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Tian Y, Zong Y, Pang Y, Zheng Z, Ma Y, Zhang C, Gao J. Platelets and diseases: signal transduction and advances in targeted therapy. Signal Transduct Target Ther 2025; 10:159. [PMID: 40374650 DOI: 10.1038/s41392-025-02198-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 12/18/2024] [Accepted: 02/24/2025] [Indexed: 05/17/2025] Open
Abstract
Platelets are essential anucleate blood cells that play pivotal roles in hemostasis, tissue repair, and immune modulation. Originating from megakaryocytes in the bone marrow, platelets are small in size but possess a highly specialized structure that enables them to execute a wide range of physiological functions. The platelet cytoplasm is enriched with functional proteins, organelles, and granules that facilitate their activation and participation in tissue repair processes. Platelet membranes are densely populated with a variety of receptors, which, upon activation, initiate complex intracellular signaling cascades. These signaling pathways govern platelet activation, aggregation, and the release of bioactive molecules, including growth factors, cytokines, and chemokines. Through these mechanisms, platelets are integral to critical physiological processes such as thrombosis, wound healing, and immune surveillance. However, dysregulated platelet function can contribute to pathological conditions, including cancer metastasis, atherosclerosis, and chronic inflammation. Due to their central involvement in both normal physiology and disease, platelets have become prominent targets for therapeutic intervention. Current treatments primarily aim to modulate platelet signaling to prevent thrombosis in cardiovascular diseases or to reduce excessive platelet aggregation in other pathological conditions. Antiplatelet therapies are widely employed in clinical practice to mitigate clot formation in high-risk patients. As platelet biology continues to evolve, emerging therapeutic strategies focus on refining platelet modulation to enhance clinical outcomes and prevent complications associated with platelet dysfunction. This review explores the structure, signaling pathways, biological functions, and therapeutic potential of platelets, highlighting their roles in both physiological and pathological contexts.
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Affiliation(s)
- Yuchen Tian
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yao Zong
- Centre for Orthopaedic Research, Medical School, The University of Western Australia, Nedlands, Western Australia, Australia
| | - Yidan Pang
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhikai Zheng
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yiyang Ma
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Changqing Zhang
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Junjie Gao
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Kaiser R, Gold C, Stark K. Recent Advances in Immunothrombosis and Thromboinflammation. Thromb Haemost 2025. [PMID: 40311639 DOI: 10.1055/a-2523-1821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/03/2025]
Abstract
Inflammation and thrombosis are traditionally considered two separate entities of acute host responses to barrier breaks. While inciting inflammatory responses is a prerequisite to fighting invading pathogens and subsequent restoration of tissue homeostasis, thrombus formation is a crucial step of the hemostatic response to prevent blood loss following vascular injury. Though originally designed to protect the host, excessive induction of either inflammatory signaling or thrombus formation and their reciprocal activation contribute to a plethora of disorders, including cardiovascular, autoimmune, and malignant diseases. In this state-of-the-art review, we summarize recent insights into the intricate interplay of inflammation and thrombosis. We focus on the protective aspects of immunothrombosis as well as evidence of detrimental sequelae of thromboinflammation, specifically regarding recent studies that elucidate its pathophysiology beyond coronavirus disease 2019 (COVID-19). We introduce recently identified molecular aspects of key cellular players like neutrophils, monocytes, and platelets that contribute to both immunothrombosis and thromboinflammation. Further, we describe the underlying mechanisms of activation involving circulating plasma proteins and immune complexes. We then illustrate how these factors skew the inflammatory state toward detrimental thromboinflammation across cardiovascular as well as septic and autoimmune inflammatory diseases. Finally, we discuss how the advent of new technologies and the integration with clinical data have been used to investigate the mechanisms and signaling cascades underlying immunothrombosis and thromboinflammation. This review highlights open questions that will need to be addressed by the field to translate our mechanistic understanding into clinically meaningful therapeutic targeting.
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Affiliation(s)
- Rainer Kaiser
- Medizinische Klinik und Poliklinik I, University Hospital Ludwig-Maximilian University, Munich, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
| | - Christoph Gold
- Medizinische Klinik und Poliklinik I, University Hospital Ludwig-Maximilian University, Munich, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
| | - Konstantin Stark
- Medizinische Klinik und Poliklinik I, University Hospital Ludwig-Maximilian University, Munich, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
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Naylor-Adamson L, Price TW, Booth Z, Leonard SVL, Gallo J, Tung LD, Harvell-Smith S, Thi Kim Thanh N, Aslam Z, Allsup D, Hondow N, Chamberlain T, Schneider JE, Naseem K, Bouillard JSG, Stasiuk GJ, Calaminus SDJ. PEGylation of indium phosphide quantum dots prevents quantum dot mediated platelet activation. J Mater Chem B 2025; 13:1052-1063. [PMID: 39635869 PMCID: PMC11619005 DOI: 10.1039/d4tb01334d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 11/07/2024] [Indexed: 12/07/2024]
Abstract
Quantum dots (QDs) are semiconducting inorganic nanocrystals, that have garnered interest in biological and medical spheres due, to their potential benefits in biomedical imaging and drug-delivery systems. Indium phosphide QDs shelled with zinc sulphide (InP/ZnS) are viewed as more biocompatible than previous heavy metal based QDs. However, little is known about how InP/ZnS QDs affect a key blood cell, the platelet. Understanding how platelets interact with QDs is critical as unwanted activation can lead to pathological thrombus formation. Herein, we demonstrate PEGylation of InP/ZnS QDs coated with lipoic acid (QD-LA) or coated with penicillamine (QD-Pen) surface ligands induced markedly less platelet aggregation, platelet-QD interactions, integrin activation, alpha granule secretion and restored platelet spreading in washed platelets in comparison to their non-PEGylated counterparts. Furthermore, in whole blood, PEGylation of QDs reduced the number of QDs in the thrombus, thereby helping to minimise the chance of dysfunctional thrombus formation. Overall, we show that QD PEGylation is important to help prevent QD mediated platelet activation. In combination with the most biocompatible coating, PEGylation markedly reduced platelet activation, widening the concentrations at which QDs were viable for development as potential drug delivery or imaging agents.
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Affiliation(s)
- Leigh Naylor-Adamson
- Biomedical Institute for Multimorbidity, Hull York Medical School, University of Hull, Hull, HU6 7RX, UK.
| | - Thomas W Price
- Department of Imaging Chemistry and Biology, School of Biomedical Engineering and Imaging Sciences, King's College London, London, SE1 7EH, UK.
| | - Zoe Booth
- Biomedical Institute for Multimorbidity, Hull York Medical School, University of Hull, Hull, HU6 7RX, UK.
| | - Sophie V L Leonard
- Biomedical Institute for Multimorbidity, Hull York Medical School, University of Hull, Hull, HU6 7RX, UK.
| | - Juan Gallo
- Advanced Magnetic Theranostic Nanostructures Lab, International Iberian Nanotechnology Laboratory, Av. Mestre José Veiga, Braga 4715-330, Portugal
| | - Le Duc Tung
- UCL Healthcare Biomagnetics and Nanomaterials Laboratories, 21 Albemarle Street, London, W1S 4BS, UK
- Biophysics Group, Department of Physics & Astronomy University College London, Gower Street, London, WC1E 6BT, UK
| | - Stanley Harvell-Smith
- UCL Healthcare Biomagnetics and Nanomaterials Laboratories, 21 Albemarle Street, London, W1S 4BS, UK
- Biophysics Group, Department of Physics & Astronomy University College London, Gower Street, London, WC1E 6BT, UK
| | - Nguyen Thi Kim Thanh
- UCL Healthcare Biomagnetics and Nanomaterials Laboratories, 21 Albemarle Street, London, W1S 4BS, UK
- Biophysics Group, Department of Physics & Astronomy University College London, Gower Street, London, WC1E 6BT, UK
| | - Zabeada Aslam
- Leeds Electron Microscopy and Spectroscopy Centre, LEMAS, The Bragg Centre for Materials Research, Faculty of Engineering and Physical Sciences, University of Leeds, LS2 9JT, UK
| | - David Allsup
- Biomedical Institute for Multimorbidity, Hull York Medical School, University of Hull, Hull, HU6 7RX, UK.
| | - Nicole Hondow
- Leeds Electron Microscopy and Spectroscopy Centre, LEMAS, The Bragg Centre for Materials Research, Faculty of Engineering and Physical Sciences, University of Leeds, LS2 9JT, UK
| | - Thomas Chamberlain
- Institute of Process Research and Development, School of Chemistry, University of Leeds, Leeds, LS2 9JT, UK
| | | | - Khalid Naseem
- Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, LS2 9JT, UK
| | - Jean-Sebastien G Bouillard
- Department of Physics and Mathematics, Nano3 Research grouping - Nanophotonics group, G. W. Gray Centre for Advanced Materials, University of Hull, Cottingham Road, Hull, HU6 7RX, UK
| | - Graeme J Stasiuk
- Department of Imaging Chemistry and Biology, School of Biomedical Engineering and Imaging Sciences, King's College London, London, SE1 7EH, UK.
| | - Simon D J Calaminus
- Biomedical Institute for Multimorbidity, Hull York Medical School, University of Hull, Hull, HU6 7RX, UK.
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Kristyanto H, Slaets L, Braams E, Scheys I, Heesbeen R, Cárdenas V, Shukarev G, Scheper G, Sadoff J, Lühn K, Schuitemaker H, Struyf F, Hendriks J. Assessment of antibodies against platelet factor 4 following vaccination with adenovirus type 26-vectored vaccines. J Thromb Haemost 2024; 22:3532-3541. [PMID: 39278600 DOI: 10.1016/j.jtha.2024.08.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 07/12/2024] [Accepted: 08/19/2024] [Indexed: 09/18/2024]
Abstract
BACKGROUND Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare adverse event identified following vaccination with some adenovirus-vectored COVID-19 vaccines, including Ad26.COV2.S. VITT is characterized by the presence of antibodies against platelet factor 4 (PF4). OBJECTIVES To evaluate whether PF4 antibodies were generally induced following vaccination with adenovirus type 26 (Ad26)-vectored vaccines. METHODS The study included 913 and 991 healthy participants without thromboembolic (TE) events in Ad26.COV2.S and non-COVID-19 Ad26-vectored vaccine clinical studies, respectively, and 1 participant with VITT following Ad26.COV2.S vaccination. PF4 antibody levels were measured in prevaccination and postvaccination sera. PF4 antibody positivity rates were assessed in a case-control setting in participants who developed TE events during participation in Ad26-vectored vaccine clinical studies. RESULTS In the 1 VITT patient, PF4 antibodies were negative before vaccination. Seroconversion for platelet-activating PF4 antibodies was observed upon Ad26.COV2.S vaccination. In participants without TE events, the PF4 antibody levels and positivity rates were similar before and after Ad26 vaccination. Ad26 vaccination did not increase PF4 antibody levels in participants who were PF4 antibody-positive at baseline (n = 47). Lastly, 1 out of 28 TE cases and 2 out of 156 non-TE controls seroconverted after Ad26.COV2.S vaccination. None of the 15 TE cases and 3 of the 77 non-TE controls seroconverted following non-COVID-19 Ad26 vaccination. CONCLUSION Ad26.COV2.S and the other Ad26-vectored vaccines studied did not generally induce PF4 antibodies or increase preexisting PF4 antibody levels. Moreover, unlike VITT, TE events that occurred at any time following Ad26 vaccination were not associated with PF4 antibodies.
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Affiliation(s)
| | - Leen Slaets
- Janssen Research & Development, Beerse, Belgium
| | - Esmée Braams
- Janssen Vaccines & Prevention B.V., Leiden, The Netherlands
| | - Ilse Scheys
- Janssen Research & Development, Beerse, Belgium
| | - Roy Heesbeen
- Janssen Vaccines & Prevention B.V., Leiden, The Netherlands
| | - Vicky Cárdenas
- Janssen Research & Development, LLC, Spring House, Pennsylvania, USA
| | | | - Gert Scheper
- Janssen Vaccines & Prevention B.V., Leiden, The Netherlands
| | - Jerald Sadoff
- Janssen Vaccines & Prevention B.V., Leiden, The Netherlands
| | - Kerstin Lühn
- Janssen Vaccines & Prevention B.V., Leiden, The Netherlands
| | | | | | - Jenny Hendriks
- Janssen Vaccines & Prevention B.V., Leiden, The Netherlands.
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Momi S, Gresele P. The Role of Platelets in Atherosclerosis: A Historical Review. Semin Thromb Hemost 2024. [PMID: 39561814 DOI: 10.1055/s-0044-1795097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2024]
Abstract
Atherosclerosis is a chronic, multifactorial inflammatory disorder of large and medium-size arteries, which is the leading cause of cardiovascular mortality and morbidity worldwide. Although platelets in cardiovascular disease have mainly been studied for their crucial role in the thrombotic event triggered by atherosclerotic plaque rupture, over the last two decades it has become clear that platelets participate also in the development of atherosclerosis, owing to their ability to interact with the damaged arterial wall and with leukocytes. Platelets participate in all phases of atherogenesis, from the initial functional damage to endothelial cells to plaque unstabilization. Platelets deposit at atherosclerosis predilection sites before the appearance of manifest lesions to the endothelium and contribute to induce endothelial dysfunction, thus supporting leukocyte adhesion to the vessel wall. In particular, platelets release matrix metalloproteinases, which interact with protease-activated receptor 1 on endothelial cells triggering adhesion molecule expression. Moreover, P-selectin and glycoprotein Ibα expressed on the surface of vessel wall-adhering platelets bind PSGL-1 and β2 integrins on leukocytes, favoring their arrest and transendothelial migration. Platelet-leukocyte interactions promote the formation of radical oxygen species which are strongly involved in the lipid peroxidation associated with atherosclerosis. Platelets themselves actively migrate through the endothelium toward the plaque core where they release chemokines that modify the microenvironment by modulating the function of other inflammatory cells, such as macrophages. While current antiplatelet agents seem unable to prevent the contribution of platelets to atherogenesis, the inhibition of platelet secretion, of the release of MMPs, and of some specific pathways of platelet adhesion to the vessel wall may represent promising future strategies for the prevention of atheroprogression.
