Ticagrelor Reduces Thromboinflammatory Markers in Patients With Pneumonia

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As expected, ticagrelor reduced ex-vivo ADP-induced aggregation in patients with pneumonia compared with placebo.
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Ticagrelor reduced platelet–leukocyte interactions as well as plasma interleukin-6 within 24 h in patients with pneumonia compared with placebo.
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Ticagrelor acutely altered NETosis biomarkers, whereas placebo had no effect.
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Ticagrelor improved lung function and reduced need for supplemental oxygen in patients with pneumonia compared with placebo.

Summary

Despite treatment advances for sepsis and pneumonia, significant improvements in outcome have not been realized. Antiplatelet therapy may improve outcome in pneumonia and sepsis. In this study, the authors show that ticagrelor reduced leukocytes with attached platelets as well as the inflammatory biomarker interleukin (IL)-6. Pneumonia patients receiving ticagrelor required less supplemental oxygen and lung function tests trended toward improvement. Disruption of the P2Y ₁₂ receptor in a murine model protected against inflammatory response, lung permeability, and mortality. Results indicate a mechanistic link between platelets, leukocytes, and lung injury in settings of pneumonia and sepsis, and suggest possible therapeutic approaches to reduce complications.(Targeting Platelet-Leukocyte Aggregates in Pneumonia With Ticagrelor [XANTHIPPE]; NCT01883869)

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Neutrophil Extracellular Traps Induce Organ Damage during Experimental and Clinical Sepsis

Paula Giselle Czaikoski, José Maurício Segundo Correia Mota, Daniele Carvalho Nascimento … (2016)

Organ dysfunction is a major concern in sepsis pathophysiology and contributes to its high mortality rate. Neutrophil extracellular traps (NETs) have been implicated in endothelial damage and take part in the pathogenesis of organ dysfunction in several conditions. NETs also have an important role in counteracting invading microorganisms during infection. The aim of this study was to evaluate systemic NETs formation, their participation in host bacterial clearance and their contribution to organ dysfunction in sepsis. C57Bl/6 mice were subjected to endotoxic shock or a polymicrobial sepsis model induced by cecal ligation and puncture (CLP). The involvement of cf-DNA/NETs in the physiopathology of sepsis was evaluated through NETs degradation by rhDNase. This treatment was also associated with a broad-spectrum antibiotic treatment (ertapenem) in mice after CLP. CLP or endotoxin administration induced a significant increase in the serum concentrations of NETs. The increase in CLP-induced NETs was sustained over a period of 3 to 24 h after surgery in mice and was not inhibited by the antibiotic treatment. Systemic rhDNase treatment reduced serum NETs and increased the bacterial load in non-antibiotic-treated septic mice. rhDNase plus antibiotics attenuated sepsis-induced organ damage and improved the survival rate. The correlation between the presence of NETs in peripheral blood and organ dysfunction was evaluated in 31 septic patients. Higher cf-DNA concentrations were detected in septic patients in comparison with healthy controls, and levels were correlated with sepsis severity and organ dysfunction. In conclusion, cf-DNA/NETs are formed during sepsis and are associated with sepsis severity. In the experimental setting, the degradation of NETs by rhDNase attenuates organ damage only when combined with antibiotics, confirming that NETs take part in sepsis pathogenesis. Altogether, our results suggest that NETs are important for host bacterial control and are relevant actors in the pathogenesis of sepsis.

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Risk of deep vein thrombosis and pulmonary embolism after acute infection in a community setting.

Richard B. Hubbard, Liam Smeeth, Claire Cook … (2006)

Acute infection increases the risk of arterial cardiovascular events, but effects on venous thromboembolic disease are less well established. Our aim was to investigate whether acute infections transiently increase the risk of venous thromboembolism. We used the self-controlled case-series method to study the risk of first deep vein thrombosis (DVT) (n=7278) and first pulmonary embolism (PE) (n=3755) after acute respiratory and urinary tract infections. Data were obtained from records from general practices who had registered patients with the UK's Health Improvement Network database between 1987 and 2004. The risks of DVT and PE were significantly raised, and were highest in the first two weeks, after urinary tract infection. The incidence ratio for DVT was 2.10 (95% CI 1.56-2.82), and that for PE 2.11 (1.38-3.23). The risk gradually fell over the subsequent months, returning to the baseline value after 1 year. The risk of DVT was also higher after respiratory tract infection, but possible diagnostic misclassification precluded a reliable estimate of the risk of PE after respiratory infection. Acute infections are associated with a transient increased risk of venous thromboembolic events in a community setting. Our results confirm that infection should be added to the list of precipitants for venous thromboembolism, and suggest a causal relation.

