Adrenaline Improves Platelet Reactivity in Ticagrelor-Treated Healthy VolunteersFunding This work was supported by the Swedish Heart and Lung Foundation (grant number 20150587 to A.J.) and the Västra Götaland Region (grant number ALFGBG-725131 to A.J.). The study sponsors had no influence on study design, analysis and interpretation of data, writing the paper or in the decision to submit the paper for publication.
08 December 2018
03 January 2019
19 February 2019 (eFirst)
Background Administration of agents that enhance platelet reactivity may reduce the perioperative bleeding risk in patients treated with the adenosine diphosphate (ADP)-receptor antagonist ticagrelor. Adrenaline potentiates ADP-induced aggregation and activation in blood samples from ticagrelor-treated patients, but it has not previously been evaluated in vivo.
Methods Ten healthy male subjects were included in an interventional study. A loading dose of ticagrelor (180 mg) was administered, followed 2 hours later by a gradually increased intravenous adrenaline infusion (0.01, 0.05, 0.10 and 0.15 µg/kg/min; 15 minutes at each step). Blood pressure, heart rate, platelet aggregation (impedance aggregometry), platelet activation (flow cytometry), clot formation (rotational thromboelastometry) and adrenaline plasma concentration were determined before and after ticagrelor administration and at the end of each adrenaline step.
Results Infusion of adrenaline increased ADP-induced aggregation at all doses above 0.01 µg/kg/min. The aggregation increased from median 17 (25−75th percentiles: 14−31) to 25 (21−34) aggregation units (p = 0.012) at 0.10 µg/kg/min. Adrenaline infusion also increased ADP-induced fibrinogen receptor activation (from 29 [22–35] to 46 [38−57%]) and P-selectin expression (from 3.7 [3.0−4.3] to 7.7 [4.7−8.6%]), both p = 0.012. Adrenaline infusion reduced clot formation time (97 [89−110] to 83 [76−90] seconds, p = 0.008) and increased maximum clot firmness (59 [57−60] to 62 [61−64] mm, p = 0.007).
Conclusion Infusion of adrenaline at clinically relevant doses improves in vivo platelet reactivity and clot formation in ticagrelor-treated subjects. Adrenaline could thus potentially be used to prevent perioperative bleeding complications in ticagrelor-treated patients. Studies in patients are necessary to determine the clinical importance of our observations.
Trial Registry Number ClinicalTrials.gov NCT03441412.
- 1 Wallentin L, Becker RC, Budaj A. , et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361 (11) 1045-1057
- 2 Hansson EC, Jidéus L, Åberg B. , et al. Coronary artery bypass grafting-related bleeding complications in patients treated with ticagrelor or clopidogrel: a nationwide study. Eur Heart J 2016; 37 (02) 189-197
- 3 Hansson EC, Shams Hakimi C, Åström-Olsson K. , et al. Effects of ex vivo platelet supplementation on platelet aggregability in blood samples from patients treated with acetylsalicylic acid, clopidogrel, or ticagrelor. Br J Anaesth 2014; 112 (03) 570-575
- 4 O'Connor SA, Amour J, Mercadier A. , et al; ACTION Study Group. Efficacy of ex vivo autologous and in vivo platelet transfusion in the reversal of P2Y12 inhibition by clopidogrel, prasugrel, and ticagrelor: the APTITUDE study. Circ Cardiovasc Interv 2015; 8 (11) e002786
- 5 Teng R, Carlson GF, Nylander S, Andersson TL. Effects of autologous platelet transfusion on platelet inhibition in ticagrelor-treated and clopidogrel-treated subjects. J Thromb Haemost 2016; 14 (12) 2342-2352