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Affiliation(s)
- Stefania Momi
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Paolo Gresele
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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6
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Mazzuchini MP, Lisboa FP, de Castro JI, Alvarenga MA, Segabinazzi LGTM, Canisso IF. In vitro antimicrobial activity of non-traditional therapies for infectious endometritis in mares. Equine Vet J 2024. [PMID: 39431554 DOI: 10.1111/evj.14423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 09/06/2024] [Indexed: 10/22/2024]
Abstract
BACKGROUND Endometritis is the leading cause of subfertility in horses, and it is a clinical problem where historically antibiotics have not always been used with prudent justification. Because of this, alternative therapies to treat endometritis are necessary for the rational use of antibiotics. OBJECTIVES To assess the in vitro antimicrobial activity of non-traditional therapies commonly used in clinical practice against microorganisms causing infectious endometritis in mares. STUDY DESIGN In vitro experiments. METHODS A microdilution technique was performed to determine the minimum inhibitory concentrations (MIC) of 50%, 90% and 100% of microorganisms and the percentage of inhibition (PI) of each therapy against each microorganism (Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Staphylococcus aureus and Candida sp.). The MIC 50% and 90% were determined using non-linear regression, while MIC 100% was assessed using the resazurin dye technique. The serial PI was evaluated for each therapy using a spectrophotometer. RESULTS All the therapies demonstrated a PI higher than positive controls for all microorganisms (p < 0.05); however, the only therapies that presented MIC 100 values were hydrogen peroxide and platelet-rich and -poor plasma. MAIN LIMITATIONS In vivo, safety and treatment efficacy were not tested. CONCLUSION Hydrogen peroxide and platelet-rich and -poor plasma might be alternatives to traditional therapies for endometritis to support a reduction in antibiotic use.
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Affiliation(s)
- Mariana P Mazzuchini
- Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois Urbana-Champaign, Champaign, Illinois, USA
- Department of Animal Reproduction and Veterinary Radiology, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
| | - Fernando Paixão Lisboa
- Department of Animal Reproduction and Veterinary Radiology, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
| | - Jessica I de Castro
- Institute of Biotechnology, University of Caxias do Sul (UCS), Caxias do Sul, Rio Grande do Sul, Brazil
| | - Marco A Alvarenga
- Department of Animal Reproduction and Veterinary Radiology, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
| | | | - Igor F Canisso
- Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois Urbana-Champaign, Champaign, Illinois, USA
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Babkina AS, Pisarev MV, Grechko AV, Golubev AM. Arterial Thrombosis in Acute Respiratory Infections: An Underestimated but Clinically Relevant Problem. J Clin Med 2024; 13:6007. [PMID: 39408067 PMCID: PMC11477565 DOI: 10.3390/jcm13196007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 10/07/2024] [Accepted: 10/07/2024] [Indexed: 10/20/2024] Open
Abstract
During the COVID-19 pandemic, there was increased interest in the issue of thrombotic complications of acute respiratory infections. Clinical reports and pathological studies have revealed that thrombus formation in COVID-19 may involve the venous and arterial vasculature. As thrombotic complications of infectious respiratory diseases are increasingly considered in the context of COVID-19, the fact that thrombosis in lung diseases of viral and bacterial etiology was described long before the pandemic is overlooked. Pre-pandemic studies show that bacterial and viral respiratory infections are associated with an increased risk of thrombotic complications such as myocardial infarction, ischemic stroke, pulmonary embolism, and other critical illnesses caused by arterial and venous thrombosis. This narrative review article aims to summarize the current evidence regarding thrombotic complications and their pathogenesis in acute lower respiratory tract infections.
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Affiliation(s)
- Anastasiya S. Babkina
- Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow 107031, Russia; (M.V.P.); (A.V.G.); (A.M.G.)
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8
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Zhu J, Xu L, Wang W, Xiao M, Li J, Wang L, Jiang X. Molecular Dynamics Simulations Reveal Octanoylated Hyaluronic Acid Enhances Liposome Stability, Stealth and Targeting. ACS OMEGA 2024; 9:33833-33844. [PMID: 39130542 PMCID: PMC11307277 DOI: 10.1021/acsomega.4c03526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 08/13/2024]
Abstract
Liposome-based drug delivery systems have been widely used in drug and gene delivery. However, issues such as instability, immune clearance, and poor targeting have significantly limited their clinical utility. Consequently, there is an urgent need for innovative strategies to improve liposome performance. In this study, we explore the interaction mechanisms of hyaluronic acid (HA), a linear anionic polysaccharide composed of repeating disaccharide units of d-glucuronic acid and N-acetyl-d-glucosamine connected by alternating β-1,3 and β-1,4 glycosidic linkages, and its octanoylated derivates (OHA) with liposomes using extensive coarse-grained molecular dynamics simulations. The octyl moieties of OHA spontaneously inserted into the phospholipid bilayer of liposomes, leading to their effective coating onto the surface of liposome and enhancing their structural stability. Furthermore, encapsulating liposome with OHA neutralized their surface potential, interfering with the formation of a protein corona known to contribute to liposomal immune clearance. Importantly, the encapsulated OHA maintained its selectivity and therefore targeting ability for CD44, which is often overexpressed in tumor cells. These molecular-scale findings shed light on the interaction mechanisms between HA and liposomes and will be useful for the development of next-generation liposome-based drug delivery systems.
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Affiliation(s)
- Jingyi Zhu
- State
Key Laboratory of Microbial Technology, National Glycoengineering
Research Center, Shandong University, Qingdao 266237, China
| | - Limei Xu
- State
Key Laboratory of Microbial Technology, National Glycoengineering
Research Center, Shandong University, Qingdao 266237, China
| | - Wenxin Wang
- Shandong
Institute for Food and Drug Control, Jinan 250000, China
| | - Min Xiao
- State
Key Laboratory of Microbial Technology, National Glycoengineering
Research Center, Shandong University, Qingdao 266237, China
| | - Jian Li
- Biomedicine
Discovery Institute, Monash University, Melbourne 3800, Australia
| | - Lushan Wang
- State
Key Laboratory of Microbial Technology, National Glycoengineering
Research Center, Shandong University, Qingdao 266237, China
| | - Xukai Jiang
- State
Key Laboratory of Microbial Technology, National Glycoengineering
Research Center, Shandong University, Qingdao 266237, China
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Petry J, Weiser T, Griesbaum L, Schröder K, Hoch CC, Bashiri Dezfouli A, Shoykhet M, Wollenberg B. 1.8-cineole prevents platelet activation and aggregation by activating the cAMP pathway via the adenosine A 2A receptor. Life Sci 2024; 350:122746. [PMID: 38810792 DOI: 10.1016/j.lfs.2024.122746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 05/16/2024] [Accepted: 05/22/2024] [Indexed: 05/31/2024]
Abstract
AIMS Dysregulated platelet aggregation is a fatal condition in many bacterial- and virus-induced diseases. However, classical antithrombotics cannot completely prevent immunothrombosis, due to the unaddressed mechanisms towards inflammation. Thus, targeting platelet hyperactivation together with inflammation might provide new treatment options in diseases, characterized by immunothrombosis, such as COVID-19 and sepsis. The aim of this study was to investigate the antiaggregatory effect and mode of action of 1.8-cineole, a monoterpene derived from the essential oil of eucalyptus leaves, known for its anti-inflammatory proprieties. MAIN METHODS Platelet activity was monitored by measuring the expression and release of platelet activation markers, i.e., P-selectin, CD63 and CCL5, as well as platelet aggregation, upon treatment with 1.8-cineole and stimulation with several classical stimuli and bacteria. A kinase activity assay was used to elucidate the mode of action, followed by a detailed analysis of the involvement of the adenylyl-cyclase (AC)-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway by Western blot and ELISA. KEY FINDINGS 1.8-cineole prevented the expression and release of platelet activation markers, as well as platelet aggregation, upon induction of aggregation with classical stimuli and immunological agonists. Mechanistically, 1.8- cineole influences the activation of the AC-cAMP-PKA pathway, leading to higher cAMP levels and vasodilator-stimulated phosphoprotein (VASP) phosphorylation. Finally, blocking the adenosine A2A receptor reversed the antithrombotic effect of 1.8-cineole. SIGNIFICANCE Given the recognized anti-inflammatory attributes of 1.8-cineole, coupled with our findings, 1.8-cineole might emerge as a promising candidate for treating conditions marked by platelet activation and abnormal inflammation.
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Affiliation(s)
- Julie Petry
- Department of Otolaryngology, Head and Neck Surgery, Technical University of Munich and Klinikum Rechts der Isar, Munich, Germany
| | - Tobias Weiser
- Department of Otolaryngology, Head and Neck Surgery, Technical University of Munich and Klinikum Rechts der Isar, Munich, Germany
| | - Lena Griesbaum
- Department of Otolaryngology, Head and Neck Surgery, Technical University of Munich and Klinikum Rechts der Isar, Munich, Germany
| | - Kathrin Schröder
- Institute for Medical Microbiology, Immunology and Hygiene, School of Medicine, Technical University of Munich, Munich, Germany
| | - Cosima C Hoch
- Department of Otolaryngology, Head and Neck Surgery, Technical University of Munich and Klinikum Rechts der Isar, Munich, Germany
| | - Ali Bashiri Dezfouli
- Department of Otolaryngology, Head and Neck Surgery, Technical University of Munich and Klinikum Rechts der Isar, Munich, Germany; Central Institute for Translational Cancer Research, Technical University of Munich (TranslaTUM), Department of Radiation Oncology, Klinikum Rechts der Isar, Munich, Germany
| | - Maria Shoykhet
- Department of Otolaryngology, Head and Neck Surgery, Technical University of Munich and Klinikum Rechts der Isar, Munich, Germany
| | - Barbara Wollenberg
- Department of Otolaryngology, Head and Neck Surgery, Technical University of Munich and Klinikum Rechts der Isar, Munich, Germany.
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Li N, Hao R, Ren P, Wang J, Dong J, Ye T, Zhao D, Qiao X, Meng Z, Gan H, Liu S, Sun Y, Dou G, Gu R. Glycosaminoglycans: Participants in Microvascular Coagulation of Sepsis. Thromb Haemost 2024; 124:599-612. [PMID: 38242171 PMCID: PMC11199054 DOI: 10.1055/a-2250-3166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 12/23/2023] [Indexed: 01/21/2024]
Abstract
Sepsis represents a syndromic response to infection and frequently acts as a common pathway leading to fatality in the context of various infectious diseases globally. The pathology of severe sepsis is marked by an excess of inflammation and activated coagulation. A substantial contributor to mortality in sepsis patients is widespread microvascular thrombosis-induced organ dysfunction. Multiple lines of evidence support the notion that sepsis induces endothelial damage, leading to the release of glycosaminoglycans, potentially causing microvascular dysfunction. This review aims to initially elucidate the relationship among endothelial damage, excessive inflammation, and thrombosis in sepsis. Following this, we present a summary of the involvement of glycosaminoglycans in coagulation, elucidating interactions among glycosaminoglycans, platelets, and inflammatory cells. In this section, we also introduce a reasoned generalization of potential signal pathways wherein glycosaminoglycans play a role in clotting. Finally, we discuss current methods for detecting microvascular conditions in sepsis patients from the perspective of glycosaminoglycans. In conclusion, it is imperative to pay closer attention to the role of glycosaminoglycans in the mechanism of microvascular thrombosis in sepsis. Dynamically assessing glycosaminoglycan levels in patients may aid in predicting microvascular conditions, enabling the monitoring of disease progression, adjustment of clinical treatment schemes, and mitigation of both acute and long-term adverse outcomes associated with sepsis.
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Affiliation(s)
- Nanxi Li
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, People Republic of China
| | - Ruolin Hao
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, People Republic of China
| | - Peng Ren
- Beijing Institute of Basic Medical Sciences, Beijing, People Republic of China
| | - Jingya Wang
- Beijing Institute of Basic Medical Sciences, Beijing, People Republic of China
| | - Jiahui Dong
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, People Republic of China
| | - Tong Ye
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, People Republic of China
| | - Danyang Zhao
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, People Republic of China
| | - Xuan Qiao
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, People Republic of China
| | - Zhiyun Meng
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, People Republic of China
| | - Hui Gan
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, People Republic of China
| | - Shuchen Liu
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, People Republic of China
| | - Yunbo Sun
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, People Republic of China
| | - Guifang Dou
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, People Republic of China
| | - Ruolan Gu
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, People Republic of China
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11
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Nicolai L, Pekayvaz K, Massberg S. Platelets: Orchestrators of immunity in host defense and beyond. Immunity 2024; 57:957-972. [PMID: 38749398 DOI: 10.1016/j.immuni.2024.04.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 04/06/2024] [Accepted: 04/12/2024] [Indexed: 06/05/2024]
Abstract
Platelets prevent blood loss during vascular injury and contribute to thrombus formation in cardiovascular disease. Beyond these classical roles, platelets are critical for the host immune response. They guard the vasculature against pathogens via specialized receptors, intracellular signaling cascades, and effector functions. Platelets also skew inflammatory responses by instructing innate immune cells, support adaptive immunosurveillance, and influence antibody production and T cell polarization. Concomitantly, platelets contribute to tissue reconstitution and maintain vascular function after inflammatory challenges. However, dysregulated activation of these multitalented cells exacerbates immunopathology with ensuing microvascular clotting, excessive inflammation, and elevated risk of macrovascular thrombosis. This dichotomy underscores the critical importance of precisely defining and potentially modulating platelet function in immunity.
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Affiliation(s)
- Leo Nicolai
- Medizinische Klinik und Poliklinik I, University Hospital Ludwig-Maximilian University, Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
| | - Kami Pekayvaz
- Medizinische Klinik und Poliklinik I, University Hospital Ludwig-Maximilian University, Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
| | - Steffen Massberg
- Medizinische Klinik und Poliklinik I, University Hospital Ludwig-Maximilian University, Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
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12
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Thom CS, Davenport P, Fazelinia H, Soule-Albridge E, Liu ZJ, Zhang H, Feldman HA, Ding H, Roof J, Spruce LA, Ischiropoulos H, Sola-Visner M. Quantitative label-free mass spectrometry reveals content and signaling differences between neonatal and adult platelets. J Thromb Haemost 2024; 22:1447-1462. [PMID: 38160730 PMCID: PMC11055671 DOI: 10.1016/j.jtha.2023.12.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 12/04/2023] [Accepted: 12/13/2023] [Indexed: 01/03/2024]
Abstract
BACKGROUND Recent clinical studies have shown that transfusions of adult platelets increase morbidity and mortality in preterm infants. Neonatal platelets are hyporesponsive to agonist stimulation, and emerging evidence suggests developmental differences in platelet immune functions. OBJECTIVES This study was designed to compare the proteome and phosphoproteome of resting adult and neonatal platelets. METHODS We isolated resting umbilical cord blood-derived platelets from healthy full-term neonates (n = 8) and resting blood platelets from healthy adults (n = 6) and compared protein and phosphoprotein contents using data-independent acquisition mass spectrometry. RESULTS We identified 4770 platelet proteins with high confidence across all samples. Adult and neonatal platelets were clustered separately by principal component analysis. Adult platelets were significantly enriched in immunomodulatory proteins, including β2 microglobulin and CXCL12, whereas neonatal platelets were enriched in ribosomal components and proteins involved in metabolic activities. Adult platelets were enriched in phosphorylated GTPase regulatory enzymes and proteins participating in trafficking, which may help prime them for activation and degranulation. Neonatal platelets were enriched in phosphorylated proteins involved in insulin growth factor signaling. CONCLUSION Using label-free data-independent acquisition mass spectrometry, our findings expanded the known neonatal platelet proteome and identified important differences in protein content and phosphorylation between neonatal and adult platelets. These developmental differences suggested enhanced immune functions for adult platelets and presence of molecular machinery related to platelet activation. These findings are important to understanding mechanisms underlying key platelet functions as well as the harmful effects of adult platelet transfusions given to preterm infants.
