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Vilahur G, Fuster V. Interplay between platelets and coagulation: from protective haemostasis to pathological arterial thrombosis. Eur Heart J 2025; 46:413-423. [PMID: 39673717 DOI: 10.1093/eurheartj/ehae776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 08/28/2024] [Accepted: 10/27/2024] [Indexed: 12/16/2024] Open
Abstract
Haemostasis refers to the physiological process aimed at repairing vessel injury and preventing bleeding. It involves four interlinked stages culminating in the formation of a platelet-fibrin haemostatic plug that is eventually dissolved once the vessel heals. In contrast, arterial thrombosis is a pathological condition resulting from atheroma exposure, triggering the formation of a platelet-rich thrombus that may obstruct blood flow, leading to the clinical manifestations of ischaemic cardiovascular disease. The following review will provide a comprehensive overview of the finely regulated endogenous antithrombotic mechanisms responsible for maintaining the haemostatic balance and preventing intravascular thrombosis. Thereafter, it will further detail the different stages and mechanisms governing the intricate interplay between the vessel, platelets, and the coagulation cascade in haemostasis, highlighting the most recent advances in platelet biology and function, to further elucidate the differential traits and players contributing to pathological arterial thrombus growth. The review will also delve into the impact of emerging cardiovascular risk factors on tilting the haemostatic balance towards a pro-thrombotic state, thereby increasing the patient's vulnerability to thrombotic events. Finally, it will underscore the importance of early screening for subclinical atherosclerosis through advanced imaging technologies capable of quantifying plaque burden and metabolic activity since they may set the stage for an increased thrombotic risk. Implementing proactive interventions to halt atherosclerosis progression or inducing its regression at early stages is crucial for preserving haemostasis and reducing the likelihood of ischaemic atherothrombotic disease.
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Affiliation(s)
- Gemma Vilahur
- Research Institute, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Carrer Sant Quintí 77-79, Barcelona 08041, Spain
- CiberCV, Institute Carlos III, Madrid 28029, Spain
| | - Valentin Fuster
- Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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2
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Wang Y, Mulder IA, Westendorp WF, Coutinho JM, van de Beek D. Immunothrombosis in Acute Ischemic Stroke. Stroke 2025; 56:553-563. [PMID: 39479751 DOI: 10.1161/strokeaha.124.048137] [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: 01/03/2025]
Abstract
Ischemic stroke is one of the leading causes of disability and mortality worldwide. Thrombosis is the main pathological process of stroke and is therefore an important therapeutic target in stroke prevention. In recent years, with the development of endovascular treatment and therefore retrieving the thrombus for further investigation, evidence is accumulating that immune cells are inextricably linked to stroke pathogenesis. Circulating immune cells have been found to induce immunothrombosis, and they actively participate in the formation of the thrombus by promoting platelet recruitment and thrombin activation. Additionally, the formation of thromboinflammation leads to increased instability of atherosclerotic plaques. We review the concepts of stroke immunothrombosis and thromboinflammation and the effect of immune cells on vessel recanalization and patient outcome. In addition, we elaborate on the possible mechanism of immune cells being activated and participating in thrombosis in ischemic stroke.
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Affiliation(s)
- Yan Wang
- Department of Neurology (Y.W., W.F.W., J.M.C., D.v.d.B.), Amsterdam University Medical Center, University of Amsterdam, the Netherlands
- Amsterdam Neurosciences, Neurovascular Disorders, the Netherlands (Y.W., I.A.M., W.F.W., J.M.C., D.v.d.B.)
| | - Inge A Mulder
- Department of Biomedical Engineering and Physics (I.A.M.), Amsterdam University Medical Center, University of Amsterdam, the Netherlands
- Amsterdam Cardiovascular Sciences, Microcirculation, the Netherlands (I.A.M.)
- Amsterdam Neurosciences, Neurovascular Disorders, the Netherlands (Y.W., I.A.M., W.F.W., J.M.C., D.v.d.B.)
| | - Willeke F Westendorp
- Department of Neurology (Y.W., W.F.W., J.M.C., D.v.d.B.), Amsterdam University Medical Center, University of Amsterdam, the Netherlands
- Amsterdam Neurosciences, Neurovascular Disorders, the Netherlands (Y.W., I.A.M., W.F.W., J.M.C., D.v.d.B.)
| | - Jonathan M Coutinho
- Department of Neurology (Y.W., W.F.W., J.M.C., D.v.d.B.), Amsterdam University Medical Center, University of Amsterdam, the Netherlands
- Amsterdam Neurosciences, Neurovascular Disorders, the Netherlands (Y.W., I.A.M., W.F.W., J.M.C., D.v.d.B.)
| | - Diederik van de Beek
- Department of Neurology (Y.W., W.F.W., J.M.C., D.v.d.B.), Amsterdam University Medical Center, University of Amsterdam, the Netherlands
- Amsterdam Neurosciences, Neurovascular Disorders, the Netherlands (Y.W., I.A.M., W.F.W., J.M.C., D.v.d.B.)
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3
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Wen X, Cai L, Gao A, Fu A, Guo D, Zhu M. Pharmacovigilance analysis of drug-induced hypofibrinogenemia using the FDA Adverse Event Reporting System. Int J Clin Pharm 2025:10.1007/s11096-025-01867-6. [PMID: 39888490 DOI: 10.1007/s11096-025-01867-6] [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: 10/24/2024] [Accepted: 01/04/2025] [Indexed: 02/01/2025]
Abstract
BACKGROUND Drug-induced hypofibrinogenemia has received increasing scrutiny; however, the specific drugs involved remain poorly characterized. Hypofibrinogenemia can have significant clinical implications, including increased bleeding risks. AIM This study aimed to utilize the FDA Adverse Event Reporting System (FAERS) to identify and analyze drugs frequently implicated in drug-induced hypofibrinogenemia. METHOD A disproportionality analysis was conducted using FAERS data from January 2004 to March 2024. Various statistical tools were used, including the Reporting Odds Ratio (ROR), Proportional Reporting Ratio, Medicines and Healthcare Products Regulatory Agency metrics, and Bayesian confidence propagation neural network. RESULTS The analysis included 17,627,340 cases involving 52,373,206 adverse events, with 1,661 cases identified as hypofibrinogenemia. The top five drugs associated with hypofibrinogenemia by case number were methotrexate (124 cases), tigecycline (119 cases), tocilizumab (100 cases), pegaspargase (83 cases), and alteplase (57 cases). The drugs ranked by signal strength based on ROR included eravacycline (ROR 2173.84, 95% CI 1208.80-3909.30), tigecycline (ROR 747.34, 95% CI 619.03-902.24), crotalidae polyvalent immune Fab (ROR 407.67, 95% CI 291.07-570.99), pegaspargase (ROR 216.06, 95% CI 173.15-269.61), and asparaginase (ROR 184.93, 95% CI 132.18-258.72). CONCLUSION This analysis of FAERS data identified 52 drugs associated with hypofibrinogenemia, most (88.5%) of which do not mention this risk in their prescribing information. These findings demonstrate the need for the monitoring of blood fibrinogen and may serve as a reference for the explore of the characteristics and underlying mechanism of drug-induced hypofibrinogenemia in the real world.
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Affiliation(s)
- Xiao Wen
- Department of Pharmacy, Medical Supplies Center of Chinese, PLA General Hospital, 28 Fu Xing Road, Beijing, 100853, China
| | - Le Cai
- Department of Pharmacy, Medical Supplies Center of Chinese, PLA General Hospital, 28 Fu Xing Road, Beijing, 100853, China
| | - Ao Gao
- Department of Pharmacy, Medical Supplies Center of Chinese, PLA General Hospital, 28 Fu Xing Road, Beijing, 100853, China
| | - An Fu
- Department of Pharmacy, Medical Supplies Center of Chinese, PLA General Hospital, 28 Fu Xing Road, Beijing, 100853, China
| | - Daihong Guo
- Department of Pharmacy, Medical Supplies Center of Chinese, PLA General Hospital, 28 Fu Xing Road, Beijing, 100853, China
| | - Man Zhu
- Department of Pharmacy, Medical Supplies Center of Chinese, PLA General Hospital, 28 Fu Xing Road, Beijing, 100853, China.
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4
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Englert H, Rangaswamy C, Kullik GA, Divivier M, Göbel J, Hermans‐Borgmeyer I, Borgmeyer U, Mowen KA, Beerens M, Frye M, Mailer RK, Gelderblom M, Stavrou EX, Preston RJS, Schneider SW, Fuchs TA, Renné T. Sepsis-induced NET formation requires MYD88 but is independent of GSDMD and PAD4. FASEB J 2025; 39:e70301. [PMID: 39777764 PMCID: PMC11707982 DOI: 10.1096/fj.202402514r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 12/18/2024] [Accepted: 12/23/2024] [Indexed: 01/30/2025]
Abstract
Neutrophils are peripheral blood-circulating leukocytes that play a pivotal role in host defense against bacterial pathogens which upon activation, they release web-like chromatin structures called neutrophil extracellular traps (NETs). Here, we analyzed and compared the importance of myeloid differentiation factor 88 (MYD88), peptidyl arginine deiminase 4 (PAD4), and gasdermin D (GSDMD) for NET formation in vivo following sepsis and neutrophilia challenge. Injection of lipopolysaccharide (LPS)/E. coli or the transgenic expression of granulocyte colony-stimulating factor (G-CSF), each induced NET-mediated lethal vascular occlusions in mice with combined genetic deficiency in Dnase1 and Dnase1l3 (D1/D1l3-/-). In accordance with the signaling of toll-like receptors, Myd88/D1/D1l3-/- animals were protected from the formation of lethal intravascular NETs during septic conditions. However, this protection was not observed during neutrophilia. It was unexpected to find that both Gsdmd/D1/D1l3-/- and Pad4/D1/D1l3-/- mice were fully capable of forming NETs upon LPS/E.coli challenge. Sepsis equally triggered a similar inflammatory response in these mice characterized by formation of DNA-rich thrombi, vessel occlusions, and mortality from pulmonary embolism, compared to D1/D1l3-/- mice. Pharmacologic GSDMD inhibitors did not reduce PMA-stimulated NET formation in ex vivo models either. Similarly, neither Pad4 nor GSDMD deficiency affected intravascular occlusive NET formation upon neutrophilia challenge. The magnitude of NET production, multi-organ damage, and lethality were comparable to those observed in challenged control mice. In conclusion, our data indicate that NET formation during experimental sepsis and neutrophilia is regulated by distinct stimulus-dependent pathways that may be independent of canonical PAD4 and GSDMD.
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Affiliation(s)
- Hanna Englert
- Institute of Clinical Chemistry and Laboratory MedicineUniversity Medical Center Hamburg‐EppendorfHamburgGermany
| | - Chandini Rangaswamy
- Institute of Clinical Chemistry and Laboratory MedicineUniversity Medical Center Hamburg‐EppendorfHamburgGermany
| | - Giuliano A. Kullik
- Institute of Clinical Chemistry and Laboratory MedicineUniversity Medical Center Hamburg‐EppendorfHamburgGermany
| | - Mylène Divivier
- Institute of Clinical Chemistry and Laboratory MedicineUniversity Medical Center Hamburg‐EppendorfHamburgGermany
| | - Josephine Göbel
- Institute of Clinical Chemistry and Laboratory MedicineUniversity Medical Center Hamburg‐EppendorfHamburgGermany
| | - Irm Hermans‐Borgmeyer
- Transgenic Mouse Unit, Center for Molecular Neurobiology HamburgUniversity Medical Center Hamburg‐EppendorfHamburgGermany
| | - Uwe Borgmeyer
- Transgenic Mouse Unit, Center for Molecular Neurobiology HamburgUniversity Medical Center Hamburg‐EppendorfHamburgGermany
| | - Kerri A. Mowen
- Chemical PhysiologyThe Scripps InstituteLa JollaCaliforniaUSA
| | - Manu Beerens
- Institute of Clinical Chemistry and Laboratory MedicineUniversity Medical Center Hamburg‐EppendorfHamburgGermany
- German Centre of Cardiovascular Research (DZHK), Partner Site Hamburg, Luebeck, KielHamburgGermany
| | - Maike Frye
- Institute of Clinical Chemistry and Laboratory MedicineUniversity Medical Center Hamburg‐EppendorfHamburgGermany
- German Centre of Cardiovascular Research (DZHK), Partner Site Hamburg, Luebeck, KielHamburgGermany
| | - Reiner K. Mailer
- Institute of Clinical Chemistry and Laboratory MedicineUniversity Medical Center Hamburg‐EppendorfHamburgGermany
| | - Mathias Gelderblom
- Department of NeurologyUniversity Medical Center Hamburg‐EppendorfHamburgGermany
| | - Evi X. Stavrou
- Medicine Service, Section of Hematology‐OncologyLouis Stokes Veterans Administration Medical CenterClevelandOhioUSA
- Department of Medicine, Hematology and Oncology DivisionCase Western Reserve University School of MedicineClevelandOhioUSA
| | - Roger J. S. Preston
- School of Pharmacy and Biomolecular Sciences, Irish Centre for Vascular BiologyRoyal College of Surgeons in IrelandDublinIreland
| | - Stefan W. Schneider
- Department of Dermatology and VenereologyUniversity Medical Center Hamburg‐EppendorfHamburgGermany
| | - Tobias A. Fuchs
- Institute of Clinical Chemistry and Laboratory MedicineUniversity Medical Center Hamburg‐EppendorfHamburgGermany
- NeutrolisCambridgeMassachusettsUSA
| | - Thomas Renné
- Institute of Clinical Chemistry and Laboratory MedicineUniversity Medical Center Hamburg‐EppendorfHamburgGermany
- School of Pharmacy and Biomolecular Sciences, Irish Centre for Vascular BiologyRoyal College of Surgeons in IrelandDublinIreland
- Center for Thrombosis and Hemostasis (CTH)Johannes Gutenberg University Medical CenterMainzGermany
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Foltan M, Dinh D, Gruber M, Müller T, Hart C, Krenkel L, Schmid C, Lehle K. Incidence of neutrophil extracellular traps (NETs) in different membrane oxygenators: pilot in vitro experiments in commercially available coated membranes. J Artif Organs 2025:10.1007/s10047-024-01486-4. [PMID: 39775204 DOI: 10.1007/s10047-024-01486-4] [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: 10/03/2024] [Accepted: 12/11/2024] [Indexed: 01/11/2025]
Abstract
Neutrophil extracellular traps (NETs) were detected in blood samples and in cellular deposits of oxygenator membranes during extracorporeal membrane oxygenation (ECMO) therapy and may be responsible for thrombogenesis. The aim was to evaluate the effect of the base material of gas fiber (GF, polymethylpentene) and heat exchange (HE) membranes and different antithrombogenic coatings on isolated granulocytes from healthy volunteers under static culture conditions. Contact of granulocytes with membranes from different ECMO oxygenators (with different surface coatings) and uncoated-GFs allowed detection of adherent cells and NETotic nuclear structures (normal, swollen, ruptured) using nuclear staining. Flow cytometry was used to identify cell activation (CD11b/CD62L, oxidative burst) of non-adherent cells. Uncoated-GFs were used as a reference. Within 3 h, granulocytes adhered to the same extent on all surfaces. In contrast, the ratio of normal to NETotic cells was significantly higher for uncoated-GFs (56-83%) compared to all coated GFs (34-72%) (p < 0.001) with no difference between the coatings. After material contact, non-adherent cells remained vital with unchanged oxidative burst function and the proportion of activated cells remained low. The expression of activation markers was independent of the origin of the GF material. In conclusion, the polymethylpentene surfaces of the GFs already induce NET formation. Antithrombogenic coatings can already reduce the proportion of NETotic nuclei. However, it cannot be ruled out that NET formation can induce thrombotic events. Therefore, new surfaces or coatings are required for future ECMO systems and long-term implantable artificial lungs.