- 6 Valgimigli M, Bueno H, Byrne RA. , et al; ESC Scientific Document Group; ESC Committee for Practice Guidelines (CPG); ESC National Cardiac Societies. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the task force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2018; 39 (03) 213-260
- 7 Malm CJ, Hansson EC, Åkesson J. , et al. Preoperative platelet function predicts perioperative bleeding complications in ticagrelor-treated cardiac surgery patients: a prospective observational study. Br J Anaesth 2016; 117 (03) 309-315
- 8 Ranucci M, Colella D, Baryshnikova E, Di Dedda U. ; Surgical and Clinical Outcome Research (SCORE) Group. Effect of preoperative P2Y12 and thrombin platelet receptor inhibition on bleeding after cardiac surgery. Br J Anaesth 2014; 113 (06) 970-976
- 9 Mahla E, Prueller F, Farzi S. , et al. Does platelet reactivity predict bleeding in patients needing urgent coronary artery bypass grafting during dual antiplatelet therapy?. Ann Thorac Surg 2016; 102 (06) 2010-2017
- 10 Spalding A, Vaitkevicius H, Dill S, MacKenzie S, Schmaier A, Lockette W. Mechanism of epinephrine-induced platelet aggregation. Hypertension 1998; 31 (02) 603-607
- 11 Mills DC, Roberts GC. Effects of adrenaline on human blood platelets. J Physiol 1967; 193 (02) 443-453
- 12 Lasch P, Jakobs KH. Agonistic and antagonistic effects of various alpha-adrenergic agonists in human platelets. Naunyn Schmiedebergs Arch Pharmacol 1979; 306 (02) 119-125
- 13 Jakobs KH, Saur W, Schultz G. Characterization of alpha- and beta-adrenergic receptors linked to human platelet adenylate cyclase. Naunyn Schmiedebergs Arch Pharmacol 1978; 302 (03) 285-291
- 14 Jin J, Kunapuli SP. Coactivation of two different G protein-coupled receptors is essential for ADP-induced platelet aggregation. Proc Natl Acad Sci U S A 1998; 95 (14) 8070-8074
- 15 Woulfe D, Jiang H, Mortensen R, Yang J, Brass LF. Activation of Rap1B by G(i) family members in platelets. J Biol Chem 2002; 277 (26) 23382-23390
- 16 Daniel JL, Dangelmaier C, Jin J, Kim YB, Kunapuli SP. Role of intracellular signaling events in ADP-induced platelet aggregation. Thromb Haemost 1999; 82 (04) 1322-1326
- 17 Singh S, Malm CJ, Ramström S, Hesse C, Jeppsson A. Adrenaline enhances in vitro platelet activation and aggregation in blood samples from ticagrelor-treated patients. Res Pract Thromb Haemost 2018; 2 (04) 718-725
- 18 Wittfeldt A, Emanuelsson H, Brandrup-Wognsen G. , et al. Ticagrelor enhances adenosine-induced coronary vasodilatory responses in humans. J Am Coll Cardiol 2013; 61 (07) 723-727
- 19 Tóth O, Calatzis A, Penz S, Losonczy H, Siess W. Multiple electrode aggregometry: a new device to measure platelet aggregation in whole blood. Thromb Haemost 2006; 96 (06) 781-788
- 20 Shattil SJ, Hoxie JA, Cunningham M, Brass LF. Changes in the platelet membrane glycoprotein IIb.IIIa complex during platelet activation. J Biol Chem 1985; 260 (20) 11107-11114
- 21 Schmitz G, Rothe G, Ruf A. , et al. European Working Group on Clinical Cell Analysis: Consensus protocol for the flow cytometric characterisation of platelet function. Thromb Haemost 1998; 79 (05) 885-896
- 22 Lang T, Bauters A, Braun SL. , et al. Multi-centre investigation on reference ranges for ROTEM thromboelastometry. Blood Coagul Fibrinolysis 2005; 16 (04) 301-310