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Affiliation(s)
- Christopher S Thom
- Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
| | - Patricia Davenport
- Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Hossein Fazelinia
- Proteomics Core, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Erin Soule-Albridge
- Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Zhi-Jian Liu
- Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Haorui Zhang
- Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Henry A Feldman
- Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts, USA; Institutional Centers for Clinical and Translational Research, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Hua Ding
- Proteomics Core, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Jennifer Roof
- Proteomics Core, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Lynn A Spruce
- Proteomics Core, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Harry Ischiropoulos
- Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania, USA
| | - Martha Sola-Visner
- Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.
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13
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Duchez AC, Heestermans M, Arthaud CA, Eyraud MA, Portier M, Prier A, Hamzeh-Cognasse H, Cognasse F. In platelet single donor apheresis, platelet factor 4 levels correlated with donor's age and decreased during storage. Sci Rep 2024; 14:6231. [PMID: 38485973 PMCID: PMC10940288 DOI: 10.1038/s41598-024-56826-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 03/12/2024] [Indexed: 03/18/2024] Open
Abstract
The human population is ageing worldwide. The World Health Organization estimated that the world's population of people aged 60 years and older will increase to at least 30%, coinciding with a growing frequency of cognitive and cardiovascular disease. Recently, in preclinical studies platelet Factor 4 (PF4) was presented as a pro-cognitive factor. This molecule is released by platelets in the circulation and could be present in blood products destined for transfusion. We wondered if PF4 levels are correlated to the age of the blood donor or to the storage time of platelet concentrates (PCs) intended for transfusion? We observed higher levels of PF4 in PCs from elderly donors compared to younger donors, while PC storage time did not determine PF4 levels expression.
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Affiliation(s)
- Anne Claire Duchez
- INSERM, U 1059 SAINBIOSE, Université Jean Monnet, Mines Saint-Étienne, 42023, Saint-Etienne, France
- Establissement Français du Sang Auvergne-Rhône-Alpes and INSERM U1059, 25 Boulevard Pasteur, 42100, Saint-Etienne, France
| | - Marco Heestermans
- INSERM, U 1059 SAINBIOSE, Université Jean Monnet, Mines Saint-Étienne, 42023, Saint-Etienne, France
- Establissement Français du Sang Auvergne-Rhône-Alpes and INSERM U1059, 25 Boulevard Pasteur, 42100, Saint-Etienne, France
| | - Charles-Antoine Arthaud
- INSERM, U 1059 SAINBIOSE, Université Jean Monnet, Mines Saint-Étienne, 42023, Saint-Etienne, France
- Establissement Français du Sang Auvergne-Rhône-Alpes and INSERM U1059, 25 Boulevard Pasteur, 42100, Saint-Etienne, France
| | - Marie-Ange Eyraud
- INSERM, U 1059 SAINBIOSE, Université Jean Monnet, Mines Saint-Étienne, 42023, Saint-Etienne, France
- Establissement Français du Sang Auvergne-Rhône-Alpes and INSERM U1059, 25 Boulevard Pasteur, 42100, Saint-Etienne, France
| | - Mailys Portier
- INSERM, U 1059 SAINBIOSE, Université Jean Monnet, Mines Saint-Étienne, 42023, Saint-Etienne, France
- Establissement Français du Sang Auvergne-Rhône-Alpes and INSERM U1059, 25 Boulevard Pasteur, 42100, Saint-Etienne, France
| | - Amélie Prier
- INSERM, U 1059 SAINBIOSE, Université Jean Monnet, Mines Saint-Étienne, 42023, Saint-Etienne, France
- Establissement Français du Sang Auvergne-Rhône-Alpes and INSERM U1059, 25 Boulevard Pasteur, 42100, Saint-Etienne, France
| | - Hind Hamzeh-Cognasse
- INSERM, U 1059 SAINBIOSE, Université Jean Monnet, Mines Saint-Étienne, 42023, Saint-Etienne, France
| | - Fabrice Cognasse
- INSERM, U 1059 SAINBIOSE, Université Jean Monnet, Mines Saint-Étienne, 42023, Saint-Etienne, France.
- Establissement Français du Sang Auvergne-Rhône-Alpes and INSERM U1059, 25 Boulevard Pasteur, 42100, Saint-Etienne, France.
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14
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Barbero AM, Hernández Del Pino RE, Fuentes F, Barrionuevo P, Pasquinelli V. Platelets promote human macrophages-mediated macropinocytosis of Clostridioides difficile. Front Cell Infect Microbiol 2024; 13:1252509. [PMID: 38249298 PMCID: PMC10796631 DOI: 10.3389/fcimb.2023.1252509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 12/11/2023] [Indexed: 01/23/2024] Open
Abstract
Clostridioides difficile is the main causative agent of hospital-acquired diarrhea and the potentially lethal disease, C. difficile infection. The cornerstone of the current therapy is the use of antibiotics, which is not fully effective. The molecular mechanisms, inflammatory conditions and host-immune responses that could benefit the persistence or elimination of C. difficile remain unclear. Macrophages perform different ways of endocytosis as part of their immune surveillance functions and platelets, classically known for their coagulatory role, are also important modulators of the immune system. The aim of this study was to evaluate the endocytosis of vegetative C. difficile by human macrophages and the involvement of platelets in this process. Our results showed that both macrophages and platelets interact with live and heat-killed C. difficile. Furthermore, platelets form complexes with human monocytes in healthy donor's fresh blood and the presence of C. difficile increased these cell-cell interactions. Using flow cytometry and confocal microscopy, we show that macrophages can internalize C. difficile and that platelets improve this uptake. By using inhibitors of different endocytic pathways, we demonstrate that macropinocytosis is the route of entry of C. difficile into the cell. Taken together, our findings are the first evidence for the internalization of vegetative non-toxigenic and hypervirulent C. difficile by human macrophages and highlight the role of platelets in innate immunity during C. difficile infection. Deciphering the crosstalk of C. difficile with immune cells could provide new tools for understanding the pathogenesis of C. difficile infection and for the development of host-directed therapies.
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Affiliation(s)
- Angela María Barbero
- Centro de Investigaciones Básicas y Aplicadas (CIBA), Universidad Nacional del Noroeste de la Provincia de Buenos Aires (UNNOBA), Buenos Aires, Argentina
- Centro de Investigaciones y Transferencias del Noroeste de la Provincia de Buenos Aires (CIT NOBA), UNNOBA-Universidad Nacional de San Antonio de Areco (UNSAdA)- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Rodrigo Emanuel Hernández Del Pino
- Centro de Investigaciones Básicas y Aplicadas (CIBA), Universidad Nacional del Noroeste de la Provincia de Buenos Aires (UNNOBA), Buenos Aires, Argentina
- Centro de Investigaciones y Transferencias del Noroeste de la Provincia de Buenos Aires (CIT NOBA), UNNOBA-Universidad Nacional de San Antonio de Areco (UNSAdA)- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Federico Fuentes
- Instituto de Medicina Experimental (CONICET-Academia Nacional de Medicina), Buenos Aires, Argentina
| | - Paula Barrionuevo
- Instituto de Medicina Experimental (CONICET-Academia Nacional de Medicina), Buenos Aires, Argentina
| | - Virginia Pasquinelli
- Centro de Investigaciones Básicas y Aplicadas (CIBA), Universidad Nacional del Noroeste de la Provincia de Buenos Aires (UNNOBA), Buenos Aires, Argentina
- Centro de Investigaciones y Transferencias del Noroeste de la Provincia de Buenos Aires (CIT NOBA), UNNOBA-Universidad Nacional de San Antonio de Areco (UNSAdA)- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
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15
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Cai Z, Feng J, Dong N, Zhou P, Huang Y, Zhang H. Platelet-derived extracellular vesicles play an important role in platelet transfusion therapy. Platelets 2023; 34:2242708. [PMID: 37578045 DOI: 10.1080/09537104.2023.2242708] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Accepted: 07/24/2023] [Indexed: 08/15/2023]
Abstract
Extracellular vesicles (EVs) contain the characteristics of their cell of origin and mediate cell-to-cell communication. Platelet-derived extracellular vesicles (PEVs) not only have procoagulant activity but also contain platelet-derived inflammatory factors (CD40L and mtDNA) that mediate inflammatory responses. Studies have shown that platelets are activated during storage to produce large amounts of PEVs, which may have implications for platelet transfusion therapy. Compared to platelets, PEVs have a longer storage time and greater procoagulant activity, making them an ideal alternative to platelets. This review describes the reasons and mechanisms by which PEVs may have a role in blood transfusion therapy.
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Affiliation(s)
- Zhi Cai
- Department of Transfusion, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People's Republic of China
| | - Junyan Feng
- Class 2018 Medical Inspection Technology, Southwest Medical University, Luzhou, China
| | - Nian Dong
- Department of Clinical Laboratory, Gulin People's Hospital, Guilin, China
| | - Pan Zhou
- Department of Clinical Laboratory, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People's Republic of China
| | - Yuanshuai Huang
- Department of Transfusion, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People's Republic of China
| | - Hongwei Zhang
- Department of Transfusion, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People's Republic of China
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16
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Boone L, Peroni J. Introduction to Equine Biologic and Regenerative Therapies. Vet Clin North Am Equine Pract 2023; 39:419-427. [PMID: 37558508 DOI: 10.1016/j.cveq.2023.06.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/11/2023] Open
Abstract
Regenerative medicine is defined as the process of replacing or regenerating cells, tissues, or organs to restore or establish normal function. The use of regenerative medicine in equine practice to treat injured musculoskeletal tissues with limited capacity for intrinsic healing is growing. This article provides the practitioner with a brief and basic overview of the regenerative products currently used in equine practice.
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Affiliation(s)
- Lindsey Boone
- Department of Clinical Sciences, Auburn University College of Veterinary Medicine, John Thomas Vaughan Large Animal Teaching Hospital, 1500 Wire Road, Auburn, AL 36849, USA.
| | - John Peroni
- Department of Large Animal Medicine, University of Georgia College of Veterinary Medicine, 501 D.W. Brooks Drive, Athens, GA 30602, USA
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17
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Carestia A, Godin LC, Jenne CN. Step up to the platelet: Role of platelets in inflammation and infection. Thromb Res 2023; 231:182-194. [PMID: 36307228 DOI: 10.1016/j.thromres.2022.10.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/28/2022] [Accepted: 10/03/2022] [Indexed: 11/18/2022]
Abstract
Platelets are anucleated cells derived from megakaryocytes that are primarily responsible for hemostasis. However, in recent years, these cytoplasts have become increasingly recognized as immune cells, able to detect, interact with, and kill pathogens. As platelets are involved in both immunity and coagulation, they have a central role in immunothrombosis, a physiological process in which immune cells induce the formation of microthrombi to both prevent the spread of pathogens, and to help facilitate clearance. In this review, we will highlight the role of platelets as key players in the inflammatory and innate immune response against bacterial and viral infection, including direct and indirect interactions with pathogens and other immune cells.
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Affiliation(s)
- Agostina Carestia
- Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Canada.
| | - Laura C Godin
- Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Canada.
| | - Craig N Jenne
- Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Canada.
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18
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Abstract
PURPOSE OF REVIEW Platelet factor 4 (PF4, CXCL4), the most abundant α-granule platelet-specific chemokine, forms tetramers with an equatorial ring of high positive charge that bind to a wide range of polyanions, after which it changes conformation to expose antigenic epitopes. Antibodies directed against PF4 not only help to clear infection but can also lead to the development of thrombotic disorders such as heparin-induced thrombocytopenia (HIT) and vaccine-induced thrombocytopenia and thrombosis (VITT). This review will outline the different mechanisms through which PF4 engagement with polyanions combats infection but also contributes to the pathogenesis of inflammatory and thrombotic disease states. RECENT FINDINGS Recent work has shown that PF4 binding to microbial polyanions may improve outcomes in infection by enhancing leukocyte-bacterial binding, tethering pathogens to neutrophil extracellular traps (NETs), decreasing the thrombotic potential of NET DNA, and modulating viral infectivity. However, PF4 binding to nucleic acids may enhance their recognition by innate immune receptors, leading to autoinflammation. Lastly, while HIT is induced by platelet activating antibodies that bind to PF4/polyanion complexes, VITT, which occurs in a small subset of patients treated with COVID-19 adenovirus vector vaccines, is characterized by prothrombotic antibodies that bind to PF4 alone. SUMMARY Investigating the complex interplay of PF4 and polyanions may provide insights relevant to the treatment of infectious disease while also improving our understanding of the pathogenesis of thrombotic disorders driven by anti-PF4/polyanion and anti-PF4 antibodies.
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Affiliation(s)
- Anh T P Ngo
- Division of Hematology, Children's Hospital of Philadelphia
| | | | - Kandace Gollomp
- Division of Hematology, Children's Hospital of Philadelphia
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
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19
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Thom CS, Davenport P, Fazelinia H, Liu ZJ, Zhang H, Ding H, Roof J, Spruce LA, Ischiropoulos H, Sola-Visner M. Phosphoproteomics reveals content and signaling differences between neonatal and adult platelets. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.09.13.557268. [PMID: 37745418 PMCID: PMC10515911 DOI: 10.1101/2023.09.13.557268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/26/2023]
Abstract
Background and Objective Recent clinical studies have shown that transfusions of adult platelets increase morbidity and mortality in preterm infants. Neonatal platelets are hyporesponsive to agonist stimulation, and emerging evidence suggests developmental differences in platelet immune functions. This study was designed to compare the proteome and phosphoproteome of resting adult and neonatal platelets. Methods We isolated resting umbilical cord blood-derived platelets from healthy full term neonates (n=9) and resting blood platelets from healthy adults (n=7), and compared protein and phosphoprotein contents using data independent acquisition mass spectrometry. Results We identified 4745 platelet proteins with high confidence across all samples. Adult and neonatal platelets clustered separately by principal component analysis. Adult platelets were significantly enriched for immunomodulatory proteins, including β2 microglobulin and CXCL12, whereas neonatal platelets were enriched for ribosomal components and proteins involved in metabolic activities. Adult platelets were enriched for phosphorylated GTPase regulatory enzymes and proteins participating in trafficking, which may help prime them for activation and degranulation. Neonatal platelets were enriched for phosphorylated proteins involved in insulin growth factor signaling. Conclusions Using state-of-the-art mass spectrometry, our findings expanded the known neonatal platelet proteome and identified important differences in protein content and phosphorylation compared with adult platelets. These developmental differences suggested enhanced immune functions for adult platelets and presence of a molecular machinery related to platelet activation. These findings are important to understanding mechanisms underlying key platelet functions as well as the harmful effects of adult platelet transfusions given to preterm infants.