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Affiliation(s)
- M Foltan
- Department for Cardiac, Thoracic and Cardiovascular Surgery, University Hospital Regensburg, Regensburg, Germany.
| | - D Dinh
- Department for Cardiac, Thoracic and Cardiovascular Surgery, University Hospital Regensburg, Regensburg, Germany
| | - M Gruber
- Department for Anaesthesiology, University Hospital Regensburg, Regensburg, Germany
| | - T Müller
- Department for Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - C Hart
- Department for Internal Medicine III, University Hospital Regensburg, Regensburg, Germany
| | - L Krenkel
- Regensburg Center of Biomedical Engineering, University and OTH Regensburg, Regensburg, Germany
| | - C Schmid
- Department for Cardiac, Thoracic and Cardiovascular Surgery, University Hospital Regensburg, Regensburg, Germany
| | - K Lehle
- Department for Cardiac, Thoracic and Cardiovascular Surgery, University Hospital Regensburg, Regensburg, Germany
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6
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Aghayan AH, Mirazimi Y, Nasehi L, Atashi A. The toxic effects of neutrophil extracellular traps on mesenchymal stem cells. Mol Biol Rep 2024; 52:30. [PMID: 39614028 DOI: 10.1007/s11033-024-10134-2] [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: 04/15/2024] [Accepted: 11/23/2024] [Indexed: 12/01/2024]
Abstract
Sepsis, a systemic inflammatory response syndrome resulting from an uncontrolled inflammatory reaction to infection, remains without a definitive cure despite therapeutic advancements. Mesenchymal stem cells (MSCs), renowned for their capacity to alleviate inflammation and modulate the immune system, have emerged as a potential treatment avenue for sepsis. In sepsis pathophysiology, hyperactivated neutrophils release extracellular neutrophil traps (NETs). NETs are essential for eradicating pathogens; however, excessive formation leads to tissue damage. Given the limited knowledge regarding the impact of NETs on MSCs used in sepsis therapy and the established interaction between MSCs and NETs, this study investigates the effects of NETs on MSCs in vitro. NETs were isolated from stimulated neutrophils, and MSCs were sourced from umbilical cord blood. After co-culturing MSCs with isolated NETs, MSCs' viability, migration, intracellular antioxidant capacity, and changes in gene expression were analyzed. Following exposure to NETs, MSCs exhibited obvious apoptosis and necrosis. NETs disrupt MSCs' mitochondrial activity. Also, NETs upregulate the pro-apoptotic gene BAX and downregulate the anti-apoptotic gene BCL2 in MSCs. Additionally, NETs reduce MSCs' intracellular antioxidant capacity. Furthermore, MSC migration is significantly impaired by NETs. This study collectively demonstrates that NETs have toxic and detrimental effects on MSCs. These effects on MSCs indicate a potential barrier to their functionality and therapeutic efficacy. Therefore, it appears that reducing the undesirable effects of NETs could serve as a novel target to enhance the therapeutic efficacy of MSCs in septic patients.
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Affiliation(s)
- Amir Hossein Aghayan
- Student Research Committee, Department of Medical Laboratory Sciences, School of Paramedical Sciences, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Yasin Mirazimi
- Student Research Committee, Department of Medical Laboratory Sciences, School of Paramedical Sciences, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Leila Nasehi
- Cancer Gene Therapy Research Center, Zanjan University of Medical Sciences, Zanjan, Iran.
- Department of Medical Laboratory Sciences, School of Paramedical Sciences, Zanjan University of Medical Sciences, Zanjan, Iran.
| | - Amir Atashi
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Shahroud University of Medical Sciences, Shahroud, Iran.
- Tissue Engineering and Stem Cells Research Center, Shahroud University of Medical Sciences, Shahroud, Iran.
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Whitefoot-Keliin KM, Benaske CC, Allen ER, Guerrero MT, Grapentine JW, Schiff BD, Mahon AR, Greenlee-Wacker MC. In response to bacteria, neutrophils release extracellular vesicles capable of initiating thrombin generation through DNA-dependent and independent pathways. J Leukoc Biol 2024; 116:1223-1236. [PMID: 38809773 PMCID: PMC11599124 DOI: 10.1093/jleuko/qiae125] [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: 11/10/2023] [Revised: 05/01/2024] [Accepted: 05/14/2024] [Indexed: 05/31/2024] Open
Abstract
Neutrophils release extracellular vesicles, and some subsets of neutrophil-derived extracellular vesicles are procoagulant. In response to Staphylococcus aureus, neutrophils produce extracellular vesicles that associate electrostatically with neutrophil extracellular traps. DNA in neutrophil extracellular traps is procoagulant, but whether neutrophil extracellular vesicles produced during bacterial challenge have similar activity is unknown. Given that extracellular vesicle activity is agonist and cell-type dependent and coagulation contributes to sepsis, we hypothesized that sepsis-causing bacteria increase production of neutrophil-derived extracellular vesicles, as well as extracellular vesicle-associated DNA, and intact extracellular vesicles and DNA cause coagulation. We recovered extracellular vesicles from neutrophils challenged with S. aureus, Staphylococcus epidermidis, Escherichia coli, and Pseudomonas aeruginosa and measured associated DNA and procoagulant activity. Extracellular vesicles from S. aureus-challenged neutrophils, which were previously characterized, displayed dose-dependent procoagulant activity as measured by thrombin generation in platelet-poor plasma. Extracellular vesicle lysis and DNase treatment reduced thrombin generation by 90% and 37%, respectively. S. epidermidis, E. coli, and P. aeruginosa also increased extracellular vesicle production and extracellular vesicle-associated extracellular DNA, and these extracellular vesicles were also procoagulant. Compared to spontaneously released extracellular vesicles, which demonstrated some ability to amplify factor XII-dependent coagulation in the presence of an activator, only extracellular vesicles produced in response to bacteria could initiate the pathway. S. aureus and S. epidermidis extracellular vesicles had more surface-associated DNA than E. coli and P. aeruginosa extracellular vesicles, and S. aureus and S. epidermidis extracellular vesicles contributed to initiation and amplification of thrombin generation in a DNA-dependent manner. However, DNA on E. coli or P. aeruginosa extracellular vesicles played no role, suggesting that neutrophils release procoagulant extracellular vesicles, which can activate the coagulation cascade through both DNA-dependent and independent mechanisms.
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Affiliation(s)
- Kaitlyn M Whitefoot-Keliin
- Deparment of Biology, Central Michigan University, 1200 S Franklin St., Mt. Pleasant, MI 48859, United States
| | - Chase C Benaske
- Deparment of Biology, Central Michigan University, 1200 S Franklin St., Mt. Pleasant, MI 48859, United States
| | - Edwina R Allen
- Deparment of Biology, Central Michigan University, 1200 S Franklin St., Mt. Pleasant, MI 48859, United States
| | - Mariana T Guerrero
- Biological Sciences Department, California Polytechnic State University, San Luis Obispo, 1 Grand Avenue, San Luis Obispo, CA 93407, United States
| | - Justin W Grapentine
- Biological Sciences Department, California Polytechnic State University, San Luis Obispo, 1 Grand Avenue, San Luis Obispo, CA 93407, United States
| | - Benjamin D Schiff
- Biological Sciences Department, California Polytechnic State University, San Luis Obispo, 1 Grand Avenue, San Luis Obispo, CA 93407, United States
| | - Andrew R Mahon
- Deparment of Biology, Central Michigan University, 1200 S Franklin St., Mt. Pleasant, MI 48859, United States
| | - Mallary C Greenlee-Wacker
- Biological Sciences Department, California Polytechnic State University, San Luis Obispo, 1 Grand Avenue, San Luis Obispo, CA 93407, United States
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Li L, Tan Q, Wu X, Mou X, Lin Z, Liu T, Huang W, Deng L, Jin T, Xia Q. Coagulopathy and acute pancreatitis: pathophysiology and clinical treatment. Front Immunol 2024; 15:1477160. [PMID: 39544925 PMCID: PMC11560453 DOI: 10.3389/fimmu.2024.1477160] [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: 08/07/2024] [Accepted: 10/10/2024] [Indexed: 11/17/2024] Open
Abstract
Coagulopathy is a critical pathophysiological mechanism of acute pancreatitis (AP), arising from the complex interplay between innate immune, endothelial cells and platelets. Although initially beneficial for the host, uncontrolled and systemic activation of coagulation cascade in AP can lead to thrombotic and hemorrhagic complications, ranging from subclinical abnormalities in coagulation tests to severe clinical manifestations, such as disseminated intravascular coagulation. Initiation of coagulation activation and consequent thrombin generation is caused by expression of tissue factor on activated monocytes and is ineffectually offset by tissue factor pathway inhibitor. At the same time, endothelial-associated anticoagulant pathways, in particular the protein C system, is impaired by pro-inflammatory cytokines. Also, fibrin removal is severely obstructed by inactivation of the endogenous fibrinolytic system, mainly as a result of upregulation of its principal inhibitor, plasminogen activator inhibitor type 1. Finally, increased fibrin generation and impaired break down lead to deposition of (micro) vascular clots, which may contribute to tissue ischemia and ensuing organ dysfunction. Despite the high burden of coagulopathy that have a negative impact on AP patients' prognosis, there is no effective treatment yet. Although a variety of anticoagulants drugs have been evaluated in clinical trials, their beneficial effects are inconsistent, and they are also characterized by hemorrhagic complications. Future studies are called to unravel the pathophysiologic mechanisms involved in coagulopathy in AP, and to test novel therapeutics block coagulopathy in AP.
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Affiliation(s)
- Lan Li
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
- Department of Integrated Traditional Chinese and Western Medicine, West China Tianfu Hospital, Sichuan University, Chengdu, China
| | - Qingyuan Tan
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
- Department of Integrated Traditional Chinese and Western Medicine, West China Tianfu Hospital, Sichuan University, Chengdu, China
| | - Xueying Wu
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaowen Mou
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
- Department of Integrated Traditional Chinese and Western Medicine, West China Tianfu Hospital, Sichuan University, Chengdu, China
| | - Ziqi Lin
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Tingting Liu
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Wei Huang
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
- West China Biobank, West China Hospital, Sichuan University, Chengdu, China
| | - Lihui Deng
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Tao Jin
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
- Department of Integrated Traditional Chinese and Western Medicine, West China Tianfu Hospital, Sichuan University, Chengdu, China
| | - Qing Xia
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China
- Department of Integrated Traditional Chinese and Western Medicine, West China Tianfu Hospital, Sichuan University, Chengdu, China
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9
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Gyorffy VJ, Dwivedi DJ, Liaw PC, Fox-Robichaud AE, Tsang JLY, Binnie A. Impact of sample processing delays on plasma markers of inflammation, chemotaxis, cell death, and blood coagulation. PLoS One 2024; 19:e0311921. [PMID: 39480839 PMCID: PMC11527306 DOI: 10.1371/journal.pone.0311921] [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: 02/20/2024] [Accepted: 09/26/2024] [Indexed: 11/02/2024] Open
Abstract
BACKGROUND Biosampling studies in critically ill patients traditionally involve bedside collection of samples followed by local processing (ie. centrifugation, aliquotting, and freezing) and storage. However, community hospitals, which care for the majority of Canadian patients, often lack the infrastructure for local processing and storage of specimens. A potential solution is a "simplified" biosampling protocol whereby blood samples are collected at the bedside and then shipped to a central site for processing and storage. One potential limitation of this approach is that delayed processing may alter sample characteristics. OBJECTIVE To determine whether delays in blood sample processing affect the stability of cytokines (IL-6, TNF, IL-10, IFN-γ), chemokines (IL-8, IP-10, MCP-1, MCP-4, MIP-1α, MIP-1β), cell-free DNA (cfDNA) (released by dying cells), and blood clotting potential in human blood samples. METHODS Venous blood was collected into EDTA and citrate sample tubes and stored at room temperature (RT) or 4°C for progressive intervals up to 72 hours, prior to processing. Plasma cytokines and chemokines were quantified using single or multiplex immunoassays. cfDNA was measured using Picogreen DNA Quantification. Blood clotting potential was measured using a thrombin generation assay. RESULTS Blood samples were collected from 9 intensive care unit (ICU) patients and 7 healthy volunteers. Admission diagnoses for the ICU patients included sepsis, trauma, ruptured abdominal aortic aneurysm, intracranial hemorrhage, gastrointestinal bleed, and hyperkalemia. After pre-processing delays of up to 72 hours at RT or 4°C, no significant changes were observed in plasma cytokines, chemokines, cfDNA, or thrombin formation. CONCLUSIONS Delayed sample processing for up to 72 hours at either RT or 4°C did not significantly affect cytokines, chemokines, cfDNA, or blood clotting potential in plasma samples from healthy volunteers and ICU patients. A "simplified" biosampling protocol is a feasible solution for conducting biosampling research at hospitals without local processing capacity.
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Affiliation(s)
- Vanessa J. Gyorffy
- Faculty of Arts and Science, McMaster University, Hamilton, ON, Canada
- Niagara Health Knowledge Institute, St. Catharines, ON, Canada
- Thrombosis and Atherosclerosis Research Institute (TaARI), McMaster University, Hamilton, ON, Canada
| | - Dhruva J. Dwivedi
- Thrombosis and Atherosclerosis Research Institute (TaARI), McMaster University, Hamilton, ON, Canada
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Patricia C. Liaw
- Thrombosis and Atherosclerosis Research Institute (TaARI), McMaster University, Hamilton, ON, Canada
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Alison E. Fox-Robichaud
- Thrombosis and Atherosclerosis Research Institute (TaARI), McMaster University, Hamilton, ON, Canada
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Jennifer L. Y. Tsang
- Niagara Health Knowledge Institute, St. Catharines, ON, Canada
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Alexandra Binnie
- Critical Care Department, William Osler Health System, Etobicoke, ON, Canada
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10
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Vappala S, Smith SA, Kizhakkedathu JN, Morrissey JH. Inhibitors of Polyphosphate and Neutrophil Extracellular Traps. Semin Thromb Hemost 2024; 50:970-977. [PMID: 37192652 PMCID: PMC10651799 DOI: 10.1055/s-0043-1768936] [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] [Indexed: 05/18/2023]
Abstract
The contact pathway of blood clotting has received intense interest in recent years as studies have linked it to thrombosis, inflammation, and innate immunity. Because the contact pathway plays little to no role in normal hemostasis, it has emerged as a potential target for safer thromboprotection, relative to currently approved antithrombotic drugs which all target the final common pathway of blood clotting. Research since the mid-2000s has identified polyphosphate, DNA, and RNA as important triggers of the contact pathway with roles in thrombosis, although these molecules also modulate blood clotting and inflammation via mechanisms other than the contact pathway of the clotting cascade. The most significant source of extracellular DNA in many disease settings is in the form of neutrophil extracellular traps (NETs), which have been shown to contribute to incidence and severity of thrombosis. This review summarizes known roles of extracellular polyphosphate and nucleic acids in thrombosis, with an emphasis on novel agents under current development that target the prothrombotic activities of polyphosphate and NETs.
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Affiliation(s)
- Sreeparna Vappala
- Department of Pathology and Laboratory Medicine; and Centre for Blood Research, Life Science Institute; University of British Columbia, Vancouver, British Columbia, Canada
| | - Stephanie A. Smith
- Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Jayachandran N. Kizhakkedathu
- Department of Pathology and Laboratory Medicine; and Centre for Blood Research, Life Science Institute; University of British Columbia, Vancouver, British Columbia, Canada
- Department of Chemistry; and School of Biomedical Engineering; University of British Columbia, Vancouver, British Columbia, Canada
| | - James H. Morrissey
- Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan, USA
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11
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Fierro-Angulo OM, González-Regueiro JA, Pereira-García A, Ruiz-Margáin A, Solis-Huerta F, Macías-Rodríguez RU. Hematological abnormalities in liver cirrhosis. World J Hepatol 2024; 16:1229-1244. [PMID: 39351511 PMCID: PMC11438588 DOI: 10.4254/wjh.v16.i9.1229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 08/09/2024] [Accepted: 08/22/2024] [Indexed: 09/23/2024] Open
Abstract
Hematological abnormalities are common in cirrhosis and are associated with various pathophysiological mechanisms. Studies have documented a prevalence of thrombocytopenia, leukopenia, and anemia in patients with compensated cirrhosis of 77.9%, 23.5%, and 21.1%, respectively. These abnormalities carry significant clinical implications, including considerations for invasive procedures, infection risk, bleeding risk, and prognosis. Previously, cirrhosis was believed to predispose patients to bleeding due to alterations observed in classical coagulation tests such as prothrombin time, partial thromboplastin time, international normalized ratio, and thrombocytopenia. However, this understanding has evolved, and cirrhosis patients are now also acknowledged as being at a high risk for thrombotic events. Hemostasis in cirrhosis patients presents a complex phenotype, with procoagulant and anticoagulant abnormalities offsetting each other. This multifactorial phenomenon is inadequately reflected by routine laboratory tests. Thrombotic complications are more prevalent in decompensated cirrhosis and may correlate with disease severity. Bleeding is primarily associated with portal hypertension, endothelial dysfunction, mechanical vessel injury, disseminated intravascular coagulation, endotoxemia, and renal injury. This review comprehensively outlines hematologic index abnormalities, mechanisms of hemostasis, coagulation, and fibrinolysis abnormalities, limitations of laboratory testing, and clinical manifestations of bleeding and thrombosis in patients with liver cirrhosis.
