A randomised trial on the effect of anti-platelet therapy on the systemic inflammatory response in human endotoxaemia

Summary

The use of acetylsalicylic acid (ASA) is associated with improved outcome in patients with sepsis, and P2Y₁₂ inhibitors have been suggested to also have immunomodulatory effects. Therefore, we evaluated the effects of clinically relevant combinations of antiplatelet therapy on the immune response in experimental endotoxaemia in humans in vivo. Forty healthy subjects were randomised to seven days of placebo, placebo with ASA, ticagrelor and ASA, or clopidogrel and ASA treatment. Systemic inflammation was elicited at day seven by intravenous administration of Escherichia coli endotoxin. ASA treatment profoundly augmented the plasma concentration of pro-inflammatory cytokines, but did not affect anti-inflammatory cytokines. Addition of either P2Y₁₂ antagonist to ASA did not affect any of the circulating cytokines, except for an attenuation of the ASA-induced increase in TNFα by ticagrelor. Systemic inflammation increased plasma adenosine, without differences between groups, and although P2Y₁₂ inhibition impaired platelet reactivity, there was no correlation with cytokine responses.

Note: This work was performed at the Radboud University Medical Center, Nijmegen, The Netherlands.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Acetylsalicylic acid - ticagrelor - clopidogrel - endotoxaemia - platelet inhibition

^* Shared last authorship.