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Affiliation(s)
- Christopher S Thom
- Division of Neonatology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Patricia Davenport
- Division of Newborn Medicine, Boston Children's Hospital, Boston, MA, USA
| | - Hossein Fazelinia
- Proteomics Core, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Zhi-Jian Liu
- Division of Newborn Medicine, Boston Children's Hospital, Boston, MA, USA
| | - Haorui Zhang
- Division of Newborn Medicine, Boston Children's Hospital, Boston, MA, USA
| | - Hua Ding
- Proteomics Core, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Jennifer Roof
- Proteomics Core, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Lynn A Spruce
- Proteomics Core, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Harry Ischiropoulos
- Division of Neonatology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Children's Hospital of Philadelphia Research Institute, Philadelphia, PA
| | - Martha Sola-Visner
- Division of Newborn Medicine, Boston Children's Hospital, Boston, MA, USA
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20
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Zhang Z, Zhou XH, Cheng ZP, Hu Y. [Research on immunological function of platelet receptor FcγRⅡA]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2023; 44:609-614. [PMID: 37749049 PMCID: PMC10509618 DOI: 10.3760/cma.j.issn.0253-2727.2023.07.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Indexed: 09/27/2023]
Affiliation(s)
- Z Zhang
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - X H Zhou
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Z P Cheng
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Y Hu
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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21
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Trivigno SMG, Guidetti GF, Barbieri SS, Zarà M. Blood Platelets in Infection: The Multiple Roles of the Platelet Signalling Machinery. Int J Mol Sci 2023; 24:ijms24087462. [PMID: 37108623 PMCID: PMC10138547 DOI: 10.3390/ijms24087462] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 04/12/2023] [Accepted: 04/14/2023] [Indexed: 04/29/2023] Open
Abstract
Platelets are classically recognized for their important role in hemostasis and thrombosis but they are also involved in many other physiological and pathophysiological processes, including infection. Platelets are among the first cells recruited to sites of inflammation and infection and they exert their antimicrobial response actively cooperating with the immune system. This review aims to summarize the current knowledge on platelet receptor interaction with different types of pathogens and the consequent modulations of innate and adaptive immune responses.
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Affiliation(s)
- Silvia M G Trivigno
- Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy
- University School for Advanced Studies, IUSS, 27100 Pavia, Italy
| | | | - Silvia Stella Barbieri
- Unit of Heart-Brain Axis: Cellular and Molecular Mechanisms, Centro Cardiologico Monzino IRCCS, 20138 Milano, Italy
| | - Marta Zarà
- Unit of Heart-Brain Axis: Cellular and Molecular Mechanisms, Centro Cardiologico Monzino IRCCS, 20138 Milano, Italy
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22
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Zhu W, Zheng Y, Yu M, Wu Y, Wei J, Zhou L, Fu G, Schneider N, Jones C, Irani M, Padmanabhan A, Aster R, Wang D, Wen R. Cloned antibodies from patients with HIT provide new clues to HIT pathogenesis. Blood 2023; 141:1060-1069. [PMID: 36493339 PMCID: PMC10023725 DOI: 10.1182/blood.2022017612] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 11/01/2022] [Accepted: 11/17/2022] [Indexed: 12/14/2022] Open
Abstract
Heparin-induced thrombocytopenia (HIT) is a serious adverse drug reaction characterized by antibodies that recognize platelet factor 4/heparin complexes (PF4/H) and activate platelets to create a prothrombotic state. Although a high percentage of heparin-treated patients produce antibodies to PF4/H, only a subset also makes antibodies that are platelet activating (PA). A close correlation between PA antibodies and the likelihood of experiencing HIT has been demonstrated in clinical studies, but how PA (presumptively pathogenic) and nonactivating (NA) (presumptively benign) antibodies differ from each other at the molecular level is unknown. To address this issue, we cloned 7 PA and 47 NA PF4/H-binding antibodies from 6 patients with HIT and characterized their structural and functional properties. Findings showed that PA clones differed significantly from NA clones in possessing 1 of 2 heavy chain complementarity-determining region 3 (HCDR3) motifs, RX1-2R/KX1-2R/H (RKH) and YYYYY (Y5), in an unusually long complementarity-determining region 3 (≥20 residues). Mutagenic studies showed that modification of either motif in PA clones reduced or abolished their PA activity and that appropriate amino acid substitutions in HCDR3 of NA clones can cause them to become PA. Repertoire sequencing showed that the frequency of peripheral blood IgG+ B cells possessing RKH or Y5 was significantly higher in patients with HIT than in patients without HIT given heparin, indicating expansion of B cells possessing RKH or Y5 in HIT. These findings imply that antibodies possessing RKH or Y5 are relevant to HIT pathogenesis and suggest new approaches to diagnosis and treatment of this condition.
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Affiliation(s)
- Wen Zhu
- Versiti Blood Research Institute, Milwaukee, WI
- Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, WI
| | | | - Mei Yu
- Versiti Blood Research Institute, Milwaukee, WI
| | - Yaling Wu
- Versiti Blood Research Institute, Milwaukee, WI
- Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University, Fuzhou, Fujian, China
| | - Jianhui Wei
- Versiti Blood Research Institute, Milwaukee, WI
- Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University, Fuzhou, Fujian, China
| | - Lu Zhou
- Versiti Blood Research Institute, Milwaukee, WI
- Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, WI
| | - Guoping Fu
- Versiti Blood Research Institute, Milwaukee, WI
| | | | | | - Mehraboon Irani
- Versiti Blood Research Institute, Milwaukee, WI
- Department of Pathology, Medical College of Wisconsin, Milwaukee, WI
| | - Anand Padmanabhan
- Versiti Blood Research Institute, Milwaukee, WI
- Department of Laboratory Medicine & Pathology, Mayo Clinic, Rochester, MN
| | - Richard Aster
- Versiti Blood Research Institute, Milwaukee, WI
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI
| | - Demin Wang
- Versiti Blood Research Institute, Milwaukee, WI
- Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, WI
| | - Renren Wen
- Versiti Blood Research Institute, Milwaukee, WI
- Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, WI
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Song Y, Zheng X, Hu J, Ma S, Li K, Chen J, Xu X, Lu X, Wang X. Recent advances of cell membrane-coated nanoparticles for therapy of bacterial infection. Front Microbiol 2023; 14:1083007. [PMID: 36876074 PMCID: PMC9981803 DOI: 10.3389/fmicb.2023.1083007] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 02/01/2023] [Indexed: 02/19/2023] Open
Abstract
The rapid evolution of antibiotic resistance and the complicated bacterial infection microenvironments are serious obstacles to traditional antibiotic therapy. Developing novel antibacterial agents or strategy to prevent the occurrence of antibiotic resistance and enhance antibacterial efficiency is of the utmost importance. Cell membrane-coated nanoparticles (CM-NPs) combine the characteristics of the naturally occurring membranes with those of the synthetic core materials. CM-NPs have shown considerable promise in neutralizing toxins, evading clearance by the immune system, targeting specific bacteria, delivering antibiotics, achieving responsive antibiotic released to the microenvironments, and eradicating biofilms. Additionally, CM-NPs can be utilized in conjunction with photodynamic, sonodynamic, and photothermal therapies. In this review, the process for preparing CM-NPs is briefly described. We focus on the functions and the recent advances in applications of several types of CM-NPs in bacterial infection, including CM-NPs derived from red blood cells, white blood cells, platelet, bacteria. CM-NPs derived from other cells, such as dendritic cells, genetically engineered cells, gastric epithelial cells and plant-derived extracellular vesicles are introduced as well. Finally, we place a novel perspective on CM-NPs' applications in bacterial infection, and list the challenges encountered in this field from the preparation and application standpoint. We believe that advances in this technology will reduce threats posed by bacteria resistance and save lives from infectious diseases in the future.
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Affiliation(s)
- Yue Song
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou, China
| | - Xia Zheng
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Juan Hu
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Subo Ma
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Kun Li
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Junyao Chen
- Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Xiaoling Xu
- Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Xiaoyang Lu
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaojuan Wang
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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Salih F, Schönborn L, Endres M, Greinacher A. Immunvermittelte Sinus- und Hirnvenenthrombosen: VITT und
prä-VITT als Modellerkrankung. AKTUEL RHEUMATOL 2022. [DOI: 10.1055/a-1936-3123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
ZusammenfassungIn diesem Übersichtsartikel beschreiben wir die klinischen und
paraklinischen Charakteristika der Vakzin-induzierten immunthrombotischen
Thrombozytopenie (VITT) und fassen den gegenwärtigen Kenntnisstand zur
Pathogenese zusammen. Bei der VITT bilden sich 5–20 Tage nach einer
Impfung mit einem Adenovirus-vektorbasiertem SARS-CoV-2-Vakzin (AstraZeneca oder
Johnson & Johnson) lebensbedrohliche Thrombosen aus, vor allem in den
zerebralen Sinus und Hirnvenen. Laborchemisch zeigt sich eine typische
Thrombozytopenie mit erhöhten D-Dimeren. Der Pathogenese liegen
immunologische Prozesse zugrunde, die Ähnlichkeiten mit der
Heparin-induzierten Thrombozytopenie aufweisen: so geht die VITT mit
hochtitrigem Immunoglobulin G gegen das thrombozytäre Protein
Plättchenfaktor 4 (PF4) einher. Durch die Interaktion mit dem Impfstoff
wird PF4 so verändert, dass es von Antikörper-produzierenden
Zellen des Immunsystems erkannt wird. Die so produzierten
Anti-PF4-Antikörper führen über thrombozytäre
FcγIIa-Rezeptoren zu einer Plättchenaktivierung. Der Nachweis
plättchenaktivierender Anti-PF4-Antikörper bestätigt die
Diagnose einer VITT. Antikoagulanzien, die die Bildung von Thrombin oder
Thrombin selbst blockieren und hochdosiertes i. v.-Immunglobulin G, das
die Fcγ-Rezeptor-vermittelte Zellaktivierung inhibiert, stellen die
wirksame und kausale Behandlung der VITT dar. Bei Patienten mit katastrophalem
Verlauf kann ein Plasmaaustausch versucht werden. Bei einigen Patienten ist ein
prä-VITT Syndrom als Prodromalstadium zu beoachten, das sich
typischerweise mit Kopfschmerzen manifestieren kann und dessen frühe
Behandlung hilft, thrombotische Komplikationen zu vermeiden. Die spezifische
Dynamik der VITT-assozierten Immunreaktion entspricht einer transienten,
sekundären Immunantwort. Aktuelle Studien gehen der Frage nach, wie PF4
an unterschiedliche adenovirale Proteine bindet und beleuchten die Rolle von
anderen Impfstoff-Bestandteilen als potentielle Liganden für die
PF4-Bindung. Einige dieser Faktoren sind auch an der Etablierung eines
proinflammatorischen Milieus („danger signal“) beteiligt, das
unmittelbar nach der Impfung die 1. Phase der VITT-Pathogenese triggert. Sobald
in der 2. Phase der VITT-Pathogenese hohe Titer von Anti-PF4-Antikörper
gebildet sind, aktivieren diese neben Thrombozyten auch Granulozyten. In einem
als NETose (von „neutrophil extracellular traps“) bezeichneten
Prozess setzen aktivierte Granulozyten dabei DNA frei, mit der PF4 weitere
Komplexe bildet, an die Anti-PF4-Antikörper binden. Dies
verstärkt die Fcγ-Rezeptor-vermittelte Zellaktivierung weiter
mit der Folge einer ausgeprägten Thrombin-Bildung. Zum Ende des Artikels
geben wir einen Ausblick, welchen Einfluss die bisherigen Erkenntnisse zur VITT
auf weitere globale Impfkampagnen gegen SARS-CoV-2 haben und beleuchten, wie
Anti-PF4-Antikörper jenseits von VITT und HIT auch eine Rolle bei
seltenen Erkrankungen spielen, die mit rezidivierenden venösen und
arteriellen Thrombosen einhergehen.
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Affiliation(s)
- Farid Salih
- Klinik für Neurologie mit Experimenteller Neurologie,
Charité Universitätsmedizin Berlin, Berlin,
Germany
| | - Linda Schönborn
- Institut für Transfusionsmedizin, Universitätsmedizin
Greifswald, Greifswald, Germany
| | - Matthias Endres
- Klinik für Neurologie mit Experimenteller Neurologie,
Charité Universitätsmedizin Berlin, Berlin,
Germany
| | - Andreas Greinacher
- Institut für Transfusionsmedizin, Universitätsmedizin
Greifswald, Greifswald, Germany
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25
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Iba T, Levi M, Levy JH. Intracellular communication and immunothrombosis in sepsis. J Thromb Haemost 2022; 20:2475-2484. [PMID: 35979601 PMCID: PMC9804233 DOI: 10.1111/jth.15852] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 07/22/2022] [Accepted: 08/10/2022] [Indexed: 01/05/2023]
Abstract
Inflammation and coagulation are the critical responses to infection that include leukocytes, platelets, and vascular endothelial cells responding in concert to eradicate the invading pathogen. In sepsis, a variety of cell surface receptors, including toll-like receptors, Fcγ-receptors, G-protein-coupled receptors, and adhesion receptors, detect the pathogens and elicit thromboinflammatory responses. Concurrently, the molecular patterns released from host damaged cells accelerate the immune responses through binding to the same pattern recognition receptors. Cytokines, chemokines, and extracellular vesicles are important mediators for amplifying the responses to distant cells as part of the systemic response to infections. At the same time, cells communicate with each other via direct contact, adhesion molecules, paracrine mediators, and tunneling nanotubes, which are important for regulating inflammation and thrombus formation. Despite increasing attention to immunothrombosis in sepsis, these close communication systems are less understood but play a critical role in host defense mechanisms. In this review, cellular activation and direct intercellular communication systems in sepsis with a focus on the coagulation response will be considered.