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Affiliation(s)
- Oscar Manuel Fierro-Angulo
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico 14080, Mexico
| | - José Alberto González-Regueiro
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico 14080, Mexico
| | - Ariana Pereira-García
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico 14080, Mexico
| | - Astrid Ruiz-Margáin
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico 14080, Mexico
| | - Fernando Solis-Huerta
- Department of Hematology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico 14080, Mexico
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12
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Pala ZR, Alves E Silva TL, Minai M, Crews B, Patino-Martinez E, Carmona-Rivera C, Valenzuela Leon PC, Martin-Martin I, Flores-Garcia Y, Cachau RE, Muslinkina L, Gittis AG, Srivastava N, Garboczi DN, Alves DA, Kaplan MJ, Fischer E, Calvo E, Vega-Rodriguez J. Mosquito salivary apyrase regulates blood meal hemostasis and facilitates malaria parasite transmission. Nat Commun 2024; 15:8194. [PMID: 39294191 PMCID: PMC11410810 DOI: 10.1038/s41467-024-52502-3] [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: 12/18/2023] [Accepted: 09/10/2024] [Indexed: 09/20/2024] Open
Abstract
The evolution of hematophagy involves a series of adaptations that allow blood-feeding insects to access and consume blood efficiently while managing and circumventing the host's hemostatic and immune responses. Mosquito, and other insects, utilize salivary proteins to regulate these responses at the bite site during and after blood feeding. We investigated the function of Anopheles gambiae salivary apyrase (AgApyrase) in regulating hemostasis in the mosquito blood meal and in Plasmodium transmission. Our results demonstrate that salivary apyrase, a known inhibitor of platelet aggregation, interacts with and activates tissue plasminogen activator, facilitating the conversion of plasminogen to plasmin, a human protease that degrades fibrin and facilitates Plasmodium transmission. We show that mosquitoes ingest a substantial amount of apyrase during blood feeding, which reduces coagulation in the blood meal by enhancing fibrin degradation and inhibiting platelet aggregation. AgApyrase significantly enhanced Plasmodium infection in the mosquito midgut, whereas AgApyrase immunization inhibited Plasmodium mosquito infection and sporozoite transmission. This study highlights a pivotal role for mosquito salivary apyrase for regulation of hemostasis in the mosquito blood meal and for Plasmodium transmission to mosquitoes and to the mammalian host, underscoring the potential for strategies to prevent malaria transmission.
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Affiliation(s)
- Zarna Rajeshkumar Pala
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, 20852, USA
| | - Thiago Luiz Alves E Silva
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, 20852, USA
| | - Mahnaz Minai
- Infectious Disease Pathogenesis Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, 20852, USA
| | - Benjamin Crews
- Microscopy Unit, Research Technologies Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, 59840, USA
| | - Eduardo Patino-Martinez
- Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Carmelo Carmona-Rivera
- Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Paola Carolina Valenzuela Leon
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, 20852, USA
| | - Ines Martin-Martin
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, 20852, USA
- Laboratory of Medical Entomology, National Center for Microbiology, Instituto de Salud Carlos III, 28220, Majadahonda, Madrid, Spain
| | - Yevel Flores-Garcia
- Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Raul E Cachau
- Integrated Data Science Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Liya Muslinkina
- Structural Biology Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Apostolos G Gittis
- Structural Biology Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Naman Srivastava
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, 20852, USA
| | - David N Garboczi
- Structural Biology Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Derron A Alves
- Infectious Disease Pathogenesis Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, 20852, USA
| | - Mariana J Kaplan
- Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Elizabeth Fischer
- Microscopy Unit, Research Technologies Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, 59840, USA
| | - Eric Calvo
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, 20852, USA
| | - Joel Vega-Rodriguez
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, 20852, USA.
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13
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Eustes AS, Ahmed A, Swamy J, Patil G, Jensen M, Wilson KM, Kudchadkar S, Wahab A, Perepu U, Miller FJ, Lentz SR, Dayal S. Extracellular histones: a unifying mechanism driving platelet-dependent extracellular vesicle release and thrombus formation in COVID-19. J Thromb Haemost 2024; 22:2514-2530. [PMID: 38815756 PMCID: PMC11343660 DOI: 10.1016/j.jtha.2024.05.019] [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: 11/21/2023] [Revised: 05/12/2024] [Accepted: 05/18/2024] [Indexed: 06/01/2024]
Abstract
BACKGROUND COVID-19 can cause profound inflammation and coagulopathy, and while many mechanisms have been proposed, there is no known common pathway leading to a prothrombotic state. OBJECTIVES From the beginning of the COVID-19 pandemic, elevated levels of extracellular histones have been found in plasma of patients infected with SARS-CoV-2. We hypothesized that platelet activation triggered by extracellular histones might represent a unifying mechanism leading to increased thrombin generation and thrombosis. METHODS We utilized blood samples collected from an early clinical trial of hospitalized COVID-19 patients (NCT04360824) and recruited healthy subjects as controls. Using plasma samples, we measured the procoagulant and prothrombotic potential of circulating extracellular histones and extracellular vesicles (EVs). Platelet prothrombotic activity was assessed via thrombin generation potential and platelet thrombus growth. Circulating EVs were assessed for thrombin generation potential in vitro in plasma and enhancement of thrombotic susceptibility in vivo in mice. RESULTS Compared with controls, COVID-19 patients had elevated plasma levels of citrullinated histone H3, cell-free DNA, nucleosomes, and EVs. Plasma from COVID-19 patients promoted platelet activation, platelet-dependent thrombin generation, thrombus growth under venous shear stress, and release of platelet-derived EVs. These prothrombotic effects of COVID-19 plasma were inhibited by an RNA aptamer that neutralizes both free and DNA-bound histones. EVs isolated from COVID-19 plasma enhanced thrombin generation in vitro and potentiated venous thrombosis in mice in vivo. CONCLUSION We conclude that extracellular histones and procoagulant EVs drive the prothrombotic state in COVID-19 and that histone-targeted therapy may prove beneficial.
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Affiliation(s)
- Alicia S Eustes
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Azaj Ahmed
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Jagadish Swamy
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Gokul Patil
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Melissa Jensen
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Katina M Wilson
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Shibani Kudchadkar
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Abdul Wahab
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Usha Perepu
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Francis J Miller
- Department of Internal Medicine, Vanderbilt University Medical Center and VA Medical Center, Nashville, Tennessee, USA
| | - Steven R Lentz
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Sanjana Dayal
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA; Iowa City VA Healthcare System, Iowa City, Iowa, USA.
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14
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Yada N, Zhang Q, Bignotti A, Ye Z, Zheng XL. ADAMTS13 or Caplacizumab Reduces the Accumulation of Neutrophil Extracellular Traps and Thrombus in Whole Blood of COVID-19 Patients under Flow. Thromb Haemost 2024; 124:725-738. [PMID: 38272066 PMCID: PMC11260255 DOI: 10.1055/a-2253-9359] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2024]
Abstract
BACKGROUND Neutrophil NETosis and neutrophil extracellular traps (NETs) play a critical role in pathogenesis of coronavirus disease 2019 (COVID-19)-associated thrombosis. However, the extents and reserve of NETosis, and potential of thrombus formation under shear in whole blood of patients with COVID-19 are not fully elucidated. Neither has the role of recombinant ADAMTS13 or caplacizumab on the accumulation of NETs and thrombus in COVID-19 patients' whole blood under shear been investigated. METHODS Flow cytometry and microfluidic assay, as well as immunoassays, were employed for the study. RESULTS We demonstrated that the percentage of H3Cit + MPO+ neutrophils, indicative of NETosis, was dramatically increased in patients with severe but not critical COVID-19 compared with that in asymptomatic or mild disease controls. Upon stimulation with poly [I:C], a double strain DNA mimicking viral infection, or bacterial shigatoxin-2, the percentage of H3Cit + MPO+ neutrophils was not significantly increased in the whole blood of severe and critical COVID-19 patients compared with that of asymptomatic controls, suggesting the reduction in NETosis reserve in these patients. Microfluidic assay demonstrated that the accumulation of NETs and thrombus was significantly enhanced in the whole blood of severe/critical COVID-19 patients compared with that of asymptomatic controls. Like DNase I, recombinant ADAMTS13 or caplacizumab dramatically reduced the NETs accumulation and thrombus formation under arterial shear. CONCLUSION Significantly increased neutrophil NETosis, reduced NETosis reserve, and enhanced thrombus formation under arterial shear may play a crucial role in the pathogenesis of COVID-19-associated coagulopathy. Recombinant ADAMTS13 or caplacizumab may be explored for the treatment of COVID-19-associated thrombosis.
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Affiliation(s)
- Noritaka Yada
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kanas City, Kansas, United States
| | - Quan Zhang
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kanas City, Kansas, United States
| | - Antonia Bignotti
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kanas City, Kansas, United States
| | - Zhan Ye
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kanas City, Kansas, United States
| | - X. Long Zheng
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kanas City, Kansas, United States
- Institute of Reproductive Medicine and Developmental Sciences, The University of Kansas Medical Center, Kanas City, Kansas, United States
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15
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Li Y, Yang D, Kang J, Cao Y, Cui L, Liu F. COVID-19 and the risk of acute cardiovascular diseases: a two-sample Mendelian randomization study. BMC Cardiovasc Disord 2024; 24:389. [PMID: 39068390 PMCID: PMC11282648 DOI: 10.1186/s12872-024-04066-9] [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: 01/09/2024] [Accepted: 07/22/2024] [Indexed: 07/30/2024] Open
Abstract
BACKGROUND Evidence suggests that coronavirus disease 2019 (COVID-19) is associated with the risk of cardiovascular diseases (CVDs). However, the results are inconsistent, and the causality remains to be established. We aimed to investigate the potential causal relationship between COVID-19 and CVDs by using two-sample Mendelian randomization (MR) analysis. METHODS Summary-level data for COVID-19 and CVDs including myocarditis, heart failure (HF), acute myocardial infarction (AMI), arrhythmia and venous thromboembolism (VTE) were obtained from the IEU OpenGWAS project, a public genome-wide association study (GWAS). Single nucleotide polymorphisms (SNPs) were used as instrumental variables. Five complementary MR methods were performed, including inverse variance weighted (IVW), MR-Egger, weighted median, weighted mode and simple mode methods. IVW method was considered as the primary approach. Besides, sensitivity analyses, including Cochran's Q test, MR-Egger intercept test, and leave-one-out analysis, were performed to evaluate the robustness of the results. RESULTS According to the IVW results, our MR study indicated that genetically predicted COVID-19 was not causally connected with the risk of CVDs [myocarditis: odds ratio (OR) = 1.407, 95% confidence interval (CI) = 0.761-2.602, p-value = 0.277; HF: OR = 1.180, 95% CI = 0.980-1.420, p-value = 0.080; AMI: OR = 1.002, 95% CI = 0.998-1.005, p-value = 0.241; arrhythmia: OR = 0.865, 95% CI = 0.717-1.044, p-value = 0.132; VTE: OR = 1.013, 95% CI = 0.997-1.028, p-value = 0.115]. The supplementary MR methods showed similar results. Sensitivity analyses suggested that the causal estimates were robust. CONCLUSION This two-sample MR analysis did not provide sufficient evidence for a causal relationship between COVID-19 and the risk of acute CVDs, which may provide new insights into the prevention of acute CVDs in COVID-19 patients.
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Affiliation(s)
- Yuling Li
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang, 110001, China
- Emergency Department, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China
| | | | - Jian Kang
- Emergency Department, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China
| | - Yaming Cao
- Department of Immunology, College of Basic Medical Sciences, China Medical University, Shenyang, China
| | - Liwang Cui
- Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
| | - Funan Liu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang, 110001, China.
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, 155 North Nanjing Street, Heping District, Shenyang, 110001, China.
- Phase I Clinical Trials Center, The First Hospital, China Medical University, 518 North Chuangxin Road, Baita Street, Hunnan District, Shenyang, Liaoning, 110102, China.
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16
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Li X, Ma Y, Wang D. The role of P-selectin/PSGL-1 in regulating NETs as a novel mechanism in cerebral ischemic injury. Front Neurol 2024; 15:1442613. [PMID: 39022737 PMCID: PMC11252044 DOI: 10.3389/fneur.2024.1442613] [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: 06/02/2024] [Accepted: 06/20/2024] [Indexed: 07/20/2024] Open
Abstract
In recent years, substantial advancements have been made in understanding the pathophysiology of ischemic stroke. Despite these developments, therapeutic options for cerebral ischemia remain limited due to stringent time windows and various contraindications. Consequently, there has been a concentrated effort to elucidate the underlying mechanisms of cerebral ischemic injury. Emerging research indicates that neutrophil extracellular traps (NETs) exacerbate inflammation and damage in ischemic brain tissue, contributing to neuronal cell death. The inhibition of NETs has shown potential in preventing thrombosis and the infiltration of immune cells. Central to the formation of NETs are P-selectin and its ligand, P-selectin glycoprotein ligand-1 (PSGL-1), which represent promising therapeutic targets. This review explores the detrimental impact of P-selectin, PSGL-1, and NETs on cerebral ischemia. Additionally, it delineates the processes by which P-selectin and PSGL-1 stimulate NETs production and provides evidence that blocking these molecules reduces NETs formation. This novel insight highlights a potential therapeutic avenue that warrants further investigation by researchers in the field.
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Affiliation(s)
- Xiao Li
- Henan University of Chinese Medicine, Zhengzhou, China
| | - Yamin Ma
- Nanyang Hospital of Traditional Chinese Medicine, Nanyang, China
| | - Dongbin Wang
- Shenzhen Pingle Orthopedic Hospital (Shenzhen Pingshan Traditional Chinese Medicine Hospital), Shenzhen, China
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17
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Ebrahimi R, Nasri F, Kalantari T. Coagulation and Inflammation in COVID-19: Reciprocal Relationship between Inflammatory and Coagulation Markers. Ann Hematol 2024; 103:1819-1831. [PMID: 38349409 DOI: 10.1007/s00277-024-05630-1] [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: 09/17/2023] [Accepted: 01/16/2024] [Indexed: 05/14/2024]
Abstract
The coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), formerly known as 2019-nCoV. Numerous cellular and biochemical issues arise after COVID-19 infection. The severe inflammation that is caused by a number of cytokines appears to be one of the key hallmarks of COVID-19. Additionally, people with severe COVID-19 have coagulopathy and fulminant thrombotic events. We briefly reviewed the COVID-19 disease at the beginning of this paper. The inflammation and coagulation markers and their alterations in COVID-19 illness are briefly discussed in the parts that follow. Next, we talked about NETosis, which is a crucial relationship between coagulation and inflammation. In the end, we mentioned the two-way relationship between inflammation and coagulation, as well as the factors involved in it. We suggest that inflammation and coagulation are integrated systems in COVID-19 that act on each other in such a way that not only inflammation can activate coagulation but also coagulation can activate inflammation.
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Affiliation(s)
- Rasoul Ebrahimi
- Division of Laboratory Hematology and Blood Banking, Department of Medical Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fatemeh Nasri
- Division of Laboratory Hematology and Blood Banking, Department of Medical Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Tahereh Kalantari
- Division of Laboratory Hematology and Blood Banking, Department of Medical Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran.
