC, we performed studies in lepirudin-based human whole blood and plasma models. In addition, immunohistological examinations of brain thrombi and vulnerable plaque material from patients with advanced carotid atherosclerosis were performed using polarization filter reflected light microscopy to identify CC. In whole blood, CC exposure induced a time- and concentration-dependent generation of prothrombin fragment 1+2 (PTF1.2), tissue factor (TF) mRNA synthesis, and monocyte TF expression. Blocking Abs against TF abolished CC-mediated coagulation, thus indicating involvement of the TF-dependent pathway. Blockade of FXII by corn trypsin inhibitor had a significant inhibitory effect on CC-induced PTF1.2 in platelet-free plasma, although the overall activation potential was low. CC exposure did not induce platelet aggregation, TF microparticle induction, or TF on granulocytes or eosinophils. Inhibition of complement C3 by CP40 (compstatin), C5 by eculizumab, or C5aR1 by PMX53 blocked CC-induced PTF1.2 by 90% and reduced TF
+ monocytes from 18-20 to 1-2%. The physiologic relevance was supported by birefringent CC structures adjacent to monocytes (CD14), TF, and activated complement iC3b and C5b-9 in a human brain thrombus. Furthermore, monocyte influx and TF induction in close proximity to CC-rich regions with activated complement were found in a vulnerable plaque. In conclusion, CC could be active, releasable contributors to thrombosis by inducing monocyte TF secondary to complement C5aR1 signaling., (Copyright © 2019 by The American Association of Immunologists, Inc.)- Published
- 2019
- Full Text
- View/download PDF
49. Hereditary Angioedema: Insights into inflammation and allergy.
- Author
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Maas C and López-Lera A
- Subjects
- Blood Coagulation immunology, Bradykinin immunology, Complement System Proteins immunology, Fibrinolysis immunology, Humans, Hypersensitivity immunology, Hypersensitivity pathology, Phenotype, Angioedemas, Hereditary immunology, Angioedemas, Hereditary pathology, Inflammation immunology, Inflammation pathology
- Abstract
Hereditary Angioedema (HAE) is a rare autosomal recessive bradykinin (BK)-mediated disease characterized by local episodes of non-pitting swelling. Initially considered a complement-mediated disease, novel pathogenic mechanisms uncovered in the last decade have revealed new HAE-associated genes and tight physiological relationships among complement, contact, coagulation, fibrinolysis and inflammation. Uncontrolled production of BK due to inefficient regulation of the plasma contact system, increased activity of contact and coagulation factors or a deficient regulation of BK receptor-triggered intracellular signalling are on the basis of HAE pathology. In this new scenario, HAE can result from different mechanisms that may generate distinct clinical phenotypes of the disease. This review focuses in the recent advances and unsolved challenges in our comprehension of this ever increasingly complex pathology., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
50. New Insights Into the Pathogenesis of Bullous Pemphigoid: 2019 Update.
- Author
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Genovese G, Di Zenzo G, Cozzani E, Berti E, Cugno M, and Marzano AV
- Subjects
- Autoantibodies immunology, Autoantigens immunology, Autoimmunity, Blood Coagulation immunology, Comorbidity, Complement Activation, Dystonin immunology, Humans, Leukocytes immunology, Non-Fibrillar Collagens immunology, Pemphigoid, Bullous pathology, Pinocytosis immunology, Collagen Type XVII, Neurodegenerative Diseases epidemiology, Pemphigoid, Bullous epidemiology, Pemphigoid, Bullous immunology, Thrombosis epidemiology, Vitamin D Deficiency epidemiology
- Abstract
There are several lines of evidence indicating that the physiopathological bases of bullous pemphigoid (BP), the most common subepidermal autoimmune bullous disease, are hallmarked by the production of autoantibodies directed against the hemidesmosomal anchoring proteins BP180 and BP230. In contrast to the robustness of the latter assumption, the multifaceted complexity of upstream and downstream mechanisms implied in the pathogenesis of BP remains an area of intense speculation. So far, an imbalance between T regulatory cells and autoreactive T helper (Th) cells has been regarded as the main pathogenic factor triggering the autoimmune response in BP patients. However, the contributory role of signaling pathways fostering the B cell stimulation, such as Toll-like receptor activation, as well as that of ancillary inflammatory mechanisms responsible for blister formation, such as Th17 axis stimulation and the activation of the coagulation cascade, are still a matter of debate. In the same way, the pathomechanisms implied in the loss of dermal-epidermal adhesion secondary to autoantibodies binding are not fully understood. Herein, we review in detail the current concepts and controversies on the complex pathogenesis of BP, shedding light on the most recent theories emerging from the literature.
- Published
- 2019
- Full Text
- View/download PDF
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