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Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study.

Christopher Cannon, Robert A Harrington, Stefan James … (2010)

Variation in and irreversibility of platelet inhibition with clopidogrel has led to controversy about its optimum dose and timing of administration in patients with acute coronary syndromes. We compared ticagrelor, a more potent reversible P2Y12 inhibitor with clopidogrel in such patients. At randomisation, an invasive strategy was planned for 13 408 (72.0%) of 18 624 patients hospitalised for acute coronary syndromes (with or without ST elevation). In a double-blind, double-dummy study, patients were randomly assigned in a one-to-one ratio to ticagrelor and placebo (180 mg loading dose followed by 90 mg twice a day), or to clopidogrel and placebo (300-600 mg loading dose or continuation with maintenance dose followed by 75 mg per day) for 6-12 months. All patients were given aspirin. The primary composite endpoint was cardiovascular death, myocardial infarction, or stroke. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00391872. 6732 patients were assigned to ticagrelor and 6676 to clopidogrel. The primary composite endpoint occurred in fewer patients in the ticagrelor group than in the clopidogrel group (569 [event rate at 360 days 9.0%] vs 668 [10.7%], hazard ratio 0.84, 95% CI 0.75-0.94; p=0.0025). There was no difference between clopidogrel and ticagrelor groups in the rates of total major bleeding (691 [11.6%] vs 689 [11.5%], 0.99 [0.89-1.10]; p=0.8803) or severe bleeding, as defined according to the Global Use of Strategies To Open occluded coronary arteries, (198 [3.2%] vs 185 [2.9%], 0.91 [0.74-1.12]; p=0.3785). Ticagrelor seems to be a better option than clopidogrel for patients with acute coronary syndromes for whom an early invasive strategy is planned. Copyright 2010 Elsevier Ltd. All rights reserved.

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Author and article information

Contributors

Susan Smyth

Journal

Journal ID (nlm-ta): JACC Basic Transl Sci

Journal ID (iso-abbrev): JACC Basic Transl Sci

Title: JACC: Basic to Translational Science

Publisher: Elsevier

ISSN (Electronic): 2452-302X

Publication date PMC-release: 28 August 2018

Publication date Collection: August 2018

Publication date (Electronic): 28 August 2018

Volume: 3

Issue: 4

Pages: 435-449

Affiliations

[a ]Gill Heart and Vascular Institute, University of Kentucky, Lexington, Kentucky

[b ]Pulmonary, Critical Care & Sleep Medicine, University of Kentucky, Lexington, Kentucky

[c ]Department of Biostatistics, College of Public Health, University of Kentucky, Lexington, Kentucky

[d ]Lexington VA Medical Center, Lexington, Kentucky

Author notes

[∗ ] Address for correspondence: Dr. Susan S. Smyth, Gill Heart and Vascular Institute, 741 South Limestone, University of Kentucky, BBSRB B345, Lexington, Kentucky 40536. ssmyt2@ 123456uky.edu

Article

Publisher ID: S2452-302X(18)30129-3

DOI: 10.1016/j.jacbts.2018.05.005

PMC ID: 6115703

PubMed ID: 30175268

SO-VID: 23415b57-82ed-4dd0-b713-3a20f47582d4

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Ticagrelor Reduces Thromboinflammatory Markers in Patients With Pneumonia

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Pneumonia, sex, and the environment

Most cited references 30

Neutrophil Extracellular Traps Induce Organ Damage during Experimental and Clinical Sepsis

Risk of deep vein thrombosis and pulmonary embolism after acute infection in a community setting.

Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study.

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