• References

• 1 Blair P, Flaumenhaft R. Platelet alpha-granules: Basic biology and clinical correlates. Blood Rev 2009; 23: 177-189.
• 2 Semple JW, Italiano JE, Freedman J. Platelets and the immune continuum. Nat Rev Immunol 2011; 11: 264-274.
• 3 Sossdorf M, Otto GP, Boettel J. et al. Benefit of low-dose aspirin and non-steroidal anti-inflammatory drugs in septic patients. Crit Care 2013; 17: 402.
• 4 Eisen DP, Reid D, McBryde ES. Acetyl salicylic acid usage and mortality in critically ill patients with the systemic inflammatory response syndrome and sepsis. Crit Care Med 2012; 40: 1761-1767.
• 5 Otto GP, Sossdorf M, Boettel J. et al. Effects of low-dose acetylsalicylic acid and atherosclerotic vascular diseases on the outcome in patients with severe sepsis or septic shock. Platelets 2013; 24: 480-485.
• 6 Tsai M-J, Ou S-M, Shih C-J. et al. Association of prior antiplatelet agents with mortality in sepsis patients: a nationwide population-based cohort study. Intensive Care Med 2015; 41: 806-813.
• 7 Falcone M, Russo A, Farcomeni A. et al. Septic shock from community-onset pneumonia: is there a role for aspirin plus macrolides combination?. Intensive Care Med 2016; 42: 301-302.
• 8 Wiewel M, de Stoppelaar SF, van Vught L. et al. Chronic antiplatelet therapy is not associated with alterations in the presentation, outcome, or host response biomarkers during sepsis: a propensity-matched analysis. Intensive Care Med 2015; 42: 352-360.
• 9 Winning J, Reichel J, Eisenhut Y. et al. Anti-platelet drugs and outcome in severe infection: clinical impact and underlying mechanisms. Platelets 2009; 20: 50-57.
• 10 Falcone M, Russo A, Cangemi R. et al. Lower mortality rate in elderly patients with community-onset pneumonia on treatment with aspirin. J Am Heart Assoc 2015; 04: 1-10.
• 11 Antonino MJ, Mahla E, Bliden KP. et al. Effect of long-term clopidogrel treatment on platelet function and inflammation in patients undergoing coronary arterial stenting. Am J Cardiol 2009; 103: 1546-1550.
• 12 Patti G, Grieco D, Dicuonzo G. et al. High versus standard clopidogrel maintenance dose after percutaneous coronary intervention and effects on platelet inhibition, endothelial function, and inflammation results of the ARMYDA-150 mg (antiplatelet therapy for reduction of myocardial damage during angioplasty) randomized study. J Am Coll Cardiol 2011; 57: 771-778.
• 13 Gross a K, Dunn SP, Feola DJ. et al. Clopidogrel treatment and the incidence and severity of community acquired pneumonia in a cohort study and meta-analysis of antiplatelet therapy in pneumonia and critical illness. J Thromb Thrombolysis 2013; 35: 147-154.
• 14 Investigation O, Blasco-Colmenares E, Perl TM. et al. Aspirin plus clopidogrel and risk of infection after coronary artery bypass surgery. Arch Intern Med 2009; 169: 788-796.
• 15 Storey RF, James SK, Siegbahn A. et al. Lower mortality following pulmonary adverse events and sepsis with ticagrelor compared to clopidogrel in the PLATO study. Platelets 2014; 25: 517-525.
• 16 Bonaca MP, Bhatt DL, Cohen M. et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015; 372: 1791-1800.
• 17 Netea MMG, Puren AAJ, Dinarello Charles A. et al. A short course of oral aspirin increases IL-18 induced interferon-g production in whole blood cultures. Eur Cytokine Netw 2000; 11: 379-382.
• 18 Pernerstorfer T, Schmid R, Bieglmayer C. et al. Acetaminophen has greater antipyretic efficacy than aspirin in endotoxaemia : A controlled trial. Clin Pharmacol Ther 1999; 66: 51-57.
• 19 Spinas GA, Bloesch D, Keller U. et al. Pretreatment with Ibuprofen Augments Circulating Tumor Necrosis Factor-alpha, Interleukin-6, and Elastase during Acute Endotoxinemia. J Infect Dis 1991; 163: 89-95.
• 20 Martich GD, Danner RL, Ceska M. et al. Detection of Interleukin 8 and Tumor Necrosis Factor In Normal Humans after Intravenous Endotoxin: The Effect of Antiinflammatory Agents. J Exp Med 1991; 173: 1021-1024.
• 21 Tunjungputri RN, Van Der Ven AJ, Riksen N. et al. Differential effects of platelets and platelet inhibition by ticagrelor on TLR2 – and TLR4-mediated inflammatory responses. Thromb Haemost 2015; 1035-1045.
• 22 Thomas MR, Outteridge SN, Ajjan Ra. et al. Platelet P2Y12 Inhibitors Reduce Systemic Inflammation and Its Prothrombotic Effects in an Experimental Human Model. Arterioscler Thromb Vasc Biol 2015; 35: 2562-2570.
• 23 Ramakers BP, Pickkers P, Deussen A. et al. Measurement of the endogenous adenosine concentration in humans in vivo: methodological considerations. Curr Drug Metab 2008; 09: 679-685.
• 24 Arts RJW, Carvalho A, La Rocca C. et al. Immunometabolic Pathways in BCG-Induced Trained Immunity. Cell Rep 2016; 17: 2562-2571.