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Affiliation(s)
- Toshiaki Iba
- Department of Emergency and Disaster MedicineJuntendo University Graduate School of MedicineTokyoJapan
| | - Marcel Levi
- Department of Vascular Medicine, Amsterdam University Medical Center, the Netherlands and Department of MedicineUniversity College London Hospitals NHS Foundation Trust, and Cardio‐metabolic Programme‐NIHR UCLH/UCL BRC LondonLondonUK
| | - Jerrold H. Levy
- Department of Anesthesiology, Critical Care, and SurgeryDuke University School of MedicineDurhamNorth CarolinaUSA
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26
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Indications that the Antimycotic Drug Amphotericin B Enhances the Impact of Platelets on Aspergillus. Antimicrob Agents Chemother 2022; 66:e0068122. [PMID: 36190233 PMCID: PMC9578436 DOI: 10.1128/aac.00681-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Platelets are currently thought to harbor antimicrobial functions and might therefore play a crucial role in infections, e.g., those caused by Aspergillus or mucormycetes. The incidence of invasive fungal infections is increasing, particularly during the coronavirus disease 2019 (COVID-19) pandemic, and such infections continue to be life-threatening in immunocompromised patients. For this reason, the interaction of antimycotics with platelets is a key issue to evaluate modern therapeutic regimens. Amphotericin B (AmB) is widely used for the therapy of invasive fungal infections either as deoxycholate (AmB-D) or as a liposomal formulation (L-AmB). We showed that AmB strongly activates platelets within a few minutes. AmB concentrations commonly measured in the blood of patients were sufficient to stimulate platelets, indicating that this effect is highly relevant in vivo. The stimulating effect was corroborated by a broad spectrum of platelet activation parameters, including degranulation, aggregation, budding of microparticles, morphological changes, and enhanced adherence to fungal hyphae. Comparison between the deoxycholate and the liposomal formulation excluded the possibility that the liposomal part of L-Amb is responsible for these effects, as no difference was visible. The induction of platelet activation and alteration by L-AmB resulted in the activation of other parts of innate immunity, such as stimulation of the complement cascade and interaction with granulocytes. These mechanisms might substantially fuel the antifungal immune reaction in invasive mycoses. On the other hand, thrombosis and excessive inflammatory processes might occur via these mechanisms. Furthermore, the viability of L-AmB-activated platelets was consequently decreased, a process that might contribute to thrombocytopenia in patients.
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27
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Jiang X, Chai S, Huang Y, Huang Z, Tan W, Gao Y, Lu X, Meng Z, Zhou H, Kong W, Tang X, Tang Y, Qi T, Liao C, Gan Q, Xiang X, Zhang Y, Wang S, Chen Y, Chen J. Design for a Multicentre Prospective Cohort for the Assessment of Platelet Function in Patients with Hepatitis-B-Virus-Related Acute-on-Chronic Liver Failure. Clin Epidemiol 2022; 14:997-1011. [PMID: 36042872 PMCID: PMC9420418 DOI: 10.2147/clep.s376068] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Accepted: 08/15/2022] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Acute-on-chronic liver failure (ACLF) has high short-term mortality and lacks sufficient medical therapy. Available algorithms are unable to precisely predict short-term outcomes or safely stratify patients with ACLF as emergent liver transplantation candidates. Therefore, a personalized prognostic tool is urgently needed. PURPOSE Platelet function and its clinical significance in ACLF patients with chronic hepatitis B virus (HBV) infection have not been investigated. This study aimed to assess changes in platelet function using thromboelastography (TEG) and platelet mapping (TEG-PM) in HBV-related ACLF patients. METHODS Chronic liver disease patients with acute decompensation or acute hepatic injury were recruited. The derivation cohort enrolled HBV-related patients at Nanfang Hospital. HBV-related and non-HBV-related patients were both enrolled in internal and external validation cohorts at seven university hospitals. TEG and TEG-PM were performed at baseline in the derivation cohort and baseline, day 7, and day 14 in the validation cohorts. The primary outcome was all-cause 28-day mortality. Status check and new-onset complications were recorded during the 3-month follow-up, but status check will extend to 5 years. CONCLUSION AND FUTURE PLANS In this study, 586 participants were enrolled, including 100 in derivation cohort, 133 in internal validation cohort, and 353 in external validation cohort. Biomaterials, including plasma, serum, urine, and some explanted liver tissues, were collected from these patients. A 3-month follow-up with survival status was completed. The baseline characteristics indicated that 51% of the patients had adenosine diphosphate (ADP)-hyporesponsive circulating platelets. The prognostic potential of platelet function will be explored in the derivation cohort (HBV-related ACLF patients) and further substantiated in the validation cohorts (HBV-related and non-HBV-related ACLF patients). Biosamples are currently used to explore the underlying mechanisms related to ADP-hyporesponsive platelets. The ongoing proteomic and metabolic analyses will provide new insights into the pathogenesis of extrahepatic organ failures in ACLF patients.
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Affiliation(s)
- Xiuhua Jiang
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Shiqi Chai
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Yan Huang
- Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, People’s Republic of China
| | - Zuxiong Huang
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, People’s Republic of China
| | - Wenting Tan
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China
| | - Yanhang Gao
- Department of Hepatology, the First Hospital of Jilin University, Changchun, People’s Republic of China
| | - Xiaobo Lu
- Infectious Disease Center, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, People’s Republic of China
| | - Zhongji Meng
- Department of Infectious Diseases, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, People’s Republic of China
| | - Huayou Zhou
- Department of Blood Transfusion, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Wenbing Kong
- Department of Blood Transfusion, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Xiaoting Tang
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Yujun Tang
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Tingting Qi
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Chengjin Liao
- Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, People’s Republic of China
| | - Qiaorong Gan
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, People’s Republic of China
| | - Xiaomei Xiang
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China
| | - Yanan Zhang
- Department of Hepatology, the First Hospital of Jilin University, Changchun, People’s Republic of China
| | - Shuai Wang
- Infectious Disease Center, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, People’s Republic of China
| | - Yuanyuan Chen
- Department of Infectious Diseases, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, People’s Republic of China
| | - Jinjun Chen
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
- Hepatology Unit, Zengcheng Branch, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
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Ezzeroug Ezzraimi A, Hannachi N, Mariotti A, Rolain JM, Camoin-Jau L. Platelets and Escherichia coli: A Complex Interaction. Biomedicines 2022; 10:biomedicines10071636. [PMID: 35884941 PMCID: PMC9313189 DOI: 10.3390/biomedicines10071636] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 07/02/2022] [Accepted: 07/06/2022] [Indexed: 12/26/2022] Open
Abstract
Apart from their involvement in hemostasis, platelets have been recognized for their contribution to inflammation and defense against microbial agents. The interaction between platelets and bacteria has been well studied in the model of Staphylococcus and Streptococcus but little described in Gram-negative bacteria, especially Escherichia coli. Being involved in the hemolytic uremic syndrome as well as sepsis, it is important to study the mechanisms of interaction between platelets and E. coli. Results of the published studies are heterogeneous. It appears that some strains interact with platelets through the toll-like receptor-4 (TLR-4) and others through the Fc gamma glycoprotein. E. coli mainly uses lipopolysaccharide (LPS) to activate platelets and cause the release of antibacterial molecules, but this is not the case for all strains. In this review, we describe the different mechanisms developed in previous studies, focusing on this heterogeneity of responses that may depend on several factors; mainly, the strain studied, the structure of the LPS and the platelet form used in the studies. We can hypothesize that the structure of O-antigen and an eventual resistance to antibiotics might explain this difference.
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Affiliation(s)
- Amina Ezzeroug Ezzraimi
- IRD, APHM, MEPHI, IHU Méditerranée Infection, Aix Marseille Université, 19-21 Boulevard Jean Moulin, 13005 Marseille, France; (A.E.E.); (N.H.); (A.M.); (J.-M.R.)
- IHU Méditerranée Infection, Boulevard Jean Moulin, 13385 Marseille, France
| | - Nadji Hannachi
- IRD, APHM, MEPHI, IHU Méditerranée Infection, Aix Marseille Université, 19-21 Boulevard Jean Moulin, 13005 Marseille, France; (A.E.E.); (N.H.); (A.M.); (J.-M.R.)
- Département de Pharmacie, Faculté de Médecine, Université Ferhat Abbas Sétif I, Sétif 19000, Algeria
| | - Antoine Mariotti
- IRD, APHM, MEPHI, IHU Méditerranée Infection, Aix Marseille Université, 19-21 Boulevard Jean Moulin, 13005 Marseille, France; (A.E.E.); (N.H.); (A.M.); (J.-M.R.)
- IHU Méditerranée Infection, Boulevard Jean Moulin, 13385 Marseille, France
- Hematology Department, Timone Hospital, APHM, Boulevard Jean Moulin, 13005 Marseille, France
| | - Jean-Marc Rolain
- IRD, APHM, MEPHI, IHU Méditerranée Infection, Aix Marseille Université, 19-21 Boulevard Jean Moulin, 13005 Marseille, France; (A.E.E.); (N.H.); (A.M.); (J.-M.R.)
- IHU Méditerranée Infection, Boulevard Jean Moulin, 13385 Marseille, France
| | - Laurence Camoin-Jau
- IRD, APHM, MEPHI, IHU Méditerranée Infection, Aix Marseille Université, 19-21 Boulevard Jean Moulin, 13005 Marseille, France; (A.E.E.); (N.H.); (A.M.); (J.-M.R.)
- IHU Méditerranée Infection, Boulevard Jean Moulin, 13385 Marseille, France
- Hematology Department, Timone Hospital, APHM, Boulevard Jean Moulin, 13005 Marseille, France
- Correspondence: ; Tel.: +33-4-9138-6049; Fax: +33-4-9138-9155
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Iba T, Levy JH. Thrombosis and thrombocytopenia in COVID-19 and after COVID-19 vaccination. Trends Cardiovasc Med 2022; 32:249-256. [PMID: 35202800 PMCID: PMC8861143 DOI: 10.1016/j.tcm.2022.02.008] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 01/31/2022] [Accepted: 02/15/2022] [Indexed: 12/30/2022]
Abstract
Thrombosis that occurs in coronavirus disease 19 (COVID-19) is a serious complication and a critical aspect of pathogenesis in the disease progression. Although thrombocytopenia is uncommon in the initial presentation, it may also reflect disease severity due to the ability of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to activate platelets. This occurs directly through the spike protein-angiotensin converting enzyme 2 (ACE2) interaction and indirectly by coagulation and inflammation activation. Dysregulation in both innate and adaptive immune systems is another critical factor that causes thrombosis and thrombocytopenia in COVID-19. Vaccination is the most potent and effective tool to mitigate COVID-19; however, rare side effects, namely vaccine-induced immune thrombotic thrombocytopenia (VITT)/thrombosis with thrombocytopenia syndrome (TTS) can occur following adenovirus-vectored vaccine administration. VITT/TTS is rare, and thrombocytopenia can be the clue to detect this serious complication. It is important to consider that thrombocytopenia and/or thromboembolism are not events limited to post-vaccination with vectored vaccine, but are also seen rarely after vaccination with other vaccines. Various conditions mimic VITT/TTS, and it is vital to achieving the correct diagnosis at an earlier stage. Antiplatelet factor 4 (PF4) antibody detection by the enzyme-linked immunosorbent assay (ELISA) is used for diagnosing VITT/TTS. However, false-positive rates also occur in vaccinated people, who do not show any thrombosis or thrombocytopenia. Vaccinated people with messenger RNA vaccine can show positive but low density and non-functional in terms of platelet aggregation, it is vital to check the optical density. If anti-PF4 ELISA is not available, discriminating other conditions such as antiphospholipid syndrome, thrombotic thrombocytopenic purpura, immune thrombocytopenic purpura, systemic lupus erythematosus, and hemophagocytic syndrome/hemophagocytic lymphohistiocytosis is critical when the patients show thrombosis with thrombocytopenia after COVID-19 vaccination.
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Affiliation(s)
- Toshiaki Iba
- Department of Emergency and Disaster Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo Bunkyo-Ku, Tokyo 113-8421, Japan.
| | - Jerrold H Levy
- Departments of Anesthesiology, Critical Care, and Surgery, Duke University School of Medicine, Durham, NC, USA.
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30
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Ezzeroug Ezzraimi A, Hannachi N, Mariotti A, Rolland C, Levasseur A, Baron SA, Rolain JM, Camoin-Jau L. The Antibacterial Effect of Platelets on Escherichia coli Strains. Biomedicines 2022; 10:biomedicines10071533. [PMID: 35884840 PMCID: PMC9313237 DOI: 10.3390/biomedicines10071533] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 06/23/2022] [Accepted: 06/24/2022] [Indexed: 01/02/2023] Open
Abstract
Platelets play an important role in defense against pathogens; however, the interaction between Escherichia coli and platelets has not been well described and detailed. Our goal was to study the interaction between platelets and selected strains of E. coli in order to evaluate the antibacterial effect of platelets and to assess bacterial effects on platelet activation. Washed platelets and supernatants of pre-activated platelets were incubated with five clinical colistin-resistant and five laboratory colistin-sensitive strains of E. coli in order to study bacterial growth. Platelet activation was measured with flow cytometry by evaluating CD62P expression. To identify the difference in strain behavior toward platelets, a pangenome analysis using Roary and O-antigen serotyping was carried out. Both whole platelets and the supernatant of activated platelets inhibited growth of three laboratory colistin-sensitive strains. In contrast, platelets promoted growth of the other strains. There was a negative correlation between platelet activation and bacterial growth. The Roary results showed no logical clustering to explain the mechanism of platelet resistance. The diversity of the responses might be due to strains of different types of O-antigen. Our results show a bidirectional interaction between platelets and E. coli whose expression is dependent on the bacterial strain involved.
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Affiliation(s)
- Amina Ezzeroug Ezzraimi
- Aix Marseille University, IRD, APHM, MEPHI, IHU Méditerranée Infection, 13385 Marseille, France; (A.E.E.); (N.H.); (A.M.); (S.A.B.); (J.-M.R.)
- IHU Méditerranée Infection, Boulevard Jean Moulin, 13385 Marseille, France; (C.R.); (A.L.)
| | - Nadji Hannachi
- Aix Marseille University, IRD, APHM, MEPHI, IHU Méditerranée Infection, 13385 Marseille, France; (A.E.E.); (N.H.); (A.M.); (S.A.B.); (J.-M.R.)
- Département de Pharmacie, Faculté de Médecine, Université Ferhat Abbas Sétif I, Sétif 19000, Algeria
| | - Antoine Mariotti
- Aix Marseille University, IRD, APHM, MEPHI, IHU Méditerranée Infection, 13385 Marseille, France; (A.E.E.); (N.H.); (A.M.); (S.A.B.); (J.-M.R.)
- IHU Méditerranée Infection, Boulevard Jean Moulin, 13385 Marseille, France; (C.R.); (A.L.)
- Laboratoire d’Hématologie, Hôpital de la Timone, APHM, Boulevard Jean-Moulin, 13385 Marseille, France
| | - Clara Rolland
- IHU Méditerranée Infection, Boulevard Jean Moulin, 13385 Marseille, France; (C.R.); (A.L.)
- Aix Marseille University, IRD, SSA, APHM, VITROME, IHU Méditerranée Infection, 13385 Marseille, France
| | - Anthony Levasseur
- IHU Méditerranée Infection, Boulevard Jean Moulin, 13385 Marseille, France; (C.R.); (A.L.)