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18
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Stensballe A, Andersen JS, Aboo C, Andersen AB, Ren J, Meyer MK, Lambertsen KL, Leutscher PDC. Naïve Inflammatory Proteome Profiles of Glucocorticoid Responsive Polymyalgia Rheumatica and Rheumatic Arthritis Patients-Links to Triggers and Proteomic Manifestations. J Pers Med 2024; 14:449. [PMID: 38793033 PMCID: PMC11122654 DOI: 10.3390/jpm14050449] [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: 03/05/2024] [Revised: 04/09/2024] [Accepted: 04/23/2024] [Indexed: 05/26/2024] Open
Abstract
Polymyalgia rheumatica (PMR) is an inflammatory disorder of unknown etiology, sharing symptoms with giant cell arthritis (GCA) and rheumatoid arthritis (RA). The pathogenic inflammatory roots are still not well understood, and there is a lack of extensive biomarker studies to explain the disease debut and post-acute phase. This study aimed to deeply analyze the serum proteome and inflammatory response of PMR patients before and after glucocorticoid treatment. We included treatment-naïve PMR patients, collecting samples before and after 3 months of treatment. For comparison, disease-modifying antirheumatic drug (DMARD)-naïve RA patients were included and matched to healthy controls (CTL). The serum proteome was examined using label-free quantitative mass spectrometry, while inflammation levels were assessed using multiplex inflammatory cytokine and cell-free DNA assays. The serum proteomes of the four groups comprised acute phase reactants, coagulation factors, complement proteins, immunoglobulins, and apolipoproteins. Serum amyloid A (SAA1) was significantly reduced by active PMR treatment. Cell-free DNA levels in PMR and RA groups were significantly higher than in healthy controls due to acute inflammation. Complement factors had minimal changes post-treatment. The individual serum proteome in PMR patients showed over 100 abundantly variable proteins, emphasizing the systemic impact of PMR disease debut and the effect of treatment. Interleukin (IL)-6 and interferon-gamma (IFN-γ) were significantly impacted by glucocorticoid treatment. Our study defines the PMR serum proteome during glucocorticoid treatment and highlights the role of SAA1, IL-6, and IFN-γ in treatment responses. An involvement of PGLYRP2 in acute PMR could indicate a response to bacterial infection, highlighting its role in the acute phase of the immune response. The results suggest that PMR may be an aberrant response to a bacterial infection with an exacerbated IL-6 and acute phase inflammatory response and molecular attempts to limit the inflammation.
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Affiliation(s)
- Allan Stensballe
- Department of Health Science and Technology, Aalborg University, Selma Lagerloefs Vej 249, 9220 Aalborg, Denmark; (J.S.A.); (C.A.); (A.B.A.)
- Clinical Cancer Research Center, Aalborg University Hospital, 9000 Aalborg, Denmark
| | - Jacob Skallerup Andersen
- Department of Health Science and Technology, Aalborg University, Selma Lagerloefs Vej 249, 9220 Aalborg, Denmark; (J.S.A.); (C.A.); (A.B.A.)
- Sino-Danish Center for Education and Research, University of Chinese Academy of Sciences, Beijing 100864, China
| | - Christopher Aboo
- Department of Health Science and Technology, Aalborg University, Selma Lagerloefs Vej 249, 9220 Aalborg, Denmark; (J.S.A.); (C.A.); (A.B.A.)
- Sino-Danish Center for Education and Research, University of Chinese Academy of Sciences, Beijing 100864, China
| | - Anders Borg Andersen
- Department of Health Science and Technology, Aalborg University, Selma Lagerloefs Vej 249, 9220 Aalborg, Denmark; (J.S.A.); (C.A.); (A.B.A.)
| | - Jie Ren
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Beijing 100101, China;
| | - Michael Kruse Meyer
- Department of Health Science and Technology, Aalborg University, Selma Lagerloefs Vej 249, 9220 Aalborg, Denmark; (J.S.A.); (C.A.); (A.B.A.)
- Department of Reumatology, North Denmark Regional Hospital, 9800 Hjoerring, Denmark
| | - Kate Lykke Lambertsen
- Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Campusvej 55, 5230 Odense, Denmark;
- Department of Neurology, Odense University Hospital, J.B. Winsloewsvej 4, 5000 Odense, Denmark
- BRIDGE, Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, Campusvej 55, 5230 Odense, Denmark
| | - Peter Derek Christian Leutscher
- Centre for Clinical Research, North Denmark Regional Hospital, 9800 Hjoerring, Denmark;
- Department of Clinical Medicine, Aalborg University, 9220 Aalborg, Denmark
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19
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Williams B, Zou L, Pittet JF, Chao W. Sepsis-Induced Coagulopathy: A Comprehensive Narrative Review of Pathophysiology, Clinical Presentation, Diagnosis, and Management Strategies. Anesth Analg 2024; 138:696-711. [PMID: 38324297 PMCID: PMC10916756 DOI: 10.1213/ane.0000000000006888] [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] [Accepted: 11/28/2023] [Indexed: 02/08/2024]
Abstract
Physiological hemostasis is a balance between pro- and anticoagulant pathways, and in sepsis, this equilibrium is disturbed, resulting in systemic thrombin generation, impaired anticoagulant activity, and suppression of fibrinolysis, a condition termed sepsis-induced coagulopathy (SIC). SIC is a common complication, being present in 24% of patients with sepsis and 66% of patients with septic shock, and is often associated with poor clinical outcomes and high mortality. 1 , 2 Recent preclinical and clinical studies have generated new insights into the molecular pathogenesis of SIC. In this article, we analyze the complex pathophysiology of SIC with a focus on the role of procoagulant innate immune signaling in hemostatic activation--tissue factor production, thrombin generation, endotheliopathy, and impaired antithrombotic functions. We also review clinical presentations of SIC, the diagnostic scoring system and laboratory tests, the current standard of care, and clinical trials evaluating the efficacies of anticoagulant therapies.
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Affiliation(s)
- Brittney Williams
- From the Division of Cardiothoracic Anesthesia, Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, Maryland
- Translational Research Program, Department of Anesthesiology & Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, Maryland
| | - Lin Zou
- Translational Research Program, Department of Anesthesiology & Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, Maryland
| | - Jean-Francois Pittet
- Division of Critical Care, Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Wei Chao
- Translational Research Program, Department of Anesthesiology & Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, Maryland
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20
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Aleksandrowicz K, Hempel D, Polityńska B, Wojtukiewicz AM, Honn KV, Tang DG, Wojtukiewicz MZ. The Complex Role of Thrombin in Cancer and Metastasis: Focus on Interactions with the Immune System. Semin Thromb Hemost 2024; 50:462-473. [PMID: 37984359 DOI: 10.1055/s-0043-1776875] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2023]
Abstract
Thrombin, a pleiotropic enzyme involved in coagulation, plays a crucial role in both procoagulant and anticoagulant pathways. Thrombin converts fibrinogen into fibrin, initiates platelet activation, and promotes clot formation. Thrombin also activates anticoagulant pathways, indirectly inhibiting factors involved in coagulation. Tissue factor triggers thrombin generation, and the overexpression of thrombin in various cancers suggests that it is involved in tumor growth, angiogenesis, and metastasis. Increased thrombin generation has been observed in cancer patients, especially those with metastases. Thrombin exerts its effects through protease-activated receptors (PARs), particularly PAR-1 and PAR-2, which are involved in cancer progression, angiogenesis, and immunological responses. Thrombin-mediated signaling promotes angiogenesis by activating endothelial cells and platelets, thereby releasing proangiogenic factors. These functions of thrombin are well recognized and have been widely described. However, in recent years, intriguing new findings concerning the association between thrombin activity and cancer development have come to light, which justifies a review of this research. In particular, there is evidence that thrombin-mediated events interact with the immune system, and may regulate its response to tumor growth. It is also worth reevaluating the impact of thrombin on thrombocytes in conjunction with its multifaceted influence on tumor progression. Understanding the role of thrombin/PAR-mediated signaling in cancer and immunological responses is crucial, particularly in the context of developing immunotherapies. In this systematic review, we focus on the impact of the thrombin-related immune system response on cancer progression.
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Affiliation(s)
- Karolina Aleksandrowicz
- Department of Clinical Oncology, Medical University, Białystok, Poland
- Comprehensive Cancer Center, Bialystok, Poland
| | - Dominika Hempel
- Department of Clinical Oncology, Medical University, Białystok, Poland
- Comprehensive Cancer Center, Bialystok, Poland
| | - Barbara Polityńska
- Department of Psychology and Philosophy, Medical University of Białystok, Białystok, Poland
| | - Anna M Wojtukiewicz
- Department of Psychology and Philosophy, Medical University of Białystok, Białystok, Poland
| | - Kenneth V Honn
- Department of Pathology-School of Medicine, Bioactive Lipids Research Program, Detroit, Michigan
- Department of Chemistry, Wayne State University, Detroit, Michigan
- Department of Oncology, Wayne State University, Detroit, Michigan
| | - Dean G Tang
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Marek Z Wojtukiewicz
- Department of Clinical Oncology, Medical University, Białystok, Poland
- Comprehensive Cancer Center, Bialystok, Poland
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21
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Kaleem S, Zhang C, Gusdon AM, Oh S, Merkler AE, Avadhani R, Awad I, Hanley DF, Kamel H, Ziai WC, Murthy SB. Association Between Neutrophil-Lymphocyte Ratio and 30-Day Infection and Thrombotic Outcomes After Intraventricular Hemorrhage: A CLEAR III Analysis. Neurocrit Care 2024; 40:529-537. [PMID: 37349600 DOI: 10.1007/s12028-023-01774-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 06/02/2023] [Indexed: 06/24/2023]
Abstract
BACKGROUND Serum neutrophil-lymphocyte ratio (NLR) is a surrogate marker for the inflammatory response after intracerebral hemorrhage (ICH) and is associated with perihematomal edema and long-term functional outcomes. Whether NLR is associated with short-term ICH complications is poorly understood. We hypothesized that NLR is associated with 30-day infection and thrombotic events after ICH. METHODS We performed a post hoc exploratory analysis of the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage III trial. The study exposure was the serum NLR obtained at baseline and on days 3 and 5. The coprimary outcomes, ascertained at 30 days, were any infection and a thrombotic event, defined as composite of cerebral infarction, myocardial infarction, or venous thromboembolism; both infection and thrombotic event were determined through adjudicated adverse event reporting. Binary logistic regression was used to study the relationship between NLR and outcomes, after adjustment for demographics, ICH severity and location, and treatment randomization. RESULTS Among the 500 patients enrolled in the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage III trial, we included 303 (60.6%) without missing data on differential white blood cell counts at baseline. There were no differences in demographics, comorbidities, or ICH severity between patients with and without data on NLR. In adjusted logistic regression models, NLR ascertained at baseline (odds ratio [OR] 1.03; 95% confidence interval [CI] 1.01-1.07, p = 0.03) and NLR ascertained at day 3 were associated with infection (OR 1.15; 95% CI 1.05-1.20, p = 0.001) but not with thrombotic events. Conversely, NLR at day 5 was associated with thrombotic events (OR 1.07, 95% CI 1.01-1.13, p = 0.03) but not with infection (OR 1.13; 95% CI 0.76-1.70, p = 0.56). NLR at baseline was not associated with either outcome. CONCLUSIONS Serum NLR ascertained at baseline and on day 3 after randomization was associated with 30-day infection, whereas NLR obtained on day 5 was associated with thrombotic events after ICH, suggesting that NLR could be a potential early biomarker for ICH-related complications.
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Affiliation(s)
- Safa Kaleem
- Clinical and Translational Neuroscience Unit, Department of Neurology, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
| | - Cenai Zhang
- Clinical and Translational Neuroscience Unit, Department of Neurology, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
| | - Aaron M Gusdon
- Department of Neurological Surgery, University of Texas Health Science Center, Houston, TX, USA
| | - Stephanie Oh
- Clinical and Translational Neuroscience Unit, Department of Neurology, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
| | - Alexander E Merkler
- Clinical and Translational Neuroscience Unit, Department of Neurology, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
| | - Radhika Avadhani
- Brain Injury Outcomes Division, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Isaam Awad
- Department of Neurological Surgery, University of Chicago School of Medicine, Chicago, IL, USA
| | - Daniel F Hanley
- Brain Injury Outcomes Division, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Hooman Kamel
- Clinical and Translational Neuroscience Unit, Department of Neurology, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
| | - Wendy C Ziai
- Brain Injury Outcomes Division, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Neurological Surgery, University of Chicago School of Medicine, Chicago, IL, USA
| | - Santosh B Murthy
- Clinical and Translational Neuroscience Unit, Department of Neurology, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
- Division of Neurosciences Critical Care, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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22
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Busch MH, Ysermans R, Aendekerk JP, Timmermans SAMEG, Potjewijd J, Damoiseaux JGMC, Spronk HMH, ten Cate H, Reutelingsperger CP, Nagy M, van Paassen P. The intrinsic coagulation pathway plays a dominant role in driving hypercoagulability in ANCA-associated vasculitis. Blood Adv 2024; 8:1295-1304. [PMID: 38175623 PMCID: PMC10918483 DOI: 10.1182/bloodadvances.2023011937] [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: 10/17/2023] [Revised: 12/22/2023] [Accepted: 12/22/2023] [Indexed: 01/05/2024] Open
Abstract
ABSTRACT The risk of a venous thrombotic event (VTE) is increased in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV); however, a detailed understanding of the underlying mechanisms of hypercoagulability is limited. We assessed prospectively different coagulation parameters in 71 patients with active AAV at baseline and after 6 months of follow-up. D-dimers and fibrinogen were increased in most patients at presentation and remained elevated in half of the patients. Particularly, thrombin-antithrombin (T:AT) complex and activated coagulation factors in complex with their natural inhibitors of the intrinsic coagulation pathway (ie, activated FXII:C1 esterase inhibitor [FXIIa:C1Inh], FXIa:AT, and FXIa:alpha1-antitrypsin [FXIa:α1AT]) were profoundly elevated in patients at baseline. Thrombin formation was dominantly correlated with coagulation factors of the intrinsic pathway (ie, FXIIa:AT, FXIa:AT, FXIa:α1AT, and FXIa:C1Inh) compared to the extrinsic pathway (ie, FVIIa:AT). Hypercoagulability correlated with higher disease activity, ANCA levels, C-reactive protein, serum creatinine, and proteinuria. VTEs were observed in 5 out of 71 (7%) patients within 1 month (interquartile range, 1-5) after inclusion. Baseline T:AT levels were significantly higher in patients with VTE than in those without VTE (P = .044), but other clinical or laboratory markers were comparable between both groups. Hypercoagulability is dominantly characterized by activation of the intrinsic coagulation pathway and elevated D-dimers in active AAV. The driving factors of hypercoagulability are yet to be studied but are most likely related to an interplay of increased disease activity, vascular inflammation, and endothelial damage. Future targets for intervention could include inhibitors of the intrinsic coagulation pathway and compounds specifically reducing the hyperinflammatory state.
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Affiliation(s)
- Matthias H. Busch
- Department Nephrology and Clinical Immunology, Maastricht University Medical Center, Maastricht, The Netherlands
- Department Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands
| | - Renée Ysermans
- Department Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands
| | - Joop P. Aendekerk
- Department Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands
| | - Sjoerd A. M. E. G. Timmermans
- Department Nephrology and Clinical Immunology, Maastricht University Medical Center, Maastricht, The Netherlands
- Department Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands
| | - Judith Potjewijd
- Department Nephrology and Clinical Immunology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Jan G. M. C. Damoiseaux
- Department of Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Henri M. H. Spronk
- Department Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands
| | - Hugo ten Cate
- Department Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands
- Department of Internal Medicine, Thrombosis Expertise Center, Maastricht University Medical Center, Maastricht, The Netherlands
| | | | - Magdolna Nagy
- Department Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands
| | - Pieter van Paassen
- Department Nephrology and Clinical Immunology, Maastricht University Medical Center, Maastricht, The Netherlands
- Department Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands
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23
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Wang J, Wang X, Peng H, Dong Z, Liangpunsakul S, Zuo L, Wang H. Platelets in Alcohol-Associated Liver Disease: Interaction With Neutrophils. Cell Mol Gastroenterol Hepatol 2024; 18:41-52. [PMID: 38461963 PMCID: PMC11127035 DOI: 10.1016/j.jcmgh.2024.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 02/29/2024] [Accepted: 03/01/2024] [Indexed: 03/12/2024]
Abstract
Alcohol-associated liver disease (ALD) is a major contributor to liver-related mortality globally. An increasing body of evidence underscores the pivotal role of platelets throughout the spectrum of liver injury and recovery, offering unique insights into liver homeostasis and pathobiology. Alcoholic-associated steatohepatitis is characterized by the infiltration of hepatic neutrophils. Recent studies have highlighted the extensive distance neutrophils travel through sinusoids to reach the liver injury site, relying on a platelet-paved endothelium for efficient crawling. The adherence of platelets to neutrophils is crucial for accurate migration from circulation to the inflammatory site. A gradual decline in platelet levels leads to diminished neutrophil recruitment. Platelets exhibit the ability to activate neutrophils. Platelet activation is heightened upon the release of platelet granule contents, which synergistically activate neutrophils through their respective receptors. The sequence culminates in the formation of platelet-neutrophil complexes and the release of neutrophil extracellular traps intensifies liver damage, fosters inflammatory immune responses, and triggers hepatotoxic processes. Neutrophil infiltration is a hallmark of alcohol-associated steatohepatitis, and the roles of neutrophils in ALD pathogenesis have been studied extensively, however, the involvement of platelets in ALD has received little attention. The current review consolidates recent findings on the intricate and diverse roles of platelets and neutrophils in liver pathophysiology and in ALD. Potential therapeutic strategies are highlighted, focusing on targeting platelet-neutrophil interactions and activation in ALD. The anticipation is that innovative methods for manipulating platelet and neutrophil functions will open promising avenues for future ALD therapy.