- 23 Scavone M, Femia EA, Caroppo V, Cattaneo M. Inhibition of the platelet P2Y12 receptor for adenosine diphosphate does not impair the capacity of platelet to synthesize thromboxane A2. Eur Heart J 2016; 37 (44) 3347-3356
- 24 Wallén NH, Goodall AH, Li N, Hjemdahl P. Activation of haemostasis by exercise, mental stress and adrenaline: effects on platelet sensitivity to thrombin and thrombin generation. Clin Sci (Lond) 1999; 97 (01) 27-35
- 25 Hollister AS, FitzGerald GA, Nadeau JH, Robertson D. Acute reduction in human platelet alpha 2-adrenoreceptor affinity for agonist by endogenous and exogenous catecholamines. J Clin Invest 1983; 72 (04) 1498-1505
- 26 Jones CR, Giembcyz M, Hamilton CA. , et al. Desensitization of platelet alpha 2-adrenoceptors after short term infusions of adrenoceptor agonist in man. Clin Sci (Lond) 1986; 70 (02) 147-153
- 27 Larsson PT, Hjemdahl P, Olsson G, Egberg N, Hornstra G. Altered platelet function during mental stress and adrenaline infusion in humans: evidence for an increased aggregability in vivo as measured by filtragometry. Clin Sci (Lond) 1989; 76 (04) 369-376
- 28 Kjeldsen SE, Weder AB, Egan B, Neubig R, Zweifler AJ, Julius S. Effect of circulating epinephrine on platelet function and hematocrit. Hypertension 1995; 25 (05) 1096-1105
- 29 Jin J, Daniel JL, Kunapuli SP. Molecular basis for ADP-induced platelet activation. II. The P2Y1 receptor mediates ADP-induced intracellular calcium mobilization and shape change in platelets. J Biol Chem 1998; 273 (04) 2030-2034
- 30 Hollopeter G, Jantzen HM, Vincent D. , et al. Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 2001; 409 (6817): 202-207
- 31 Zhang FL, Luo L, Gustafson E. , et al. ADP is the cognate ligand for the orphan G protein-coupled receptor SP1999. J Biol Chem 2001; 276 (11) 8608-8615
- 32 Savi P, Beauverger P, Labouret C. , et al. Role of P2Y1 purinoceptor in ADP-induced platelet activation. FEBS Lett 1998; 422 (03) 291-295
- 33 Foster CJ, Prosser DM, Agans JM. , et al. Molecular identification and characterization of the platelet ADP receptor targeted by thienopyridine antithrombotic drugs. J Clin Invest 2001; 107 (12) 1591-1598
- 34 Nylander S, Mattsson C, Ramström S, Lindahl TL. The relative importance of the ADP receptors, P2Y12 and P2Y1, in thrombin-induced platelet activation. Thromb Res 2003; 111 (1–2): 65-73
- 35 Wadenvik H, Kutti J. The effect of an adrenaline infusion on the splenic blood flow and intrasplenic platelet kinetics. Br J Haematol 1987; 67 (02) 187-192
- 36 Hanke AA, Roberg K, Monaca E. , et al. Impact of platelet count on results obtained from multiple electrode platelet aggregometry (Multiplate). Eur J Med Res 2010; 15 (05) 214-219
- 37 Ensinger H, Lindner KH, Dirks B, Kilian J, Grünert A, Ahnefeld FW. Adrenaline: relationship between infusion rate, plasma concentration, metabolic and haemodynamic effects in volunteers. Eur J Anaesthesiol 1992; 9 (06) 435-446
- 38 Jern C, Eriksson E, Tengborn L, Risberg B, Wadenvik H, Jern S. Changes of plasma coagulation and fibrinolysis in response to mental stress. Thromb Haemost 1989; 62 (02) 767-771
- 39 Melamed N, Yogev Y, Bouganim T, Altman E, Calatzis A, Glezerman M. The effect of menstrual cycle on platelet aggregation in reproductive-age women. Platelets 2010; 21 (05) 343-347
- 40 Grenegård M, Vretenbrant-Oberg K, Nylander M. , et al. The ATP-gated P2 × 1 receptor plays a pivotal role in activation of aspirin-treated platelets by thrombin and epinephrine. J Biol Chem 2008; 283 (27) 18493-18504