- Aix Marseille University, IRD, SSA, APHM, VITROME, IHU Méditerranée Infection, 13385 Marseille, France
| | - Sophie Alexandra Baron
- Aix Marseille University, IRD, APHM, MEPHI, IHU Méditerranée Infection, 13385 Marseille, France; (A.E.E.); (N.H.); (A.M.); (S.A.B.); (J.-M.R.)
- IHU Méditerranée Infection, Boulevard Jean Moulin, 13385 Marseille, France; (C.R.); (A.L.)
| | - Jean-Marc Rolain
- Aix Marseille University, IRD, APHM, MEPHI, IHU Méditerranée Infection, 13385 Marseille, France; (A.E.E.); (N.H.); (A.M.); (S.A.B.); (J.-M.R.)
- IHU Méditerranée Infection, Boulevard Jean Moulin, 13385 Marseille, France; (C.R.); (A.L.)
| | - Laurence Camoin-Jau
- Aix Marseille University, IRD, APHM, MEPHI, IHU Méditerranée Infection, 13385 Marseille, France; (A.E.E.); (N.H.); (A.M.); (S.A.B.); (J.-M.R.)
- IHU Méditerranée Infection, Boulevard Jean Moulin, 13385 Marseille, France; (C.R.); (A.L.)
- Laboratoire d’Hématologie, Hôpital de la Timone, APHM, Boulevard Jean-Moulin, 13385 Marseille, France
- Correspondence: ; Tel.: +33-4-13-73-24-01; Fax: +33-4-13-73-24-02
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31
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Zhang J, Li W, Lu H, Lu R, Zhan Y, Meng H. Interactions of periodontal pathogens with platelets in the gingival crevicular fluid of patients with periodontitis. J Clin Periodontol 2022; 49:922-931. [PMID: 35713232 DOI: 10.1111/jcpe.13683] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 06/02/2022] [Accepted: 06/12/2022] [Indexed: 11/30/2022]
Abstract
AIM To explore the immunological defensive effects of platelets on periodontal pathogens in the gingival crevicular fluid (GCF). MATERIALS AND METHODS GCF samples were collected from 20 patients with periodontitis and 10 healthy controls. Platelets in the GCF were detected by immunocytochemistry and immunofluorescence. Isolated platelets from healthy volunteers were co-cultured with Porphyromonas gingivalis (Pg) and Fusobacterium nucleatum (Fn). The interactions between platelets and periodontal pathogens were observed by transmission and scanning electron microscopy. The isolated platelets plus neutrophils were co-cultured with Pg or Fn, and the formation of neutrophil extracellular traps (NETs) was evaluated by staining with Sytox Green. RESULTS The platelet level in the GCF was higher in patients with periodontitis than in healthy controls. Platelets interacted with bacteria and neutrophils in the GCF. In vitro, platelets recruited and engulfed periodontal pathogens. In response to periodontal pathogens, neutrophils released web chromatin, and platelets promoted the formation of intensive NETs. CONCLUSIONS Platelets, migrating to the gingival sulcus, may exert direct antibacterial effects or assist neutrophils.
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Affiliation(s)
- Jie Zhang
- Department of Periodontology, Peking University School and Hospital of Stomatology and National Center of Stomatology and National Clinical Research Center for Oral Diseases and National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, People's Republic of China
| | - Wenjing Li
- Department of Periodontology, Peking University School and Hospital of Stomatology and National Center of Stomatology and National Clinical Research Center for Oral Diseases and National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, People's Republic of China
| | - Hongye Lu
- The Affiliated Hospital of Stomatology, Zhejiang University School of Medicine and Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou, People's Republic of China
| | - Ruifang Lu
- Department of Periodontology, Peking University School and Hospital of Stomatology and National Center of Stomatology and National Clinical Research Center for Oral Diseases and National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, People's Republic of China
| | - Yalin Zhan
- Department of Periodontology, Peking University School and Hospital of Stomatology and National Center of Stomatology and National Clinical Research Center for Oral Diseases and National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, People's Republic of China.,First Clinical Division, Peking University School and Hospital of Stomatology, Beijing, People's Republic of China
| | - Huanxin Meng
- Department of Periodontology, Peking University School and Hospital of Stomatology and National Center of Stomatology and National Clinical Research Center for Oral Diseases and National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, People's Republic of China
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32
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Winskel-Wood B, Padula MP, Marks DC, Johnson L. Cold storage alters the immune characteristics of platelets and potentiates bacterial-induced aggregation. Vox Sang 2022; 117:1006-1015. [PMID: 35579630 DOI: 10.1111/vox.13293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 04/13/2022] [Accepted: 04/20/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND AND OBJECTIVES Cold-stored platelets are currently under clinical evaluation and have been approved for limited clinical use in the United States. Most studies have focused on the haemostatic functionality of cold-stored platelets; however, limited information is available examining changes to their immune function. MATERIALS AND METHODS Two buffy-coat-derived platelet components were combined and split into two treatment arms: room temperature (RT)-stored (20-24°C) or refrigerated (cold-stored, 2-6°C). The concentration of select soluble factors was measured in the supernatant using commercial ELISA kits. The abundance of surface receptors associated with immunological function was assessed by flow cytometry. Platelet aggregation was assessed in response to Escherichia coli and Staphylococcus aureus, in the presence and absence of RGDS (blocks active conformation of integrin α2 β3 ). RESULTS Cold-stored platelet components contained a lower supernatant concentration of C3a, RANTES and PF4. The abundance of surface-bound P-selectin and integrin α2 β3 in the activated conformation increased during cold storage. In comparison, the abundance of CD86, CD44, ICAM-2, CD40, TLR1, TLR2, TLR4, TLR3, TLR7 and TLR9 was lower on the surface membrane of cold-stored platelets compared to RT-stored components. Cold-stored platelets exhibited an increased responsiveness to E. coli- and S. aureus-induced aggregation compared to RT-stored platelets. Inhibition of the active conformation of integrin α2 β3 using RGDS reduced the potentiation of bacterial-induced aggregation in cold-stored platelets. CONCLUSION Our data highlight that cold storage changes the in vitro immune characteristics of platelets, including their sensitivity to bacterial-induced aggregation. Changes in these immune characteristics may have clinical implications post transfusion.
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Affiliation(s)
- Ben Winskel-Wood
- Research and Development, Australian Red Cross Lifeblood, Alexandria, New South Wales, Australia.,School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia
| | - Matthew P Padula
- School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia
| | - Denese C Marks
- Research and Development, Australian Red Cross Lifeblood, Alexandria, New South Wales, Australia.,Sydney Medical School, The University of Sydney, Camperdown, New South Wales, Australia
| | - Lacey Johnson
- Research and Development, Australian Red Cross Lifeblood, Alexandria, New South Wales, Australia.,School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia
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33
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Palankar R, Sachs L, Wesche J, Greinacher A. Cytoskeleton Dependent Mobility Dynamics of FcγRIIA Facilitates Platelet Haptotaxis and Capture of Opsonized Bacteria. Cells 2022; 11:cells11101615. [PMID: 35626650 PMCID: PMC9139458 DOI: 10.3390/cells11101615] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 05/05/2022] [Accepted: 05/10/2022] [Indexed: 12/04/2022] Open
Abstract
Platelet adhesion and spreading at the sites of vascular injury is vital to hemostasis. As an integral part of the innate immune system, platelets interact with opsonized bacterial pathogens through FcγRIIA and contribute to host defense. As mechanoscavangers, platelets actively migrate and capture bacteria via cytoskeleton-rich, dynamic structures, such as filopodia and lamellipodia. However, the role of human platelet FcγRIIA in cytoskeleton-dependent interaction with opsonized bacteria is not well understood. To decipher this, we used a reductionist approach with well-defined micropatterns functionalized with immunoglobulins mimicking immune complexes at planar interfaces and bacteriamimetic microbeads. By specifically blocking of FcγRIIA and selective disruption of the platelet cytoskeleton, we show that both functional FcγRIIA and cytoskeleton are necessary for human platelet adhesion and haptotaxis. The direct link between FcγRIIA and the cytoskeleton is further explored by single-particle tracking. We then demonstrate the relevance of cytoskeleton-dependent differential mobilities of FcγRIIA on bacteria opsonized with the chemokine platelet factor 4 (PF4) and patient-derived anti-PF4/polyanion IgG. Our data suggest that efficient capture of opsonized bacteria during host-defense is governed by mobility dynamics of FcγRIIA on filopodia and lamellipodia, and the cytoskeleton plays an essential role in platelet morphodynamics at biological interfaces that display immune complexes.
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34
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Thiele T, Schwarz SL, Handtke S. Platelet size as a mirror for the immune response after SARS-CoV-2 vaccination. J Thromb Haemost 2022; 20:818-820. [PMID: 35156282 PMCID: PMC9115134 DOI: 10.1111/jth.15659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 01/26/2022] [Accepted: 01/26/2022] [Indexed: 11/18/2022]
Affiliation(s)
- Thomas Thiele
- Institut für Immunologie und Transfusionsmedizin, Universitätsmedizin Greifswald, Greifswald, Germany
| | - Silas L Schwarz
- Institut für Immunologie und Transfusionsmedizin, Universitätsmedizin Greifswald, Greifswald, Germany
| | - Stefan Handtke
- Institut für Immunologie und Transfusionsmedizin, Universitätsmedizin Greifswald, Greifswald, Germany
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35
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Greinacher A, Schönborn L, Siegerist F, Steil L, Palankar R, Handtke S, Reder A, Thiele T, Aurich K, Methling K, Lalk M, Völker U, Endlich N. Pathogenesis of vaccine-induced immune thrombotic thrombocytopenia (VITT). Semin Hematol 2022; 59:97-107. [PMID: 35512907 PMCID: PMC8863951 DOI: 10.1053/j.seminhematol.2022.02.004] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Accepted: 02/16/2022] [Indexed: 02/06/2023]
Abstract
Vaccine-induced immune thrombotic thrombocytopenia (VITT; synonym, thrombosis with thrombocytopenia syndrome, is associated with high-titer immunoglobulin G antibodies directed against platelet factor 4 (PF4). These antibodies activate platelets via platelet FcγIIa receptors, with platelet activation greatly enhanced by PF4. Here we summarize the current concepts in the pathogenesis of VITT. We first address parallels between heparin-induced thrombocytopenia and VITT, and provide recent findings on binding of PF4 to adenovirus particles and non-assembled adenovirus proteins in the 2 adenovirus vector-based COVID-19 vaccines, ChAdOx1 nCoV-19 and Ad26.COV2.S. Further, we discuss the potential role of vaccine constituents such as glycosaminoglycans, EDTA, polysorbate 80, human cell-line proteins and nucleotides as potential binding partners of PF4. The immune response towards PF4 in VITT is likely triggered by a proinflammatory milieu. Human cell-line proteins, non-assembled virus proteins, and potentially EDTA may contribute to the proinflammatory state. The transient nature of the immune response towards PF4 in VITT makes it likely that-as in heparin-induced thrombocytopenia -marginal zone B cells are key for antibody production. Once high-titer anti-PF4 antibodies have been formed 5 to 20 days after vaccination, they activate platelets and granulocytes. Activated granulocytes undergo NETosis and the released DNA also forms complexes with PF4, which fuels the Fcγ receptor-dependent cell activation process, ultimately leading to massive thrombin generation. Finally, we summarize our initial observations indicating that VITT-like antibodies might also be present in rare patients with recurrent venous and arterial thrombotic complications, independent of vaccination.
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Affiliation(s)
- Andreas Greinacher
- Institute of Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany.
| | - Linda Schönborn
- Institute of Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Florian Siegerist
- Institute for Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany
| | - Leif Steil
- Interfaculty Institute of Genetics and Functional Genomics, Department Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Raghavendra Palankar
- Institute of Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Stefan Handtke
- Institute of Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Alexander Reder
- Interfaculty Institute of Genetics and Functional Genomics, Department Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Thomas Thiele
- Institute of Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Konstanze Aurich
- Institute of Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Karen Methling
- Institute of Biochemistry, University of Greifswald, Greifswald, Germany
| | - Michael Lalk
- Institute of Biochemistry, University of Greifswald, Greifswald, Germany
| | - Uwe Völker
- Interfaculty Institute of Genetics and Functional Genomics, Department Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Nicole Endlich
- Institute for Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany
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36
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Platelets, a Key Cell in Inflammation and Atherosclerosis Progression. Cells 2022; 11:cells11061014. [PMID: 35326465 PMCID: PMC8947573 DOI: 10.3390/cells11061014] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 03/11/2022] [Accepted: 03/13/2022] [Indexed: 12/21/2022] Open
Abstract
Platelets play important roles in thrombosis-dependent obstructive cardiovascular diseases. In addition, it has now become evident that platelets also participate in the earliest stages of atherosclerosis, including the genesis of the atherosclerotic lesion. Moreover, while the link between platelet activity and hemostasis has been well established, the role of platelets as modulators of inflammation has only recently been recognized. Thus, through their secretory activities, platelets can chemically attract a diverse repertoire of cells to inflammatory foci. Although monocytes and lymphocytes act as key cells in the progression of an inflammatory event and play a central role in plaque formation and progression, there is also evidence that platelets can traverse the endothelium, and therefore be a direct mediator in the progression of atherosclerotic plaque. This review provides an overview of platelet interactions and regulation in atherosclerosis.
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37
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Tavakoli M, Mirhaj M, Labbaf S, Varshosaz J, Taymori S, Jafarpour F, Salehi S, Abadi SAM, Sepyani A. Fabrication and evaluation of Cs/PVP sponge containing platelet-rich fibrin as a wound healing accelerator: An in vitro and in vivo study. Int J Biol Macromol 2022; 204:245-257. [PMID: 35131230 DOI: 10.1016/j.ijbiomac.2022.02.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 11/05/2021] [Accepted: 02/01/2022] [Indexed: 12/12/2022]
Abstract
Despite significant advances in surgery and postoperative care, there are still challenges in the treatment of wounds. In the current study, a freeze-dried chitosan (Cs)/polyvinylpyrrolidone (PVP) sponges containing platelet-rich fibrin (PRF at 1, 1.5 and 2% w/v) for wound dressing application is fabricated and fully characterized. Addition of 1% w/v of PRF to Cs/PVP (CS/PVP/1PRF) sample significantly increased the tensile strength (from 0.147 ± 0.005 to 0.242 ± 0.001 MPa), elastic modulus (from 0.414 ± 0.014 to 0.611 ± 0.022 MPa) and strain at break (from 53.4 ± 0.9 to 61.83 ± 1.17%) compared to Cs sample, and was hence selected as the optimal sample. The antibacterial activity of Cs/PVP/1PRF sponge wound dressing against E. coli and S. aureus was confirmed to be effective. Enzyme-linked immunosorbent assays revealed that the release of both VEGF and PDGF-AB from PRF powder, as well as PDGF-AB from Cs/PVP/1PRF sample was time-independent, but the release of VEGF from Cs/PVP/1PRF sample increased significantly with time. According to MTT and CAM assays, the Cs/PVP/1PRF sample significantly increased proliferation and angiogenic potential, respectively. Furthermore, in vivo studies demonstrated a 97.16 ± 1.55% wound closure for Cs/PVP/1PRF group after 14 days.