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Affiliation(s)
- Juan Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, Anhui, China
| | - Xianda Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, Anhui, China
| | - Haodong Peng
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China; The First School of Clinical Medicine, Anhui Medical University, Hefei, Anhui, China
| | - Zijian Dong
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, Anhui, China
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Li Zuo
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China; Laboratory of Molecular Biology, Department of Biochemistry, Anhui Medical University, Hefei, Anhui, China.
| | - Hua Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, Anhui, China.
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24
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Chen WA, Boskovic DS. Neutrophil Extracellular DNA Traps in Response to Infection or Inflammation, and the Roles of Platelet Interactions. Int J Mol Sci 2024; 25:3025. [PMID: 38474270 DOI: 10.3390/ijms25053025] [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: 11/30/2023] [Revised: 02/29/2024] [Accepted: 03/01/2024] [Indexed: 03/14/2024] Open
Abstract
Neutrophils present the host's first line of defense against bacterial infections. These immune effector cells are mobilized rapidly to destroy invading pathogens by (a) reactive oxygen species (ROS)-mediated oxidative bursts and (b) via phagocytosis. In addition, their antimicrobial service is capped via a distinct cell death mechanism, by the release of their own decondensed nuclear DNA, supplemented with a variety of embedded proteins and enzymes. The extracellular DNA meshwork ensnares the pathogenic bacteria and neutralizes them. Such neutrophil extracellular DNA traps (NETs) have the potential to trigger a hemostatic response to pathogenic infections. The web-like chromatin serves as a prothrombotic scaffold for platelet adhesion and activation. What is less obvious is that platelets can also be involved during the initial release of NETs, forming heterotypic interactions with neutrophils and facilitating their responses to pathogens. Together, the platelet and neutrophil responses can effectively localize an infection until it is cleared. However, not all microbial infections are easily cleared. Certain pathogenic organisms may trigger dysregulated platelet-neutrophil interactions, with a potential to subsequently propagate thromboinflammatory processes. These may also include the release of some NETs. Therefore, in order to make rational intervention easier, further elucidation of platelet, neutrophil, and pathogen interactions is still needed.
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Affiliation(s)
- William A Chen
- Division of Biochemistry, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA 92350, USA
- Department of Pharmaceutical and Administrative Sciences, School of Pharmacy, Loma Linda University, Loma Linda, CA 92350, USA
| | - Danilo S Boskovic
- Division of Biochemistry, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA 92350, USA
- Department of Earth and Biological Sciences, School of Medicine, Loma Linda University, Loma Linda, CA 92350, USA
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25
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Gando S, Levi M, Toh CH. Trauma-induced innate immune activation and disseminated intravascular coagulation. J Thromb Haemost 2024; 22:337-351. [PMID: 37816463 DOI: 10.1016/j.jtha.2023.09.028] [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: 05/19/2023] [Revised: 09/25/2023] [Accepted: 09/26/2023] [Indexed: 10/12/2023]
Abstract
Dysregulated innate immunity participates in the pathomechanisms of disseminated intravascular coagulation (DIC) in trauma-induced coagulopathy. Accidental and regulated cell deaths and neutrophil extracellular traps release damage-associated molecular patterns (DAMPs), such as histones, nuclear and mitochondrial DNA, and high-mobility group box 1, into circulation immediately after trauma. DAMP-induced inflammation activation releases tissue factor-bearing procoagulant extracellular vesicles through gasdermin D-mediated pore formation and plasma membrane rupture by regulated cell death. DAMPs also evoke systemic inflammation, platelet, coagulation activation, and impaired fibrinolysis associated with endothelial injury, leading to the dysfunction of anticoagulation systems, which are the main pathophysiological mechanisms of DIC. All these processes induce systemic thrombin generation in vivo, not restricted to the injury sites immediately after trauma. Thrombin generation at the site of injury stops bleeding and maintains homeostasis. However, DIC associated with endothelial injury generates massive thrombin, enhancing protease-activated, receptor-mediated bidirectional interplays between inflammation and coagulation, aggravating the diverse actions of thrombin and disturbing homeostasis. Insufficiently regulated thrombin causes disseminated microvascular thrombosis, resulting in tissue hypoxia due to reduced oxygen delivery, and mitochondrial dysfunction due to DAMPs causes tissue dysoxia. In addition, DAMP-induced calcium influx and overload, as well as neutrophil activation, play a role in endothelial cell injury. Tissue hypoxia and cytotoxicity result in multiple organ dysfunction in DIC after trauma. Controls against dysregulated innate immunity evoking systemic inflammation, thrombin generation, and cytotoxicity are key issues in improving the prognosis of DIC in trauma-induced coagulopathy.
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Affiliation(s)
- Satoshi Gando
- Department of Acute and Critical Care Medicine, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan; Division of Acute and Critical Care Medicine, Department of Anesthesiology and Critical Care Medicine, Hokkaido University Faculty of Medicine, Sapporo, Japan.
| | - Marcel Levi
- Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands; Department of Medicine, University College London Hospitals NHS Foundation Trust, and Cardio-Metabolic Program - NIHR UCLH/UCL BRC London, London, United Kingdom
| | - Cheng-Hock Toh
- Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, United Kingdom; Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
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26
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Liu X, Li T, Chen H, Yuan L, Ao H. Role and intervention of PAD4 in NETs in acute respiratory distress syndrome. Respir Res 2024; 25:63. [PMID: 38291476 PMCID: PMC10829387 DOI: 10.1186/s12931-024-02676-7] [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: 09/02/2023] [Accepted: 01/03/2024] [Indexed: 02/01/2024] Open
Abstract
BACKGROUND Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection. Acute respiratory distress syndrome (ARDS) is a common sepsis-associated injury that can increase postoperative mortality but the mechanism is still unclear. MAIN TEXT The role of neutrophils in the pathophysiology of sepsis was deeply challenged after the discovery of NETosis, a process resulting in neutrophil extracellular traps (NETs) release. NETs can support thrombin generation and the concept of immunothrombosis has emerged as a new innate response to infection. Immunothrombosis leads to thrombosis in microvessels and supports immune cells together with specific thrombus-related molecules. ARDS is a common sepsis-associated organ injury. Immunothrombosis participates in thrombosis in pulmonary capillaries. Intervention regarding immunothrombosis in ARDS is a key scientific problem. PAD4 is the key enzyme regulating the NET skeleton protein histone H3 to citrulline histone to form NETs in immune thrombosis. This review summarizes NETosis and immunohaemostasis, ARDS and therapeutic opportunities targeting PAD4 via PAD4 inhibitors and lncRNAs potentially, providing future therapies. CONCLUSIONS We identified and summarized the fundamental definition of ARDS and the concept of immune thrombosis and its composition. NETs activation has become particularly relevant in the formation of immune thrombosis. The taskforce highlighted the intervention targets of PAD4, including noncoding RNAs, potentially providing future therapeutic targets to confront the high postoperative mortality of ARDS.
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Affiliation(s)
- Xiaojie Liu
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Qingdao, Shandong, China
| | - Tianjun Li
- Department of Oncology, The Affiliated Hospital of Qingdao University, No. 59, Haier Road, Qingdao, Shandong, China
| | - Huailong Chen
- Department of Anestheiology, The Qingdao Eighth People's Hospital, No. 210 Jinshui Road, Licang District, Qingdao City, Shandong, China
| | - Li Yuan
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Qingdao, Shandong, China.
| | - Hushan Ao
- Department of Anesthesiology, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.167 North Lishi Road, Xicheng District, Beijing, China.
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27
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Zhou X, Jin J, Lv T, Song Y. A Narrative Review: The Role of NETs in Acute Respiratory Distress Syndrome/Acute Lung Injury. Int J Mol Sci 2024; 25:1464. [PMID: 38338744 PMCID: PMC10855305 DOI: 10.3390/ijms25031464] [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: 11/09/2023] [Revised: 12/14/2023] [Accepted: 01/16/2024] [Indexed: 02/12/2024] Open
Abstract
Nowadays, acute respiratory distress syndrome (ARDS) still has a high mortality rate, and the alleviation and treatment of ARDS remains a major research focus. There are various causes of ARDS, among which pneumonia and non-pulmonary sepsis are the most common. Trauma and blood transfusion can also cause ARDS. In ARDS, the aggregation and infiltration of neutrophils in the lungs have a great influence on the development of the disease. Neutrophils regulate inflammatory responses through various pathways, and the release of neutrophils through neutrophil extracellular traps (NETs) is considered to be one of the most important mechanisms. NETs are mainly composed of DNA, histones, and granuloproteins, all of which can mediate downstream signaling pathways that can activate inflammatory responses, generate immune clots, and cause damage to surrounding tissues. At the same time, the components of NETs can also promote the formation and release of NETs, thus forming a vicious cycle that continuously aggravates the progression of the disease. NETs are also associated with cytokine storms and immune balance. Since DNA is the main component of NETs, DNase I is considered a viable drug for removing NETs. Other therapeutic methods to inhibit the formation of NETs are also worthy of further exploration. This review discusses the formation and mechanism of NETs in ARDS. Understanding the association between NETs and ARDS may help to develop new perspectives on the treatment of ARDS.
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Affiliation(s)
| | | | - Tangfeng Lv
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210093, China; (X.Z.); (J.J.)
| | - Yong Song
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210093, China; (X.Z.); (J.J.)
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28
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Yong J, Toh CH. Rethinking coagulation: from enzymatic cascade and cell-based reactions to a convergent model involving innate immune activation. Blood 2023; 142:2133-2145. [PMID: 37890148 DOI: 10.1182/blood.2023021166] [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: 08/11/2023] [Revised: 10/12/2023] [Accepted: 10/20/2023] [Indexed: 10/29/2023] Open
Abstract
ABSTRACT Advancements in the conceptual thinking of hemostasis and thrombosis have been catalyzed by major developments within health research over several decades. The cascade model of coagulation was first described in the 1960s, when biochemistry gained prominence through innovative experimentation and technical developments. This was followed by the cell-based model, which integrated cellular coordination to the enzymology of clot formation and was conceptualized during the growth period in cell biology at the turn of the millennium. Each step forward has heralded a revolution in clinical therapeutics, both in procoagulant and anticoagulant treatments to improve patient care. In current times, the COVID-19 pandemic may also prove to be a catalyst: thrombotic challenges including the mixed responses to anticoagulant treatment and the vaccine-induced immune thrombotic thrombocytopenia have exposed limitations in our preexisting concepts while simultaneously demanding novel therapeutic approaches. It is increasingly clear that innate immune activation as part of the host response to injury is not separate but integrated into adaptive clot formation. Our review summarizes current understanding of the major molecules facilitating such a cross talk between immunity, inflammation and coagulation. We demonstrate how such effects can be layered upon the cascade and cell-based models to evolve conceptual understanding of the physiology of immunohemostasis and the pathology of immunothrombosis.
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Affiliation(s)
- Jun Yong
- Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, United Kingdom
- The Roald Dahl Haemostasis and Thrombosis Centre, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
| | - Cheng-Hock Toh
- Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, United Kingdom
- The Roald Dahl Haemostasis and Thrombosis Centre, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
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Chooklin S, Chuklin S. The role of neutrophil extracellular traps in thrombosis. EMERGENCY MEDICINE 2023; 19:448-457. [DOI: 10.22141/2224-0586.19.7.2023.1627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/02/2024]
Abstract
According to the cellular model of hemostasis, the process of blood coagulation is presented in the form of three phases: initiation, amplification and propagation, each of them includes several consecutive stages. At the same time, thrombus formation is often explained by Virchow’s triad: blood stasis, damage to the blood vessel walls, and hypercoagulation. Classically, the appearance of one of the three mentioned parameters can lead to thrombus formation. Over the past decade, our knowledge of the cross-talk between coagulation, inflammation, and innate immune activation and the involvement of neutrophil extracellular traps in these processes has expanded. This brief review shows their role in thrombosis through the mechanisms of activation of platelets, complement, interaction with blood coagulation factors and damage to the vascular endothelium. We searched the literature in the MEDLINE database on the PubMed platform.
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Zafarani A, Razizadeh MH, Haghi A. Neutrophil extracellular traps in influenza infection. Heliyon 2023; 9:e23306. [PMID: 38144312 PMCID: PMC10746519 DOI: 10.1016/j.heliyon.2023.e23306] [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: 05/19/2023] [Revised: 11/22/2023] [Accepted: 11/30/2023] [Indexed: 12/26/2023] Open
Abstract
Despite recent progress in developing novel therapeutic approaches and vaccines, influenza is still considered a global health threat, with about half a million mortality worldwide. This disease is caused by Influenza viruses, which are known for their rapid evolution due to different genetical mechanisms that help them develop new strains with the ability to evade therapies and immunization. Neutrophils are one of the first immune effectors that act against pathogens. They use multiple mechanisms, including phagocytosis, releasing the reactive oxygen species, degranulation, and the production of neutrophil extracellular traps. Neutrophil extracellular traps are used to ensnare pathogens; however, their dysregulation is attributed to inflammatory and infectious diseases. Here, we discuss the effects of these extracellular traps in the clinical course of influenza infection and their ability to be a potential target in treating influenza infection.
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Affiliation(s)
- Alireza Zafarani
- Department of Hematology & Blood Banking, School of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hossein Razizadeh
- Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Antimicrobial Resistance Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Atousa Haghi
- Young Researchers & Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
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Ząbczyk M, Kruk A, Natorska J, Undas A. Low-grade endotoxemia in acute pulmonary embolism: Links with prothrombotic plasma fibrin clot phenotype. Thromb Res 2023; 232:70-76. [PMID: 37949000 DOI: 10.1016/j.thromres.2023.10.020] [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: 08/29/2023] [Revised: 10/25/2023] [Accepted: 10/30/2023] [Indexed: 11/12/2023]
Abstract
BACKGROUND Lipopolysaccharide (LPS) can traverse the intestinal barrier and enter bloodstream, causing endotoxemia and triggering inflammation. Increased circulating LPS was reported in arterial thromboembolism. We investigated whether increased LPS levels occur in acute pulmonary embolism (PE) and if it is associated with a prothrombotic state. METHODS We studied 120 normotensive PE patients (aged 59 [48-68] years) on admission, after 5-7 days, and after a 3-month anticoagulation. Serum LPS levels, along with zonulin, a marker of gut permeability, endogenous thrombin potential (ETP), fibrin clot permeability (Ks), clot lysis time (CLT), fibrinolysis proteins, and platelet markers were assessed. RESULTS Median LPS concentration on admission was 70.5 (61.5-82) pg/mL (min-max, 34-134 pg/mL), in association with C-reactive protein (r = 0.22, p = 0.018), but not with fibrinogen, D-dimer or platelet markers. Patients with more severe PE had higher LPS levels compared with the remainder. Median zonulin level was 3.26 (2.74-4.08) ng/mL and correlated with LPS (r = 0.66, p < 0.0001). Patients with baseline LPS levels in the top quartile (≥82 pg/mL; n = 29) compared to lower quartiles had 18.6 % increased ETP, 14.5 % reduced Ks, and 25.3 % prolonged CLT, related to higher plasminogen activator inhibitor type 1 (PAI-1) levels. LPS decreased by 23.4 % after 5-7 days and by 40.4 % after 3-month anticoagulation together with reduced zonulin by 18.4 % and 22.3 %, respectively, compared to baseline (all p < 0.001). LPS levels were not related with fibrin characteristics and other variables assessed at 3 months. CONCLUSIONS Low-grade endotoxemia is detectable in patients with acute PE and may contribute to increased thrombin generation and PAI-1-mediated hypofibrinolysis.