• 25 Eltzschig HK, Sitkovsky MV, Robson SC. Purinergic signaling during inflammation. N Engl J Med 2012; 367: 2322-2333.
• 26 van Giezen JJJ, Sidaway J, Glaves P. et al. Ticagrelor inhibits adenosine uptake in vitro and enhances adenosine-mediated hyperemia responses in a canine model. J Cardiovasc Pharmacol Ther 2012; 17: 164-172.
• 27 Osterod B, Olsen JO, Wilsgard L. Increased lipopolysaccharide-induced tissue factor activity and tumor necrosis factor production in monocytes after intake of aspirin: possible role of prostaglandin E2. Blood Coagul Fibrinolysis 1992; 03: 309-313.
• 28 Kharbanda RK. Prevention of Inflammation-Induced Endothelial Dysfunction: A Novel Vasculo-Protective Action of Aspirin. Circulation 2002; 105: 2600-2604.
• 29 Marcinkiewicz J. In vitro cytokine release by activated murine peritoneal macrophages: Role of prostaglandins in the differential regulation of tumor necrosis factor alpha, interleukin 1, and interleukin 6. Cytokine 1991; 03: 327-332.
• 30 Kunkel SL, Spengler M, May MA. et al. Prostaglandin E2 Regulates Macrophage-derived Tumor Necrosis Factor Gene Expression. J Biol Chem 1988; 263: 5380-5384.
• 31 McAdam BF, Mardini IA, Habib A. et al. Effect of regulated expression of human cyclooxygenase isoforms on eicosanoid and isoeicosanoid production in inflammation. J Clin Invest 2000; 105: 1473-1482.
• 32 Xiang B, Zhang G, Guo L. et al. Platelets protect from septic shock by inhibiting macrophage-dependent inflammation via the cyclooxygenase 1 signalling pathway. Nat Commun 2013; 04: 2657.
• 33 Garcia AE, Mada SR, Rico MC. et al. Clopidogrel, a P2Y12 receptor antagonist, potentiates the inflammatory response in a rat model of peptidoglycan polysaccharide-induced arthritis. PLoS One 2011; 06: e26035.
• 34 Rahman M, Gustafsson D, Wang Y. et al. Ticagrelor reduces neutrophil recruitment and lung damage in abdominal sepsis. Platelets 2014; 25: 257-263.
• 35 Seidel M, Winning J, Claus Ra. et al. Beneficial effect of clopidogrel in a mouse model of polymicrobial sepsis. J Thromb Haemost 2009; 07: 1030-1032.
• 36 Watts AE, Ness SL, Divers TJ. et al. Effects of clopidogrel on horses with experimentally induced endotoxaemia. Am J Vet Res 2014; 75: 760-769.
• 37 Bonello L, Laine M, Kipson N. et al. Ticagrelor increases adenosine plasma concentration in patients with an acute coronary syndrome. J Am Coll Cardiol 2014; 63: 872-877.
• 38 Armstrong D, Summers C, Ewart L. et al. Characterisation of the adenosine pharmacology of ticagrelor reveals therapeutically relevant inhibition of equilibrative nucleoside transporter 1. J Cardiovasc Pharmacol Ther 2014; 19: 209-219.
• 39 van den Berg TNA, El Messaoudi S, Rongen Ga. et al. Ticagrelor Does Not Inhibit Adenosine Transport at Relevant Concentrations: A Randomised Cross-Over Study in Healthy Subjects In Vivo. PLoS One 2015; 10: e0137560
• 40 Chen W, Janz DR, Bastarache Ja. et al. Prehospital aspirin use is associated with reduced risk of acute respiratory distress syndrome in critically ill patients: a propensity-adjusted analysis. Crit Care Med 2015; 43: 801-807.
• 41 Kor DJ, Erlich J, Gong MN. et al. Association of prehospitalisation aspirin therapy and acute lung injury: results of a multicenter international observational study of at-risk patients. Crit Care Med 2011; 39: 2393-2400.
• 42 Al Harbi SA, Tamim HM, Al-Dorzi HM. et al. Association between aspirin therapy and the outcome in critically ill patients: a nested cohort study. BMC Pharmacol Toxicol 2016; 17: 5.
• 43 Netea M. Proinflammatory cytokines and sepsis syndrome: not enough, or too much of a good thing?. Trends Immunol 2003; 24: 254-258.
• 44 Leentjens J, Kox M, van der Hoeven JG. et al. Immunotherapy for the adjunctive treatment of sepsis: from immunosuppression to immunostimulation. Time for a paradigm change? Am J Respir Crit Care Med 2013; 187: 1287-1293.
• 45 Cohen J, Vincent J-L, Adhikari NKJ. et al. Sepsis: a roadmap for future research. Lancet Infect Dis Elsevier Ltd 2015; 15: 581-614.
• 46 Bernard GR, Wheeler AP, Russell JA. et al. The effects of ibuprofen on the physiology and survival of patients with sepsis. N Engl J Med 1997; 336: 912-918.
• 47 Memiş D, Karamanlioğlu B, Turan A. et al. Effects of lornoxicam on the physiology of severe sepsis. Crit Care 2004; 08: R474-482.
• 48 Furman MI, Benoit SE, Barnard MR. et al. Increased platelet reactivity and circulating monocyte-platelet aggregates in patients with stable coronary artery disease. J Am Coll Cardiol 1998; 31: 352-358.
• 49 Tunjungputri R, van der Heijden W, Urbanus R. et al. Gram-positive bacterial sepsis induces platelet reactivity and platelet-monocyte aggregation, in contrast to Gram-negative bacterial sepsis. Eur Congr Clin Microbiololgy Infect Dis 2016; EP00041.