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Affiliation(s)
- Mohamadreza Tavakoli
- Department of Materials Engineering, Isfahan University of Technology, Isfahan 84156-83111, Iran
| | - Marjan Mirhaj
- Department of Materials Engineering, Isfahan University of Technology, Isfahan 84156-83111, Iran
| | - Sheyda Labbaf
- Department of Materials Engineering, Isfahan University of Technology, Isfahan 84156-83111, Iran.
| | - Jaleh Varshosaz
- Department of Pharmaceutics, School of Pharmacy and Novel Drug Delivery Systems Research Centre, Isfahan University of Medical Sciences, Iran.
| | - Somayeh Taymori
- Department of Pharmaceutics, School of Pharmacy and Novel Drug Delivery Systems Research Centre, Isfahan University of Medical Sciences, Iran
| | - Franoosh Jafarpour
- Department of Animal Biotechnology, Reproductive Biomedicine Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Saeedeh Salehi
- Department of Materials Engineering, Islamic Azad University, Najafabad, Iran
| | | | - Azadeh Sepyani
- Department of Tissue Engineering, Najafabad Branch, Islamic Azad University, Najafabad, Iran
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38
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Warkentin TE. Platelet-activating anti-PF4 disorders: an overview. Semin Hematol 2022; 59:59-71. [DOI: 10.1053/j.seminhematol.2022.02.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 02/16/2022] [Indexed: 11/11/2022]
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39
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Sachs L, Wesche J, Lenkeit L, Greinacher A, Bender M, Otto O, Palankar R. Ex vivo anticoagulants affect human blood platelet biomechanics with implications for high-throughput functional mechanophenotyping. Commun Biol 2022; 5:86. [PMID: 35064207 PMCID: PMC8782918 DOI: 10.1038/s42003-021-02982-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 12/17/2021] [Indexed: 11/30/2022] Open
Abstract
Inherited platelet disorders affecting the human platelet cytoskeleton result in increased bleeding risk. However, deciphering their impact on cytoskeleton-dependent intrinsic biomechanics of platelets remains challenging and represents an unmet need from a diagnostic and prognostic perspective. It is currently unclear whether ex vivo anticoagulants used during collection of peripheral blood impact the mechanophenotype of cellular components of blood. Using unbiased, high-throughput functional mechanophenotyping of single human platelets by real-time deformability cytometry, we found that ex vivo anticoagulants are a critical pre-analytical variable that differentially influences platelet deformation, their size, and functional response to agonists by altering the cytoskeleton. We applied our findings to characterize the functional mechanophenotype of platelets from a patient with Myosin Heavy Chain 9 (MYH9) related macrothrombocytopenia. Our data suggest that platelets from MYH9 p.E1841K mutation in humans affecting platelet non-muscle myosin heavy chain IIa (NMMHC-IIA) are biomechanically less deformable in comparison to platelets from healthy individuals. Sachs et al. examine the effects of different ex vivo anticoagulants on the biomechanical and functional properties of single platelets using high-throughput real-time fluorescence and deformability cytometry (RT-FDC). Their results demonstrate that the choice of ex vivo anticoagulant may strongly impact the outcomes of mechanophenotyping.
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40
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Barale C, Melchionda E, Morotti A, Russo I. Prothrombotic Phenotype in COVID-19: Focus on Platelets. Int J Mol Sci 2021; 22:ijms222413638. [PMID: 34948438 PMCID: PMC8705811 DOI: 10.3390/ijms222413638] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 12/16/2021] [Accepted: 12/17/2021] [Indexed: 12/15/2022] Open
Abstract
COVID-19 infection is associated with a broad spectrum of presentations, but alveolar capillary microthrombi have been described as a common finding in COVID-19 patients, appearing as a consequence of a severe endothelial injury with endothelial cell membrane disruption. These observations clearly point to the identification of a COVID-19-associated coagulopathy, which may contribute to thrombosis, multi-organ damage, and cause of severity and fatality. One significant finding that emerges in prothrombotic abnormalities observed in COVID-19 patients is that the coagulation alterations are mainly mediated by the activation of platelets and intrinsically related to viral-mediated endothelial inflammation. Beyond the well-known role in hemostasis, the ability of platelets to also release various potent cytokines and chemokines has elevated these small cells from simple cell fragments to crucial modulators in the blood, including their inflammatory functions, that have a large influence on the immune response during infectious disease. Indeed, platelets are involved in the pathogenesis of acute lung injury also by promoting NET formation and affecting vascular permeability. Specifically, the deposition by activated platelets of the chemokine platelet factor 4 at sites of inflammation promotes adhesion of neutrophils on endothelial cells and thrombogenesis, and it seems deeply involved in the phenomenon of vaccine-induced thrombocytopenia and thrombosis. Importantly, the hyperactivated platelet phenotype along with evidence of cytokine storm, high levels of P-selectin, D-dimer, and, on the other hand, decreased levels of fibrinogen, von Willebrand factor, and thrombocytopenia may be considered suitable biomarkers that distinguish the late stage of COVID-19 progression in critically ill patients.
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Affiliation(s)
| | | | | | - Isabella Russo
- Correspondence: ; Tel.: +39-011-6705447; Fax: +39-011-9038639
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41
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Naylor-Adamson L, Chacko AR, Booth Z, Caserta S, Jarvis J, Khan S, Hart SP, Rivero F, Allsup DJ, Arman M. Bruton's Tyrosine Kinase Inhibitors Impair FcγRIIA-Driven Platelet Responses to Bacteria in Chronic Lymphocytic Leukemia. Front Immunol 2021; 12:766272. [PMID: 34912339 PMCID: PMC8667317 DOI: 10.3389/fimmu.2021.766272] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Accepted: 10/25/2021] [Indexed: 01/01/2023] Open
Abstract
Bacterial infections are a major cause of morbidity and mortality in chronic lymphocytic leukemia (CLL), and infection risk increases in patients treated with the Bruton’s tyrosine kinase (Btk) inhibitor, ibrutinib. Btk and related kinases (like Tec) are expressed in non-leukemic hematopoietic cells and can be targeted by ibrutinib. In platelets, ibrutinib therapy is associated with bleeding complications mostly due to off-target effects. But the ability of platelets to respond to bacteria in CLL, and the potential impact of ibrutinib on platelet innate immune functions remain unknown. FcγRIIA is a tyrosine kinase-dependent receptor critical for platelet activation in response to IgG-coated pathogens. Crosslinking of this receptor with monoclonal antibodies causes downstream activation of Btk and Tec in platelets, however, this has not been investigated in response to bacteria. We asked whether ibrutinib impacts on FcγRIIA-mediated activation of platelets derived from CLL patients and healthy donors after exposure to Staphylococcus aureus Newman and Escherichia coli RS218. Platelet aggregation, α-granule secretion and integrin αIIbβ3-dependent scavenging of bacteria were detected in CLL platelets but impaired in platelets from ibrutinib-treated patients and in healthy donor-derived platelets exposed to ibrutinib in vitro. While levels of surface FcγRIIA remained unaffected, CLL platelets had reduced expression of integrin αIIbβ3 and GPVI compared to controls regardless of therapy. In respect of intracellular signaling, bacteria induced Btk and Tec phosphorylation in both CLL and control platelets that was inhibited by ibrutinib. To address if Btk is essential for platelet activation in response to bacteria, platelets derived from X-linked agammaglobulinemia patients (lacking functional Btk) were exposed to S. aureus Newman and E. coli RS218, and FcγRIIA-dependent aggregation was observed. Our data suggest that ibrutinib impairment of FcγRIIA-mediated platelet activation by bacteria results from a combination of Btk and Tec inhibition, although off-target effects on additional kinases cannot be discarded. This is potentially relevant to control infection-risk in CLL patients and, thus, future studies should carefully evaluate the effects of CLL therapies, including Btk inhibitors with higher specificity for Btk, on platelet-mediated immune functions.
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Affiliation(s)
- Leigh Naylor-Adamson
- Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, Faculty of Health Sciences, University of Hull, Hull, United Kingdom
| | - Anisha R Chacko
- Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, Faculty of Health Sciences, University of Hull, Hull, United Kingdom
| | - Zoe Booth
- Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, Faculty of Health Sciences, University of Hull, Hull, United Kingdom
| | - Stefano Caserta
- Department of Biomedical Sciences, Faculty of Health Sciences, University of Hull, Hull, United Kingdom
| | - Jenna Jarvis
- Department of Biomedical Sciences, Faculty of Health Sciences, University of Hull, Hull, United Kingdom
| | - Sujoy Khan
- Department of Immunology & Allergy, Queens Centre, Castle Hill Hospital, Hull University Teaching Hospitals NHS Trust, Cottingham, United Kingdom
| | - Simon P Hart
- Respiratory Research Group, Hull York Medical School, Faculty of Health Sciences, University of Hull, Hull, United Kingdom
| | - Francisco Rivero
- Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, Faculty of Health Sciences, University of Hull, Hull, United Kingdom
| | - David J Allsup
- Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, Faculty of Health Sciences, University of Hull, Hull, United Kingdom.,Department of Haematology, Queens Centre for Oncology and Haematology, Castle Hill Hospital, Hull University Teaching Hospitals NHS Trust, Cottingham, United Kingdom
| | - Mònica Arman
- Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, Faculty of Health Sciences, University of Hull, Hull, United Kingdom
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42
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Gunn BM, Bai S. Building a better antibody through the Fc: advances and challenges in harnessing antibody Fc effector functions for antiviral protection. Hum Vaccin Immunother 2021; 17:4328-4344. [PMID: 34613865 PMCID: PMC8827636 DOI: 10.1080/21645515.2021.1976580] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 08/23/2021] [Accepted: 08/30/2021] [Indexed: 12/15/2022] Open
Abstract
Antibodies can provide antiviral protection through neutralization and recruitment of innate effector functions through the Fc domain. While neutralization has long been appreciated for its role in antibody-mediated protection, a growing body of work indicates that the antibody Fc domain also significantly contributes to antiviral protection. Recruitment of innate immune cells such as natural killer cells, neutrophils, monocytes, macrophages, dendritic cells and the complement system by antibodies can lead to direct restriction of viral infection as well as promoting long-term antiviral immunity. Monoclonal antibody therapeutics against viruses are increasingly incorporating Fc-enhancing features to take advantage of the Fc domain, uncovering a surprising breadth of mechanisms through which antibodies can control viral infection. Here, we review the recent advances in our understanding of antibody-mediated innate immune effector functions in protection from viral infection and review the current approaches and challenges to effectively leverage innate immune cells via antibodies.
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Affiliation(s)
- Bronwyn M. Gunn
- Paul G. Allen School of Global Health, College of Veterinary Medicine, Washington State University, Pullman, WA, USA
| | - Shuangyi Bai
- Paul G. Allen School of Global Health, College of Veterinary Medicine, Washington State University, Pullman, WA, USA
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43
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Gordon J, Álvarez-Narváez S, Peroni JF. Antimicrobial Effects of Equine Platelet Lysate. Front Vet Sci 2021; 8:703414. [PMID: 34490395 PMCID: PMC8416987 DOI: 10.3389/fvets.2021.703414] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 07/27/2021] [Indexed: 11/23/2022] Open
Abstract
The development of antimicrobial resistant bacteria and the lack of novel antibiotic strategies to combat those bacteria is an ever-present problem in both veterinary and human medicine. The goal of this study is to evaluate platelet lysate (PL) as a biological alternative antimicrobial product. Platelet lysate is an acellular platelet-derived product rich in growth factors and cytokines that is manufactured via plateletpheresis and pooled from donor horses. In the current study, we sought to define the antimicrobial properties of PL on select gram-positive and gram-negative bacteria. Results from an end-point in vitro assay showed that PL did not support bacterial growth, and in fact significantly reduced bacterial content compared to normal growth media. An in vitro assay was then utilized to further determine the effects on bacterial growth dynamics and showed that all strains exhibited a slower growth rate and lower yield in the presence of PL. The specific effects of PL were unique for each bacterial strain: E. coli and P. aeruginosa growth was affected in a concentration-dependent manner, such that higher amounts of PL had a greater effect, while this was not true for S. aureus or E. faecalis. Furthermore, the onset of exponential growth was delayed for E. coli and P. aeruginosa in the presence of PL, which has significant clinical implications for developing a dosing schedule. In conclusion, our findings demonstrate the potential value of PL as a broad-spectrum antimicrobial that would offer an alternative to traditional antibiotics for the treatment of bacterial infection in equine species.
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Affiliation(s)
- Julie Gordon
- Department of Large Animal Medicine, Veterinary Medical Center, College of Veterinary Medicine, University of Georgia, Athens, GA, United States
| | - Sonsiray Álvarez-Narváez
- Athens Veterinary Diagnostic Laboratory, Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA, United States
| | - John F Peroni
- Department of Large Animal Medicine, Veterinary Medical Center, College of Veterinary Medicine, University of Georgia, Athens, GA, United States
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The roles of platelets in COVID-19-associated coagulopathy and vaccine-induced immune thrombotic thrombocytopenia. Trends Cardiovasc Med 2021; 32:1-9. [PMID: 34455073 PMCID: PMC8390120 DOI: 10.1016/j.tcm.2021.08.012] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Revised: 08/06/2021] [Accepted: 08/23/2021] [Indexed: 02/07/2023]
Abstract
In coronavirus disease 2019 (COVID-19), multiple thromboinflammatory events contribute to the pathophysiology, including coagulation system activation, suppressed fibrinolysis, vascular endothelial cell injury, and prothrombotic alterations in immune cells such as macrophages and neutrophils. Although thrombocytopenia is not an initial presentation as an infectious coagulopathy, recent studies have demonstrated the vital role of platelets in COVID-19-associated coagulopathy SARS-CoV-2 and its spike protein have been known to directly or indirectly promote release of prothrombotic and inflammatory mediators that lead to COVID-19-associated coagulopathy. Although clinical features of vaccine-induced immune thrombotic thrombocytopenia include uncommon locations of thrombosis, including cerebral venous sinus, we speculate coronavirus spike-protein-initiated prothrombotic pathways are involved in the pathogenesis of vaccine-induced immune thrombotic thrombocytopenia, as current evidence suggests that the spike protein is the promotor and other cofactors such as perturbed immune response and inflammatory reaction enhance the production of anti-platelet factor 4 antibody.