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Affiliation(s)
- Michał Ząbczyk
- St. John Paul II Hospital, Kraków, Poland; Institute of Cardiology, Jagiellonian University Medical College, Kraków, Poland
| | | | - Joanna Natorska
- St. John Paul II Hospital, Kraków, Poland; Institute of Cardiology, Jagiellonian University Medical College, Kraków, Poland
| | - Anetta Undas
- St. John Paul II Hospital, Kraków, Poland; Institute of Cardiology, Jagiellonian University Medical College, Kraków, Poland.
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Eichhorn T, Weiss R, Huber S, Ebeyer-Masotta M, Mostageer M, Emprechtinger R, Knabl L, Knabl L, Würzner R, Weber V. Expression of Tissue Factor and Platelet/Leukocyte Markers on Extracellular Vesicles Reflect Platelet-Leukocyte Interaction in Severe COVID-19. Int J Mol Sci 2023; 24:16886. [PMID: 38069209 PMCID: PMC10707108 DOI: 10.3390/ijms242316886] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 11/21/2023] [Accepted: 11/24/2023] [Indexed: 12/18/2023] Open
Abstract
Severe COVID-19 is frequently associated with thromboembolic complications. Increased platelet activation and platelet-leukocyte aggregate formation can amplify thrombotic responses by inducing tissue factor (TF) expression on leukocytes. Here, we characterized TF-positive extracellular vesicles (EVs) and their cellular origin in 12 patients suffering from severe COVID-19 (time course, 134 samples overall) and 25 healthy controls. EVs exposing phosphatidylserine (PS) were characterized by flow cytometry. Their cellular origin was determined by staining with anti-CD41, anti-CD45, anti-CD235a, and anti-CD105 as platelet, leukocyte, red blood cell, and endothelial markers. We further investigated the association of EVs with TF, platelet factor 4 (PF4), C-reactive protein (CRP), and high mobility group box-1 protein (HMGB-1). COVID-19 patients showed higher levels of PS-exposing EVs compared to controls. The majority of these EVs originated from platelets. A higher amount of EVs in patient samples was associated with CRP, HMGB-1, PF4, and TF as compared to EVs from healthy donors. In COVID-19 samples, 16.5% of all CD41+ EVs displayed the leukocyte marker CD45, and 55.5% of all EV aggregates (CD41+CD45+) co-expressed TF, which reflects the interaction of platelets and leukocytes in COVID-19 on an EV level.
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Affiliation(s)
- Tanja Eichhorn
- Center for Biomedical Technology, Department for Biomedical Research, University for Continuing Education Krems, 3500 Krems, Austria; (R.W.); (M.E.-M.); (M.M.); (V.W.)
| | - René Weiss
- Center for Biomedical Technology, Department for Biomedical Research, University for Continuing Education Krems, 3500 Krems, Austria; (R.W.); (M.E.-M.); (M.M.); (V.W.)
| | - Silke Huber
- Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, 6020 Innsbruck, Austria; (S.H.); (R.W.)
| | - Marie Ebeyer-Masotta
- Center for Biomedical Technology, Department for Biomedical Research, University for Continuing Education Krems, 3500 Krems, Austria; (R.W.); (M.E.-M.); (M.M.); (V.W.)
| | - Marwa Mostageer
- Center for Biomedical Technology, Department for Biomedical Research, University for Continuing Education Krems, 3500 Krems, Austria; (R.W.); (M.E.-M.); (M.M.); (V.W.)
| | - Robert Emprechtinger
- Faculty of Health and Medicine, University for Continuing Education Krems, 3500 Krems, Austria;
| | - Ludwig Knabl
- Department of Internal Medicine, Hospital St. Vinzenz, 6511 Zams, Austria;
| | | | - Reinhard Würzner
- Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, 6020 Innsbruck, Austria; (S.H.); (R.W.)
| | - Viktoria Weber
- Center for Biomedical Technology, Department for Biomedical Research, University for Continuing Education Krems, 3500 Krems, Austria; (R.W.); (M.E.-M.); (M.M.); (V.W.)
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Kumar R, Patil G, Dayal S. NLRP3-Induced NETosis: A Potential Therapeutic Target for Ischemic Thrombotic Diseases? Cells 2023; 12:2709. [PMID: 38067137 PMCID: PMC10706381 DOI: 10.3390/cells12232709] [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: 09/22/2023] [Revised: 11/22/2023] [Accepted: 11/24/2023] [Indexed: 12/18/2023] Open
Abstract
Ischemic thrombotic disease, characterized by the formation of obstructive blood clots within arteries or veins, is a condition associated with life-threatening events, such as stroke, myocardial infarction, deep vein thrombosis, and pulmonary embolism. The conventional therapeutic strategy relies on treatments with anticoagulants that unfortunately pose an inherent risk of bleeding complications. These anticoagulants primarily target clotting factors, often overlooking upstream events, including the release of neutrophil extracellular traps (NETs). Neutrophils are integral components of the innate immune system, traditionally known for their role in combating pathogens through NET formation. Emerging evidence has now revealed that NETs contribute to a prothrombotic milieu by promoting platelet activation, increasing thrombin generation, and providing a scaffold for clot formation. Additionally, NET components enhance clot stability and resistance to fibrinolysis. Clinical and preclinical studies have underscored the mechanistic involvement of NETs in the pathogenesis of thrombotic complications, since the clots obtained from patients and experimental models consistently exhibit the presence of NETs. Given these insights, the inhibition of NETs or NET formation is emerging as a promising therapeutic approach for ischemic thrombotic diseases. Recent investigations also implicate a role for the nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome as a mediator of NETosis and thrombosis, suggesting that NLRP3 inhibition may also hold potential for mitigating thrombotic events. Therefore, future preclinical and clinical studies aimed at identifying and validating NLRP3 inhibition as a novel therapeutic intervention for thrombotic disorders are imperative.
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Affiliation(s)
- Rahul Kumar
- Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; (R.K.); (G.P.)
- Department of Biotechnology, GITAM School of Sciences, GITAM (Deemed to be) University, Visakhapatnam 530045, India
| | - Gokul Patil
- Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; (R.K.); (G.P.)
| | - Sanjana Dayal
- Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; (R.K.); (G.P.)
- Holden Comprehensive Cancer Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
- Iowa City VA Healthcare System, Iowa City, IA 52246, USA
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Popal Z, Nickel KF, Wöltje M, Aibibu D, Knipfer C, Smeets R, Renné T. Polyphosphate-loaded silk fibroin membrane as hemostatic agent in oral surgery: a pilot study. Int J Implant Dent 2023; 9:44. [PMID: 37975954 PMCID: PMC10656390 DOI: 10.1186/s40729-023-00503-0] [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: 04/16/2023] [Accepted: 10/04/2023] [Indexed: 11/19/2023] Open
Abstract
PURPOSE Post-interventional hemorrhage can result in serious complications, especially in patients with hemostatic disorders. Identification of safe and efficient local hemostatic agents is important, particularly in the context of an ageing society and the emergence of new oral anticoagulants. The aim of this in vitro study was to investigate the potential of silk fibroin membranes coated with the inorganic polymer polyphosphate (polyP) as a novel hemostatic device in oral surgery. METHODS Cocoons of the silkworm Bombyx mori were degummed and dissolved. Varying amounts of long-chain polyP (2-2000 µg/mm2) were adsorbed to the surface of silk fibroin membranes. Analysis of the procoagulant effect of polyP-coated silk membranes was performed using real-time thrombin generation assays in human plasma. Increasing concentrations of polyP (0.15-500 µg/ml) served as a positive control, while uncoated silk fibroin membranes were used as negative control. RESULTS PolyP-coated silk fibroin membranes triggered coagulation when compared to plasma samples and pure silk fibroin membranes. A polyP-dose-dependent effect of thrombin generation could be found with a maximum (ETP = 1525.7 nM⋅min, peak thrombin = 310.1 nM, time to peak = 9.8 min, lag time = 7.6 min.) at 200 µg/mm2 of polymer loading on the silk fibroin membrane surface. CONCLUSIONS In this study, it was demonstrated that silk fibroin membranes coated with polyP have the potential to act as a promising novel hemostatic device.
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Affiliation(s)
- Zohal Popal
- Department of Anesthesiology, Center of Anesthesiology and Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Katrin F Nickel
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Michael Wöltje
- Institute of Textile Machinery and High-Performance Material Technology, TUD Dresden University of Technology, Dresden, Germany
| | - Dilbar Aibibu
- Institute of Textile Machinery and High-Performance Material Technology, TUD Dresden University of Technology, Dresden, Germany
| | - Christian Knipfer
- Department of Oral and Maxillofacial Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ralf Smeets
- Department of Oral and Maxillofacial Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- Department of Oral and Maxillofacial Surgery, Division of Regenerative Orofacial Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Thomas Renné
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Center for Thrombosis and Hemostasis (CTH), Johannes Gutenberg University Medical Center, Mainz, Germany
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
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Charoensappakit A, Sae-Khow K, Rattanaliam P, Vutthikraivit N, Pecheenbuvan M, Udomkarnjananun S, Leelahavanichkul A. Cell-free DNA as diagnostic and prognostic biomarkers for adult sepsis: a systematic review and meta-analysis. Sci Rep 2023; 13:19624. [PMID: 37949942 PMCID: PMC10638380 DOI: 10.1038/s41598-023-46663-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 11/03/2023] [Indexed: 11/12/2023] Open
Abstract
Although cell-free DNA (cfDNA) is an emerging sepsis biomarker, the use of cfDNA, especially as diagnostic and prognostic indicators, has surprisingly not been systemically analyzed. Data of adult patients with sepsis that conducted cfDNA measurement within 24 h of the admission was collected from PubMed, ScienceDirect, Scopus, and Cochrane Library until October 2022. The Quality in Prognosis Studies (QUIPS) and Quality Assessment in Diagnostic Studies-2 (QUADAS-2) tools were used to reduce the risk of biased assessment. The mean difference (MD) of cfDNA concentration and the standardized mean difference (SMD) between populations was calculated using Review Manager (RevMan) version 5.4.1 package software. Pooled analysis from 18 included studies demonstrated increased serum cfDNA levels in sepsis when compared with healthy control (SMD = 1.02; 95% confidence interval (CI) 0.46-1.57) or non-sepsis patients in the intensive care unit (ICU) (SMD = 1.03; 95% CI 0.65-1.40), respectively. Meanwhile, a slight decrease in the statistical value was observed when compared with non-sepsis ICU patients with SIRS (SMD = 0.74; 95% 0.41-1.06). The lower cfDNA levels were also observed in sepsis survivors compared to the non-survivors (SMD at 1.43; 95%CI 0.69-2.17) with the pooled area under the receiver operating characteristic curve (AUC) of 0.76 (95% CI 0.64-0.87) for the mortality prediction. Levels of cfDNA showed a pooled sensitivity of 0.81 (95% CI 0.75-0.86) and specificity of 0.72 (95% CI 0.65-0.78) with pooled diagnostic odd ratio (DOR) at 25.03 (95% CI 5.48-114.43) for the identification of sepsis in critically ill conditions. The cfDNA levels were significantly higher in patients with sepsis and being a helpful indicator for the critically ill conditions of sepsis. Nevertheless, results of the test must be interpreted carefully with the context of all clinical situations.
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Affiliation(s)
- Awirut Charoensappakit
- Medical Microbiology, Interdisciplinary and International Program, Graduate School, Chulalongkorn University, Bangkok, 10330, Thailand
- Center of Excellence on Translational Research in Inflammation and Immunology (CETRII), Faculty of Medicines, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Kritsanawan Sae-Khow
- Center of Excellence on Translational Research in Inflammation and Immunology (CETRII), Faculty of Medicines, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Pongpera Rattanaliam
- Department of Clinical Microscopy, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Nuntanuj Vutthikraivit
- Division of Critical Care Medicine, Department of Internal Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Monvasi Pecheenbuvan
- Division of Critical Care Medicine, Department of Internal Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Suwasin Udomkarnjananun
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Asada Leelahavanichkul
- Center of Excellence on Translational Research in Inflammation and Immunology (CETRII), Faculty of Medicines, Chulalongkorn University, Bangkok, 10330, Thailand.
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand.
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Ning S, Gupta A, Batarfi K, Liu Y, Lucier KJ, Barty R, Heddle NM. Exploring the potential harm of varied blood storage on patients undergoing cardiovascular surgery. Vox Sang 2023; 118:947-954. [PMID: 37673792 DOI: 10.1111/vox.13526] [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: 05/04/2023] [Revised: 08/17/2023] [Accepted: 08/18/2023] [Indexed: 09/08/2023]
Abstract
BACKGROUND AND OBJECTIVES Debate exists surrounding the optimal duration of red blood cell (RBC) storage. A hypothesis emerging from previous research suggests that exposure to fresh blood may be harmful to patients undergoing cardiac surgery. This study uses a large transfusion medicine database to explore the association between in-hospital mortality and red cell storage duration. MATERIALS AND METHODS This is an exploratory retrospective cohort study of all adult patients at Hamilton, Canada, over a 14-year period that received at least one allogeneic red cell transfusion during their hospitalization for cardiac surgery requiring bypass. The primary outcome for the study was in-hospital death. Analysis was performed using multivariate Cox regression modelling with time-dependent and time-independent covariates and stratification variables. Five models with varying definitions for short, intermediate and prolonged duration of RBC storage were tested. RESULTS From March 2004 to December 2017, 11,205 patients met the inclusion criteria and were included in the regression analyses. No significant effect of short-duration red storage on patient mortality was observed in all statistical models, with the red cells stored for the longest duration as the reference group. When patients who received exclusively fresh (hazard ratio [HR] 1.040, 95% confidence interval [CI] 0.588-1.841, p-value = 0.893) and older aged (HR 1.038, 95% CI 0.769-1.1.402, p-value = 0.0801) RBCs were compared with those who received exclusively mid-age red cells as the reference, statistical significance was similarly not reached. CONCLUSION Red cells stored for the shortest duration are not associated with increased risk of mortality among cardiac surgery patients.
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Affiliation(s)
- Shuoyan Ning
- Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
- Canadian Blood Services, Ottawa, Ontario, Canada
- Department of Laboratory Medicine and Pathobiology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
- Michael G. DeGroote Centre for Transfusion Research, McMaster University, Hamilton, Ontario, Canada
| | - Akash Gupta
- Department of Laboratory Medicine and Pathobiology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Khalid Batarfi
- Michael G. DeGroote Centre for Transfusion Research, McMaster University, Hamilton, Ontario, Canada
| | - Yang Liu
- Canadian Blood Services, Ottawa, Ontario, Canada
| | | | | | - Nancy M Heddle
- Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
- Canadian Blood Services, Ottawa, Ontario, Canada
- Centre for Innovation, Canadian Blood Services, Ottawa, Ontario, Canada
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Zhang L, Zheng B, Bai Y, Zhou J, Zhang X, Yang Y, Yu J, Zhao H, Ma D, Wu H, Wen J. Exosomes-transferred LINC00668 Contributes to Thrombosis by Promoting NETs Formation in Inflammatory Bowel Disease. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2300560. [PMID: 37590310 PMCID: PMC10558653 DOI: 10.1002/advs.202300560] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 06/03/2023] [Indexed: 08/19/2023]
Abstract
Epidemiological studies show an association between inflammatory bowel disease (IBD) and increased risk of thrombosis. However, how IBD influences thrombosis remains unknown. The current study shows that formation of neutrophil extracellular traps (NETs) significantly increased in the dextran sulfate sodium (DSS)-induced IBD mice, which in turn, contributes to thrombus formation in a NETs-dependent fashion. Furthermore, the exosomes isolated from the plasma of the IBD mice induce arterial and venous thrombosis in vivo. Importantly, proinflammatory factors-exposed intestinal epithelial cells (inflamed IECs) promote neutrophils to release NETs through their secreted exosomes. RNA sequencing revealed that LINC00668 is highly enriched in the inflamed IECs-derived exosomes. Mechanistically, LINC00668 facilitates the translocation of neutrophil elastase (NE) from the cytoplasmic granules to the nucleus via its interaction with NE in a sequence-specific manner, thereby inducing NETs release and thrombus formation. Importantly, berberine (BBR) suppresses the nuclear translocation of NE and subsequent NETs formation by inhibiting the interaction of LINC00668 with NE, thus exerting its antithrombotic effects. This study provides a novel pathobiological mechanism linking IBD and thrombosis by exosome-mediated NETs formation. Targeting LINC00668 can serve as a novel molecular treatment strategy to treat IBD-related thrombosis.