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Ebermeyer T, Cognasse F, Berthelot P, Mismetti P, Garraud O, Hamzeh-Cognasse H. Platelet Innate Immune Receptors and TLRs: A Double-Edged Sword. Int J Mol Sci 2021; 22:ijms22157894. [PMID: 34360659 PMCID: PMC8347377 DOI: 10.3390/ijms22157894] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 07/14/2021] [Accepted: 07/20/2021] [Indexed: 12/17/2022] Open
Abstract
Platelets are hematopoietic cells whose main function has for a long time been considered to be the maintenance of vascular integrity. They have an essential role in the hemostatic response, but they also have functional capabilities that go far beyond it. This review will provide an overview of platelet functions. Indeed, stress signals may induce platelet apoptosis through proapoptotis or hemostasis receptors, necrosis, and even autophagy. Platelets also interact with immune cells and modulate immune responses in terms of activation, maturation, recruitment and cytokine secretion. This review will also show that platelets, thanks to their wide range of innate immune receptors, and in particular toll-like receptors, and can be considered sentinels actively participating in the immuno-surveillance of the body. We will discuss the diversity of platelet responses following the engagement of these receptors as well as the signaling pathways involved. Finally, we will show that while platelets contribute significantly, via their TLRs, to immune response and inflammation, these receptors also participate in the pathophysiological processes associated with various pathogens and diseases, including cancer and atherosclerosis.
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Affiliation(s)
- Théo Ebermeyer
- INSERM U1059-SAINBIOSE, Université de Lyon, F-42023 Saint-Etienne, France; (T.E.); (F.C.); (P.M.); (O.G.)
| | - Fabrice Cognasse
- INSERM U1059-SAINBIOSE, Université de Lyon, F-42023 Saint-Etienne, France; (T.E.); (F.C.); (P.M.); (O.G.)
- Etablissement Français du Sang Auvergne-Rhône-Alpes, 25 bd Pasteur, F-42100 Saint-Étienne, France
| | - Philippe Berthelot
- Team GIMAP, CIRI—Centre International de Recherche en Infectiologie, Université de Lyon, U1111, UMR5308, F-69007 Lyon, France;
- Infectious Diseases Department, CHU de St-Etienne, F-42055 Saint-Etienne, France
| | - Patrick Mismetti
- INSERM U1059-SAINBIOSE, Université de Lyon, F-42023 Saint-Etienne, France; (T.E.); (F.C.); (P.M.); (O.G.)
- Department of Vascular Medicine and Therapeutics, INNOVTE, CHU de St-Etienne, F-42055 Saint-Etienne, France
| | - Olivier Garraud
- INSERM U1059-SAINBIOSE, Université de Lyon, F-42023 Saint-Etienne, France; (T.E.); (F.C.); (P.M.); (O.G.)
| | - Hind Hamzeh-Cognasse
- INSERM U1059-SAINBIOSE, Université de Lyon, F-42023 Saint-Etienne, France; (T.E.); (F.C.); (P.M.); (O.G.)
- Correspondence:
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Warkentin TE, Greinacher A. Spontaneous HIT syndrome: Knee replacement, infection, and parallels with vaccine-induced immune thrombotic thrombocytopenia. Thromb Res 2021; 204:40-51. [PMID: 34144250 DOI: 10.1016/j.thromres.2021.05.018] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 05/26/2021] [Accepted: 05/28/2021] [Indexed: 12/21/2022]
Abstract
Heparin-induced thrombocytopenia (HIT) is characterized clinically by thrombocytopenia, hypercoagulability, and increased thrombosis risk, and serologically by platelet-activating anti-platelet factor 4 (PF4)/heparin antibodies. Heparin-"induced" acknowledges that HIT is usually triggered by a proximate immunizing exposure to heparin. However, certain non-heparin medications (pentosan polysulfate, hypersulfated chondroitin sulfate, fondaparinux) can trigger "HIT". Further, naturally-occurring polyanions (bacterial lipopolysaccharide, DNA/RNA) can interact with PF4 to recapitulate HIT antigens. Indeed, immunologic presensitization to naturally-occurring polyanions could explain why HIT more closely resembles a secondary, rather than a primary, immune response. In 2008 it was first reported that a HIT-mimicking disorder can occur without any preceding exposure to heparin or polyanionic medications. Termed "spontaneous HIT syndrome", two subtypes are recognized: (a) surgical (post-orthopedic, especially post-total knee arthroplasty, and (b) medical (usually post-infectious). Recently, COVID-19 adenoviral vector vaccination has been associated with a thrombotic thrombocytopenic disorder associated with positive PF4-dependent enzyme-immunoassays and serum-induced platelet activation that is maximal when PF4 is added. Vaccine-induced immune thrombotic thrombocytopenia (VITT) features unusual thromboses (cerebral venous thrombosis, splanchnic vein thrombosis) similar to those seen in spontaneous HIT syndrome. The emerging concept is that classic HIT reflects platelet-activating anti-PF4/heparin antibodies whereas spontaneous HIT syndrome and other atypical "autoimmune HIT" presentations (delayed-onset HIT, persisting HIT, heparin "flush" HIT) reflect heparin-independent platelet-activating anti-PF4 antibodies-although the precise relationships between PF4 epitope targets and the clinical syndromes remain to be determined. Treatment of spontaneous HIT syndrome includes non-heparin anticoagulation (direct oral Xa inhibitors favored over direct thrombin inhibitors) and high-dose immunoglobulin.
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Affiliation(s)
- Theodore E Warkentin
- Department of Pathology and Molecular Medicine, and Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Hamilton Regional Laboratory Medicine Program (Transfusion Medicine), Hamilton, Ontario, Canada; Service of Benign Hematology, Hamilton Health Sciences (Hamilton General Hospital), Canada.
| | - Andreas Greinacher
- From Institut für Immunologie und Transfusionsmedizin, Universitätsmedizin Greifswald, Greifswald, Germany
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Patel P, Michael JV, Naik UP, McKenzie SE. Platelet FcγRIIA in immunity and thrombosis: Adaptive immunothrombosis. J Thromb Haemost 2021; 19:1149-1160. [PMID: 33587783 DOI: 10.1111/jth.15265] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 01/14/2021] [Accepted: 02/09/2021] [Indexed: 12/16/2022]
Abstract
Sepsis and autoimmune diseases remain major causes of morbidity and mortality. The last decade has seen a new appreciation of platelets in host defense, in both immunity and thrombosis. Platelets are first responders in the blood to microbes or non-microbial antigens. The role of platelets in physiologic immunity is counterbalanced by their role in pathology, for example, microvascular thrombosis. Platelets encounter microbes and antigens via both innate and adaptive immune processes; platelets also help to shape the subsequent adaptive response. FcγRIIA is a receptor for immune complexes opsonized by IgG or pentraxins, and expressed in humans by platelets, granulocytes, monocytes and macrophages. With consideration of the roles of IgG and Fc receptors, the host response to microbes and autoantigens can be called adaptive immunothrombosis. Here we review newer developments involving platelet FcγRIIA in humans and humanized mice in immunity and thrombosis, with special attention to heparin-induced thrombocytopenia, systemic lupus erythematosus, and bacterial sepsis. Human genetic diversity in platelet receptors and the utility of humanized mouse models are highlighted.
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Affiliation(s)
- Pravin Patel
- Department of Medicine, Cardeza Foundation for Hematological Research, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - James V Michael
- Department of Medicine, Cardeza Foundation for Hematological Research, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Ulhas P Naik
- Department of Medicine, Cardeza Foundation for Hematological Research, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Steven E McKenzie
- Department of Medicine, Cardeza Foundation for Hematological Research, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
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McMullen PD, Cho JH, Miller JL, Husain AN, Pytel P, Krausz T. A Descriptive and Quantitative Immunohistochemical Study Demonstrating a Spectrum of Platelet Recruitment Patterns Across Pulmonary Infections Including COVID-19. Am J Clin Pathol 2021; 155:354-363. [PMID: 33174599 PMCID: PMC7717231 DOI: 10.1093/ajcp/aqaa230] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVES Pulmonary platelet deposition and microangiopathy are increasingly recognized components of coronavirus disease 2019 (COVID-19) infection. Thrombosis is a known component of sepsis and disseminated intravascular coagulation. We sought to compare the level of platelet deposition in the pulmonary vasculature in cases of confirmed COVID-19 infection to other lung injuries and infections. METHODS Immunohistochemistry was performed on 27 autopsy cases and 2 surgical pathology cases targeting CD61. Multiple cases of normal lung, diffuse alveolar damage, COVID-19, influenza, and bacterial and fungal infections, as well as one case of pulmonary emboli, were included. The levels of CD61 staining were compared quantitatively in the autopsy cases, and patterns of staining were described. RESULTS Nearly all specimens exhibited an increase in CD61 staining relative to control lung tissue. The area of CD61 staining in COVID-19 infection was higher than influenza but still comparable to many other infectious diseases. Cases of aspiration pneumonia, Staphylococcus aureus infection, and blastomycosis exhibited the highest levels of CD61 staining. CONCLUSIONS Platelet deposition is a phenomenon common to many pulmonary insults. A spectrum of staining patterns was observed, suggestive of pathogen-specific mechanisms of platelet deposition. Further study into the mechanisms driving platelet deposition in pulmonary injuries and infections is warranted.
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Affiliation(s)
- Phillip D McMullen
- Department of Pathology, University of Chicago Medical Center, Chicago, IL
| | - Joseph H Cho
- Department of Pathology, University of Chicago Medical Center, Chicago, IL
| | - Jonathan L Miller
- Department of Pathology, University of Chicago Medical Center, Chicago, IL
| | - Aliya N Husain
- Department of Pathology, University of Chicago Medical Center, Chicago, IL
| | - Peter Pytel
- Department of Pathology, University of Chicago Medical Center, Chicago, IL
| | - Thomas Krausz
- Department of Pathology, University of Chicago Medical Center, Chicago, IL
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49
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Shannon O. The role of platelets in sepsis. Res Pract Thromb Haemost 2021; 5:27-37. [PMID: 33537527 PMCID: PMC7845078 DOI: 10.1002/rth2.12465] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 10/06/2020] [Accepted: 10/30/2020] [Indexed: 12/12/2022] Open
Abstract
A State of the Art lecture titled "The role of platelets in sepsis" was presented at the ISTH congress in 2020. Sepsis is a life-threatening organ dysfunction caused by a dysregulated and multifaceted host response to infection. Platelets play a significant role in the coordinated immune response to infection and therefore in the inflammation and coagulation dysfunction that contributes to organ damage in sepsis. Thrombocytopenia has a high incidence in sepsis, and it is a marker of poor prognosis. The genesis of thrombocytopenia is likely multifactorial, and unraveling the involved molecular mechanisms will allow development of biomarkers of platelet function in sepsis. Such platelet biomarkers can facilitate study of antiplatelet interventions as immunomodulatory treatment in sepsis. Finally, relevant new data on this topic presented during the 2020 ISTH virtual congress are reviewed.
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Affiliation(s)
- Oonagh Shannon
- Division of Infection MedicineDepartment of Clinical SciencesFaculty of MedicineLund UniversityLundSweden
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50
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Starling AP, Liu C, Shen G, Yang IV, Kechris K, Borengasser SJ, Boyle KE, Zhang W, Smith HA, Calafat AM, Hamman RF, Adgate JL, Dabelea D. Prenatal Exposure to Per- and Polyfluoroalkyl Substances, Umbilical Cord Blood DNA Methylation, and Cardio-Metabolic Indicators in Newborns: The Healthy Start Study. ENVIRONMENTAL HEALTH PERSPECTIVES 2020; 128:127014. [PMID: 33356526 PMCID: PMC7759236 DOI: 10.1289/ehp6888] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Revised: 12/05/2020] [Accepted: 12/07/2020] [Indexed: 05/02/2023]
Abstract
BACKGROUND Per- and polyfluoroalkyl substances (PFAS) are environmentally persistent chemicals widely detected in women of reproductive age. Prenatal PFAS exposure is associated with adverse health outcomes in children. We hypothesized that DNA methylation changes may result from prenatal PFAS exposure and may be linked to offspring cardio-metabolic phenotype. OBJECTIVES We estimated associations of prenatal PFAS with DNA methylation in umbilical cord blood. We evaluated associations of methylation at selected sites with neonatal cardio-metabolic indicators. METHODS Among 583 mother-infant pairs in a prospective cohort, five PFAS were quantified in maternal serum (median 27 wk of gestation). Umbilical cord blood DNA methylation was evaluated using the Illumina HumanMethylation450 array. Differentially methylated positions (DMPs) were evaluated at a false discovery rate ( FDR ) < 0.05 and differentially methylated regions (DMRs) were identified using comb-p (Šidák-adjusted p < 0.05 ). We estimated associations between methylation at candidate DMPs and DMR sites and the following outcomes: newborn weight, adiposity, and cord blood glucose, insulin, lipids, and leptin. RESULTS Maternal serum PFAS concentrations were below the median for females in the U.S. general population. Moderate to high pairwise correlations were observed between PFAS concentrations (ρ = 0.28 - 0.76 ). Methylation at one DMP (cg18587484), annotated to the gene TJAP1, was associated with perfluorooctanoate (PFOA) at FDR < 0.05 . Comb-p detected between 4 and 15 DMRs for each PFAS. Associated genes, some common across multiple PFAS, were implicated in growth (RPTOR), lipid homeostasis (PON1, PON3, CIDEB, NR1H2), inflammation and immune activity (RASL11B, RNF39), among other functions. There was suggestive evidence that two PFAS-associated loci (cg09093485, cg09637273) were associated with cord blood triglycerides and birth weight, respectively (FDR < 0.1 ). DISCUSSION DNA methylation in umbilical cord blood was associated with maternal serum PFAS concentrations during pregnancy, suggesting potential associations with offspring growth, metabolism, and immune function. Future research should explore whether DNA methylation changes mediate associations between prenatal PFAS exposures and child health outcomes. https://doi.org/10.1289/EHP6888.
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Affiliation(s)
- Anne P. Starling
- Department of Epidemiology, Colorado School of Public Health, Aurora, Colorado, USA
- Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Cuining Liu
- Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, Colorado, USA
| | - Guannan Shen
- Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, Colorado, USA
| | - Ivana V. Yang
- Department of Epidemiology, Colorado School of Public Health, Aurora, Colorado, USA
- Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA
- Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado, USA
| | - Katerina Kechris
- Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, Colorado, USA
- Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Sarah J. Borengasser
- Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Kristen E. Boyle
- Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Weiming Zhang
- Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, Colorado, USA
| | - Harry A. Smith
- Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, Colorado, USA
| | - Antonia M. Calafat
- Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Richard F. Hamman
- Department of Epidemiology, Colorado School of Public Health, Aurora, Colorado, USA
- Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - John L. Adgate
- Department of Environmental and Occupational Health, Colorado School of Public Health, Aurora, Colorado, USA
| | - Dana Dabelea
- Department of Epidemiology, Colorado School of Public Health, Aurora, Colorado, USA
- Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
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