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Affiliation(s)
- Long Zhang
- Department of Biochemistry and Molecular BiologyThe Key Laboratory of Neural and Vascular BiologyMinistry of Education of ChinaHebei Medical UniversityShijiazhuang050017China
| | - Bin Zheng
- Department of Biochemistry and Molecular BiologyThe Key Laboratory of Neural and Vascular BiologyMinistry of Education of ChinaHebei Medical UniversityShijiazhuang050017China
| | - Yang Bai
- Department of Biochemistry and Molecular BiologyThe Key Laboratory of Neural and Vascular BiologyMinistry of Education of ChinaHebei Medical UniversityShijiazhuang050017China
| | - Jing Zhou
- Department of EndocrineThe Second Hospital of Hebei Medical UniversityShijiazhuang050017China
| | - Xin‐hua Zhang
- Department of Biochemistry and Molecular BiologyThe Key Laboratory of Neural and Vascular BiologyMinistry of Education of ChinaHebei Medical UniversityShijiazhuang050017China
- Institution of Chinese Integrative MedicineHebei Medical UniversityShijiazhuang050017China
| | - Yu‐qin Yang
- Department of Biochemistry and Molecular BiologyThe Key Laboratory of Neural and Vascular BiologyMinistry of Education of ChinaHebei Medical UniversityShijiazhuang050017China
| | - Jing Yu
- Department of RespiratoryThe Second Hospital of Hebei Medical UniversityShijiazhuang050017China
| | - Hong‐ye Zhao
- Department of Biochemistry and Molecular BiologyThe Key Laboratory of Neural and Vascular BiologyMinistry of Education of ChinaHebei Medical UniversityShijiazhuang050017China
| | - Dong Ma
- Department of Biochemistry and Molecular BiologyThe Key Laboratory of Neural and Vascular BiologyMinistry of Education of ChinaHebei Medical UniversityShijiazhuang050017China
| | - Han Wu
- Department of Biochemistry and Molecular BiologyThe Key Laboratory of Neural and Vascular BiologyMinistry of Education of ChinaHebei Medical UniversityShijiazhuang050017China
| | - Jin‐kun Wen
- Department of Biochemistry and Molecular BiologyThe Key Laboratory of Neural and Vascular BiologyMinistry of Education of ChinaHebei Medical UniversityShijiazhuang050017China
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Reshetnyak T, Nurbaeva K. The Role of Neutrophil Extracellular Traps (NETs) in the Pathogenesis of Systemic Lupus Erythematosus and Antiphospholipid Syndrome. Int J Mol Sci 2023; 24:13581. [PMID: 37686381 PMCID: PMC10487763 DOI: 10.3390/ijms241713581] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Revised: 08/10/2023] [Accepted: 08/30/2023] [Indexed: 09/10/2023] Open
Abstract
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease of unknown aetiology [...].
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Affiliation(s)
- Tatiana Reshetnyak
- Department of Thromboinflammation, V.A. Nasonova Research Institute of Rheumatology, 115522 Moscow, Russia;
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Medeiros SK, Sharma N, Dwivedi D, Liaw PC. INVESTIGATION OF THE PATHOLOGICAL EFFECTS OF HISTONES, DNA, AND NUCLEOSOMES IN A MURINE MODEL OF SEPSIS. Shock 2023; 60:291-297. [PMID: 37329563 DOI: 10.1097/shk.0000000000002165] [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] [Indexed: 06/19/2023]
Abstract
ABSTRACT Background: In sepsis, neutrophil extracellular traps (NETs) are an important interface between innate immunity and coagulation. The major structural component of neutrophil extracellular traps is nucleosomes (DNA-histone complexes). In vitro, DNA and histones exert procoagulant/cytotoxic effects whereas nucleosomes are not harmful. However, whether DNA, histones, and/or nucleosomes exert harmful effects in vivo remain unclear. Objectives: (1) The aims of the study are to investigate the cytotoxic effects of nucleosomes ± DNase I and heparin in vitro and (2) to investigate whether DNA, histones, and/or nucleosomes are harmful when injected into healthy and septic mice. Methods : The cytotoxic effects of DNA, histones, and nucleosomes (± DNaseI or ±heparin) were assessed in HEK293 cells. Mice underwent cecal ligation and puncture or sham surgery and then received injections of DNA (8 mg/kg), histones (8.5 mg/kg), or nucleosomes at 4 and 6 h. Organs and blood were harvested at 8 h. Cell-free DNA, IL-6, thrombin-anti-thrombin, and protein C were quantified from plasma. Results:In vitro , incubation of HEK293 cells with DNaseI-treated nucleosomes reduced cell survival compared with nucleosome-treated cells, suggesting that DNaseI releases cytotoxic histones from nucleosomes. Addition of heparin to DNaseI-treated nucleosomes rescued cell death. In vivo, administration of histones to septic mice increased markers of inflammation (IL-6) and coagulation (thrombin-anti-thrombin), which was not observed in sham or septic mice administered DNA or nucleosomes. Conclusions: Our studies suggest that DNA masks the harmful effects of histones in vitro and in vivo . Although administration of histones contributed to the pathogenesis of sepsis, administration of nucleosomes or DNA was not harmful in healthy or septic mice.
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Li S, Wang H, Shao Q. The central role of neutrophil extracellular traps (NETs) and by-products in COVID-19 related pulmonary thrombosis. Immun Inflamm Dis 2023; 11:e949. [PMID: 37647446 PMCID: PMC10461423 DOI: 10.1002/iid3.949] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 06/26/2023] [Accepted: 07/08/2023] [Indexed: 09/01/2023] Open
Abstract
Extracellular trap networks (neutrophil extracellular traps [NETs]) of polymorphonuclear neutrophils are mesh-like substances that prevent the spread of pathogens. They primarily consist of DNA skeletons, histones, granule components, and cytoplasmic proteins. NETs formation requires a certain environment and there are different pathways for NETs production. However, it is still not clear how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) promotes NETs. NETs exert antiinflammatory effects through immune response, while they can also lead to certain adverse outcomes, such as the development of immunothrombosis. Coronavirus disease 2019 (COVID-19) is an inflammatory reaction affecting various organs caused by SARS-CoV-2, especially the lungs. NETs production and disease severity are linked with unique neutrophil clusters by single-cell RNA sequencing. NETs might exert an anti-inflammatory role in the initial stage of lung tissue inflammation. Nevertheless, numerous studies and cases have shown that they can also result in pulmonary thrombosis. There is mounting evidence that NETs are tightly related with COVID-19 pulmonary thrombosis, and many studies on the mechanisms are involved. The role and mechanism of NETs in the development of pulmonary thrombosis will be the main topics of this manuscript. Additionally, we address the potential targeting of NETs in COVID-19 patients.
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Affiliation(s)
- Shi Li
- Department of ImmunologySchool of Medicine, Jiangsu UniversityZhenjiangJiangsuChina
| | - Hui Wang
- Department of ImmunologySchool of Medicine, Jiangsu UniversityZhenjiangJiangsuChina
| | - Qixiang Shao
- Department of ImmunologySchool of Medicine, Jiangsu UniversityZhenjiangJiangsuChina
- Department of Medical Microbiology and Immunology, Institute of Medical Genetics and Reproductive Immunity, School of Medical Science and Laboratory MedicineJiangsu College of NursingHuai'anJiangsuChina
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Wichaiyo S, Parichatikanond W, Visansirikul S, Saengklub N, Rattanavipanon W. Determination of the Potential Clinical Benefits of Small Molecule Factor XIa Inhibitors in Arterial Thrombosis. ACS Pharmacol Transl Sci 2023; 6:970-981. [PMID: 37470020 PMCID: PMC10353063 DOI: 10.1021/acsptsci.3c00052] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Indexed: 07/21/2023]
Abstract
Anticoagulants are the mainstay for the prevention and treatment of thrombosis. However, bleeding complications remain a primary concern. Recent advances in understanding the contribution of activated factor XI (FXIa) in arterial thrombosis with a limited impact on hemostasis have led to the development of several FXIa-targeting modalities. Injectable agents including monoclonal antibodies and antisense oligonucleotides against FXIa have been primarily studied in venous thrombosis. The orally active small molecules that specifically inhibit the active site of FXIa are currently being investigated for their antithrombotic activity in both arteries and veins. This review focuses on a discussion of the potential clinical benefits of small molecule FXIa inhibitors, mainly asundexian and milvexian, in arterial thrombosis based on their pharmacological profiles and the compelling results of phase 2 clinical studies. The preclinical and epidemiological basis for the impact of FXIa in hemostasis and arterial thrombosis is also addressed. In recent clinical study results, asundexian appears to reduce ischemic events in patients with myocardial infarction and minor-to-moderate stroke, whereas milvexian possibly provides benefits in patients with minor stroke or high-risk transient ischemic attack (TIA). In addition, asundexian and milvexian had a minor impact on hemostasis even in combination with dual-antiplatelet therapy. Other orally active FXIa inhibitors also produce antithrombotic activity in vivo with low bleeding risk. Therefore, FXIa inhibitors might represent a new class of direct-acting oral anticoagulants (DOACs) for the treatment of thrombosis, although the explicit clinical positions of asundexian and milvexian in patients with ischemic stroke, high-risk TIA, and coronary artery disease require confirmation from the outcomes of ongoing phase 3 trials.
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Affiliation(s)
- Surasak Wichaiyo
- Department
of Pharmacology, Faculty of Pharmacy, Mahidol
University, Bangkok 10400, Thailand
- Centre
of Biopharmaceutical Science for Healthy Ageing, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand
| | - Warisara Parichatikanond
- Department
of Pharmacology, Faculty of Pharmacy, Mahidol
University, Bangkok 10400, Thailand
- Centre
of Biopharmaceutical Science for Healthy Ageing, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand
| | - Satsawat Visansirikul
- Department
of Pharmaceutical Chemistry, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand
| | - Nakkawee Saengklub
- Centre
of Biopharmaceutical Science for Healthy Ageing, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand
- Department
of Physiology, Faculty of Pharmacy, Mahidol
University, Bangkok 10400, Thailand
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Liu Y, Shu H, Wan P, Wang X, Xie H. Neutrophil extracellular traps predict postoperative pulmonary complications in paediatric patients undergoing parental liver transplantation. BMC Gastroenterol 2023; 23:237. [PMID: 37442949 DOI: 10.1186/s12876-023-02744-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Accepted: 03/25/2023] [Indexed: 07/15/2023] Open
Abstract
BACKGROUND Parental liver transplantation (PLT) improves long-term survival rates in paediatric hepatic failure patients; however, the mechanism of PLT-induced postoperative pulmonary complications (PPCs) is unclear. METHODS A total of 133 paediatric patients undergoing PLT were included. Serum levels of NET components, including circulating free DNA (cfDNA), DNA-histone complex, and myeloperoxidase (MPO)-DNA complex, were detected. The occurrence of PPCs post-PLT, prolonged intensive care unit (ICU) stay and death within one year were recorded as the primary and secondary outcomes. RESULTS The overall rate of PPCs in the hospital was 47.4%. High levels of serum cfDNA, DNA-histone complexes and MPO-DNA complexes were associated with an increased risk of PPCs (for cfDNA, OR 2.24; for DNA-histone complex, OR 1.64; and for MPO-DNA, OR 1.94), prolonged ICU stay (OR 1.98, 4.26 and 3.69, respectively), and death within one year (OR 1.53, 2.65 and 1.85, respectively). The area under the curve of NET components for the prediction of PPCs was 0.843 for cfDNA, 0.813 for DNA-histone complexes, and 0.906 for MPO-DNA complexes. During the one-year follow-up, the death rate was higher in patients with PPCs than in patients without PPCs (14.3% vs. 2.9%, P = 0.001). CONCLUSIONS High serum levels of NET components are associated with an increased incidence of PPCs and death within one year in paediatric patients undergoing PLT. Serum levels of NET components serve as a biomarker for post-PLT PPCs and a prognostic indicator.
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Affiliation(s)
- Yaling Liu
- Department of Anesthesiology, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road Suzhou, Jiangsu, China
- Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, 160 Pujian Road, Shanghai, 200127, China
| | - Huigang Shu
- Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, 160 Pujian Road, Shanghai, 200127, China
| | - Ping Wan
- Department of Liver Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xiaodong Wang
- Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai, China.
| | - Hong Xie
- Department of Anesthesiology, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road Suzhou, Jiangsu, China.
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Liu Y, Dai D, Abbasi M, Mereuta OM, Gamb SI, Kadirvel R, Kallmes DF, Brinjikji W. An in vitro model for Extracellular DNA Traps (ETs)-rich Human Thrombus Analogs. J Neurointerv Surg 2023; 15:589-593. [PMID: 35483911 PMCID: PMC11094997 DOI: 10.1136/neurintsurg-2022-018790] [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: 02/08/2022] [Accepted: 04/16/2022] [Indexed: 11/03/2022]
Abstract
BACKGROUND Extracellular DNA traps (ETs) have important implications in both thrombosis and thrombolysis. Thus, developing benchtop thrombus analogs that recapitulate clinical ETs is potentially of great value for preclinical development and testing of thrombolytic agents and thrombectomy devices. In this study, we aimed to develop ETs-rich thrombus analogs for preclinical testing. METHODS Red blood cell (RBC)-rich, fibrin-rich, and platelet-rich thrombus analogs were created using human whole blood, platelet-poor plasma, and platelet-rich plasma obtained from the blood bank following institutional approval. Peripheral blood mononuclear cells (9.9×106 cells/mL) isolated from human whole blood and lipopolysaccharide (1 µg/mL) were added to induce ETs. Histochemical, immunohistochemistry and immunofluorescence were used to identify thrombus components and ETs. Scanning electronic microscopy was used to investigate the ultrastructure of the thrombus analogs. The thrombus compositions, morphologic features of ETs and citrullinated histone H3 (H3Cit) expression were compared with those of thrombi retrieved from patients by thrombectomy. RESULTS ETs-rich thrombus analogs were more compacted th-an the ETs-poor thrombus analogs. ETs were identified in both ETs-rich thrombus analogs and patient thrombi showing morphologic features including nuclear lobulation, nuclear swelling, diffused chromatin within cytoplasm, DNA/chromatin extending intracellularly and extracellularly, and extracellular chromatin patches and bundles. In the ETs-poor thrombus analogs, ETs were not observed and H3Cit expression was absent to minimal. The compositions and H3Cit expression in the ETs-rich thrombus analogs fell in the range of patient thrombi. CONCLUSIONS ETs-rich thrombus analogs can be consistently created in vitro and may benefit the preclinical development and testing of new thrombolytic agents and thrombectomy devices.
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Affiliation(s)
- Yang Liu
- Radiology, Mayo Clinic, Rochester, Minnesota, USA
- Global Institute of Future Technology, Shanghai Jiao Tong University, Shanghai, China
| | - Daying Dai
- Radiology, Mayo Clinic, Rochester, Minnesota, USA
| | - Mehdi Abbasi
- Radiology, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Scott I Gamb
- Electron Microscopy Core Facility, Mayo Clinic, Rochester, Minnesota, USA
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Yokoyama APH, Kutner JM, de Moraes Mazetto Fonseca B, Mesquita GLTV, Sakashita AM, Dos Santos APR, Nakazawa CY, de Almeida MD, de Andrade Orsi FL. Neutrophil extracellular traps (NETs), transfusion requirements and clinical outcomes in orthotopic liver transplantation. J Thromb Thrombolysis 2023:10.1007/s11239-023-02825-7. [PMID: 37227652 DOI: 10.1007/s11239-023-02825-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/25/2023] [Indexed: 05/26/2023]
Abstract
Inflammatory phenomena have a direct impact on the prognosis of orthotopic liver transplantation (OLT). Neutrophil extracellular traps (NETs) contribute to OLT inflammation and hemostasis imbalance in OLT. The association between NETosis, clinical outcomes and transfusion requirements is not determined. To evaluate NETs release during OLT and the effect of NETosis ontransfusion requirements and adverse outcomes in a prospective cohort of patients submitted to OLT. We quantified citrullinated histones (cit-H3) and circulating-free-DNA (cf-DNA) in ninety-three patients submitted to OLT in three periods: pre-transplant, after graft reperfusion and before discharge. NETs markers were compared between these periods using ANOVA test. The association of NETosis and adverse outcomes was evaluated using regression models adjusted for age, sex and corrected MELD. We observed a peak of circulating NETs following reperfusion, evidenced by a 2.4-fold increase in cit-H3 levels in the post-graft reperfusion period (median levels of cit-H3 pre transplant: 0.5 ng/mL, after reperfusion: 1.2 ng/mL and at discharge 0.5 ng/mL, p < 0.0001). We observed an association between increased levels of cit-H3 and in-hospital death (OR = 1.168, 95% CI 1.021-1.336, p = 0.024). No association was found between NETs markers and transfusion requirements. There is a prompt release of NETs after reperfusion that is associated with poorer outcomes and death. Intraoperative NETs release seems to be independent of transfusion requirements. These findings highlight the relevance of inflammation promoted by NETS and its impact on OLT adverse clinical outcomes.
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Affiliation(s)
- Ana Paula Hitomi Yokoyama
- Hemotherapy and Cell Therapy Department, Hospital Israelita Albert Einstein, Av Albert Einstein, 627-3o Andar, São Paulo, SP, 05652-000, Brazil.
- Faculty of Medical Sciences, University of Campinas, Campinas, Brazil.
| | - Jose Mauro Kutner
- Hemotherapy and Cell Therapy Department, Hospital Israelita Albert Einstein, Av Albert Einstein, 627-3o Andar, São Paulo, SP, 05652-000, Brazil
| | | | | | - Araci Massami Sakashita
- Hemotherapy and Cell Therapy Department, Hospital Israelita Albert Einstein, Av Albert Einstein, 627-3o Andar, São Paulo, SP, 05652-000, Brazil
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Zdanyte M, Borst O, Münzer P. NET-(works) in arterial and venous thrombo-occlusive diseases. Front Cardiovasc Med 2023; 10:1155512. [PMID: 37283578 PMCID: PMC10239889 DOI: 10.3389/fcvm.2023.1155512] [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: 01/31/2023] [Accepted: 05/02/2023] [Indexed: 06/08/2023] Open
Abstract
Formation of Neutrophil Extracellular Traps (NETosis), accompanied by the release of extracellular decondensed chromatin and pro-inflammatory as well as pro-thrombotic factors, is a pivotal element in the development and progression of thrombo-occlusive diseases. While the process of NETosis is based on complex intracellular signalling mechanisms, it impacts a wide variety of cells including platelets, leukocytes and endothelial cells. Consequently, although initially mainly associated with venous thromboembolism, NETs also affect and mediate atherothrombosis and its acute complications in the coronary, cerebral and peripheral arterial vasculature. In this context, besides deep vein thrombosis and pulmonary embolism, NETs in atherosclerosis and especially its acute complications such as myocardial infarction and ischemic stroke gained a lot of attention in the cardiovascular research field in the last decade. Thus, since the effect of NETosis on platelets and thrombosis in general is extensively discussed in other review articles, this review focusses on the translational and clinical relevance of NETosis research in cardiovascular thrombo-occlusive diseases. Consequently, after a brief summary of the neutrophil physiology and the cellular and molecular mechanisms underlying NETosis are presented, the role of NETosis in atherosclerotic and venous thrombo-occlusive diseases in chronic and acute settings are discussed. Finally, potential prevention and treatment strategies of NET-associated thrombo-occlusive diseases are considered.
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Affiliation(s)
- Monika Zdanyte
- DFG Heisenberg Group Thrombocardiology, Eberhard Karl University Tübingen, Tübingen, Germany
- Department of Cardiology and Angiology, University Hospital Tübingen, Tübingen, Germany
| | - Oliver Borst
- DFG Heisenberg Group Thrombocardiology, Eberhard Karl University Tübingen, Tübingen, Germany
- Department of Cardiology and Angiology, University Hospital Tübingen, Tübingen, Germany
| | - Patrick Münzer
- DFG Heisenberg Group Thrombocardiology, Eberhard Karl University Tübingen, Tübingen, Germany
- Department of Cardiology and Angiology, University Hospital Tübingen, Tübingen, Germany
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46
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Pala ZR, Alves e Silva TL, Minai M, Crews B, Patino-Martinez E, Carmona-Rivera C, Valenzuela-Leon PC, Martin-Martin I, Flores-Garcia Y, Cachau RE, Srivastava N, Moore IN, Alves DA, Kaplan MJ, Fischer E, Calvo E, Vega-Rodriguez J. Anopheles salivary apyrase regulates blood meal hemostasis and drives malaria parasite transmission. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.22.541827. [PMID: 37292610 PMCID: PMC10245845 DOI: 10.1101/2023.05.22.541827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Mosquito salivary proteins play a crucial role in regulating hemostatic responses at the bite site during blood feeding. In this study, we investigate the function of Anopheles gambiae salivary apyrase (AgApyrase) in Plasmodium transmission. Our results demonstrate that salivary apyrase interacts with and activates tissue plasminogen activator, facilitating the conversion of plasminogen to plasmin, a human protein previously shown to be required for Plasmodium transmission. Microscopy imaging shows that mosquitoes ingest a substantial amount of apyrase during blood feeding which reduces coagulation in the blood meal by enhancing fibrin degradation and inhibiting platelet aggregation. Supplementation of Plasmodium infected blood with apyrase significantly enhanced Plasmodium infection in the mosquito midgut. In contrast, AgApyrase immunization inhibited Plasmodium mosquito infection and sporozoite transmission. This study highlights a pivotal role for mosquito salivary apyrase for regulation of hemostasis in the mosquito blood meal and for Plasmodium transmission to mosquitoes and to the mammal host, underscoring the potential for new strategies to prevent malaria transmission.
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Affiliation(s)
- Zarna Rajeshkumar Pala
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
| | - Thiago Luiz Alves e Silva
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
| | - Mahnaz Minai
- Infectious Disease Pathogenesis Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
| | - Benjamin Crews
- Microscopy Unit, Research Technologies Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA
| | - Eduardo Patino-Martinez
- Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Carmelo Carmona-Rivera
- Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Paola Carolina Valenzuela-Leon
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
| | - Ines Martin-Martin
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
- Current address: Laboratory of Medical Entomology, National Center for Microbiology, Instituto de Salud Carlos III, 28220 Majadahonda, Madrid, Spain
| | - Yevel Flores-Garcia
- Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Raul E. Cachau
- Integrated Data Science Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Naman Srivastava
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
| | - Ian N. Moore
- Infectious Disease Pathogenesis Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
| | - Derron A. Alves
- Infectious Disease Pathogenesis Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
| | - Mariana J Kaplan
- Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Elizabeth Fischer
- Microscopy Unit, Research Technologies Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA
| | - Eric Calvo
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
| | - Joel Vega-Rodriguez
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
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47
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Liatsos GD. SARS-CoV-2 induced liver injury: Incidence, risk factors, impact on COVID-19 severity and prognosis in different population groups. World J Gastroenterol 2023; 29:2397-2432. [PMID: 37179584 PMCID: PMC10167898 DOI: 10.3748/wjg.v29.i16.2397] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 02/17/2023] [Accepted: 04/07/2023] [Indexed: 04/24/2023] Open
Abstract
Liver is unlikely the key organ driving mortality in coronavirus disease 2019 (COVID-19) however, liver function tests (LFTs) abnormalities are widely observed mostly in moderate and severe cases. According to this review, the overall prevalence of abnormal LFTs in COVID-19 patients ranges from 2.5% to 96.8% worldwide. The geographical variability in the prevalence of underlying diseases is the determinant for the observed discrepancies between East and West. Multifactorial mechanisms are implicated in COVID-19-induced liver injury. Among them, hypercytokinemia with "bystander hepatitis", cytokine storm syndrome with subsequent oxidative stress and endotheliopathy, hypercoagulable state and immuno-thromboinflammation are the most determinant mechanisms leading to tissue injury. Liver hypoxia may also contribute under specific conditions, while direct hepatocyte injury is an emerging mechanism. Except for initially observed severe acute respiratory distress syndrome corona virus-2 (SARS-CoV-2) tropism for cholangiocytes, more recent cumulative data show SARS-CoV-2 virions within hepatocytes and sinusoidal endothelial cells using electron microscopy (EM). The best evidence for hepatocellular invasion by the virus is the identification of replicating SARS-CoV-2 RNA, S protein RNA and viral nucleocapsid protein within hepatocytes using in-situ hybridization and immunostaining with observed intrahepatic presence of SARS-CoV-2 by EM and by in-situ hybridization. New data mostly derived from imaging findings indicate possible long-term sequelae for the liver months after recovery, suggesting a post-COVID-19 persistent live injury.
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Affiliation(s)
- George D Liatsos
- Department of Internal Medicine, Hippokration General Hospital, Athens 11527, Attiki, Greece
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48
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Tweddell JS, Kharnaf M, Zafar F, Riggs KW, Reagor JA, Monia BP, Revenko A, Leino DG, Owens AP, Martin JK, Gourley B, Rosenfeldt L, Palumbo JS. Targeting the contact system in a rabbit model of extracorporeal membrane oxygenation. Blood Adv 2023; 7:1404-1417. [PMID: 36240297 PMCID: PMC10139951 DOI: 10.1182/bloodadvances.2022007586] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 09/06/2022] [Accepted: 09/07/2022] [Indexed: 11/20/2022] Open
Abstract
Previous studies suggested that contact pathway factors drive thrombosis in mechanical circulation. We used a rabbit model of veno-arterial extracorporeal circulation (VA-ECMO) to evaluate the role of factors XI and XII in ECMO-associated thrombosis and organ damage. Factors XI and XII (FXI, FXII) were depleted using established antisense oligonucleotides before placement on a blood-primed VA-ECMO circuit. Decreasing FXII or FXI to < 5% of baseline activity significantly prolonged ECMO circuit lifespan, limited the development of coagulopathy, and prevented fibrinogen consumption. Histological analysis suggested that FXII depletion mitigated interstitial pulmonary edema and hemorrhage whereas heparin and FXI depletion did not. Neither FXI nor FXII depletion was associated with significant hemorrhage in other organs. In vitro analysis showed that membrane oxygenator fibers (MOFs) alone are capable of driving significant thrombin generation in a FXII- and FXI-dependent manner. MOFs also augment thrombin generation triggered by low (1 pM) or high (5 pM) tissue factor concentrations. However, only FXI elimination completely prevented the increase in thrombin generation driven by MOFs, suggesting MOFs augment thrombin-mediated FXI activation. Together, these results suggest that therapies targeting FXII or FXI limit thromboembolic complications associated with ECMO. Further studies are needed to determine the contexts wherein targeting FXI and FXII, either alone or in combination, would be most beneficial in ECMO. Moreover, studies are also needed to determine the potential mechanisms coupling FXII to end-organ damage in ECMO.
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Affiliation(s)
- James S. Tweddell
- The Heart Institute, Cincinnati Children’s Hospital Medical Center and The University of Cincinnati College of Medicine, Cincinnati, OH
| | - Mousa Kharnaf
- The Heart Institute, Cincinnati Children’s Hospital Medical Center and The University of Cincinnati College of Medicine, Cincinnati, OH
| | - Farhan Zafar
- The Heart Institute, Cincinnati Children’s Hospital Medical Center and The University of Cincinnati College of Medicine, Cincinnati, OH
| | - Kyle W. Riggs
- The Heart Institute, Cincinnati Children’s Hospital Medical Center and The University of Cincinnati College of Medicine, Cincinnati, OH
| | - James A. Reagor
- The Heart Institute, Cincinnati Children’s Hospital Medical Center and The University of Cincinnati College of Medicine, Cincinnati, OH
| | | | | | - Daniel G. Leino
- Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center and The University of Cincinnati College of Medicine, Cincinnati, OH
| | - A. Phillip Owens
- Department of Internal Medicine, The University of Cincinnati College of Medicine, Cincinnati, OH
| | - Janine K. Martin
- Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center and The University of Cincinnati College of Medicine, Cincinnati, OH
| | - Benjamin Gourley
- Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center and The University of Cincinnati College of Medicine, Cincinnati, OH
| | - Leah Rosenfeldt
- Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center and The University of Cincinnati College of Medicine, Cincinnati, OH
| | - Joseph S. Palumbo
- Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center and The University of Cincinnati College of Medicine, Cincinnati, OH
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Sayyadi M, Hassani S, Shams M, Dorgalaleh A. Status of major hemostatic components in the setting of COVID-19: the effect on endothelium, platelets, coagulation factors, fibrinolytic system, and complement. Ann Hematol 2023; 102:1307-1322. [PMID: 37074380 PMCID: PMC10115391 DOI: 10.1007/s00277-023-05234-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 04/14/2023] [Indexed: 04/20/2023]
Abstract
The coagulation, fibrinolytic, anticoagulation, and complement systems are in delicate balance with the vessel wall endothelium ensuring appropriate hemostasis. Coagulopathy in coronavirus disease 2019 (COVID-19) is not a simple disorder of one hemostatic component but a complicated process affecting most of the hemostasis system. COVID-19 disturbs the balance between the procoagulant systems and the regulatory mechanisms. Here, we investigate the effect of COVID-19 on key hemostatic components, including platelets, endothelial cells, coagulation factors, fibrinolytic system, anticoagulant protein system, and complement system, to improve our understanding of the pathophysiological processes underlying COVID-19 coagulopathy based on evidence.
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Affiliation(s)
- Mohammad Sayyadi
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Arak University of Medical Sciences, Arak, Iran
| | - Saeed Hassani
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Arak University of Medical Sciences, Arak, Iran.
| | - Mahmood Shams
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
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50
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Thakur M, Junho CVC, Bernhard SM, Schindewolf M, Noels H, Döring Y. NETs-Induced Thrombosis Impacts on Cardiovascular and Chronic Kidney Disease. Circ Res 2023; 132:933-949. [PMID: 37053273 PMCID: PMC10377271 DOI: 10.1161/circresaha.123.321750] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/15/2023]
Abstract
Arterial and venous thrombosis constitute a major source of morbidity and mortality worldwide. Association between thrombotic complications and cardiovascular and other chronic inflammatory diseases are well described. Inflammation and subsequent initiation of thrombotic events, termed immunothrombosis, also receive growing attention but are still incompletely understood. Nevertheless, the clinical relevance of aberrant immunothrombosis, referred to as thromboinflammation, is evident by an increased risk of thrombosis and cardiovascular events in patients with inflammatory or infectious diseases. Proinflammatory mediators released from platelets, complement activation, and the formation of NETs (neutrophil extracellular traps) initiate and foster immunothrombosis. In this review, we highlight and discuss prominent and emerging interrelationships and functions between NETs and other mediators in immunothrombosis in cardiovascular disease. Also, with patients with chronic kidney disease suffering from increased cardiovascular and thrombotic risk, we summarize current knowledge on neutrophil phenotype, function, and NET formation in chronic kidney disease. In addition, we elaborate on therapeutic targeting of NETs-induced immunothrombosis. A better understanding of the functional relevance of antithrombotic mediators which do not increase bleeding risk may provide opportunities for successful therapeutic interventions to reduce thrombotic risk beyond current treatment options.
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Affiliation(s)
- Manovriti Thakur
- Division of Angiology, Swiss Cardiovascular Center, Inselspital (M.T., S.M.B., M.S., Y.D.), Bern University Hospital, University of Bern, Switzerland
- Department for BioMedical Research (DBMR) (M.T., S.M.B., M.S., Y.D.), Bern University Hospital, University of Bern, Switzerland
| | - Carolina Victoria Cruz Junho
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Germany (C.V.C.J., H.N.)
| | - Sarah Maike Bernhard
- Division of Angiology, Swiss Cardiovascular Center, Inselspital (M.T., S.M.B., M.S., Y.D.), Bern University Hospital, University of Bern, Switzerland
- Department for BioMedical Research (DBMR) (M.T., S.M.B., M.S., Y.D.), Bern University Hospital, University of Bern, Switzerland
| | - Marc Schindewolf
- Division of Angiology, Swiss Cardiovascular Center, Inselspital (M.T., S.M.B., M.S., Y.D.), Bern University Hospital, University of Bern, Switzerland
- Department for BioMedical Research (DBMR) (M.T., S.M.B., M.S., Y.D.), Bern University Hospital, University of Bern, Switzerland
| | - Heidi Noels
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Germany (C.V.C.J., H.N.)
- Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, the Netherlands (H.N.)
| | - Yvonne Döring
- Division of Angiology, Swiss Cardiovascular Center, Inselspital (M.T., S.M.B., M.S., Y.D.), Bern University Hospital, University of Bern, Switzerland
- Department for BioMedical Research (DBMR) (M.T., S.M.B., M.S., Y.D.), Bern University Hospital, University of Bern, Switzerland
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany (Y.D.)
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich (LMU), Munich, Germany (Y.D.)
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