Adrenaline Improves Platelet Reactivity in Ticagrelor-Treated Healthy Volunteers

Abstract

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.

Comparative In Vitro Study of Various α2-Adrenoreceptor Agonist Drugs for Ticagrelor Reversal

“…As expected, ADP decreased cAMP level compared with control (4 (3-15) vs. 114 (81-128) pmol/10 9 platelets) and ticagrelor-inhibited ADP-induced suppression of intracellular cAMP (131 (97-150) vs. 4 (3-15) pmol/10 9 platelets, Figure 4A). Combining ADP and either epinephrine, norepinephrine, or brimonidine in the presence of ticagrelor fully restored suppression of intracellular cAMP production, achieving the same level as obtained with ADP alone in the absence of ticagrelor (16 (9-17), 20 (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26), or 23 (17-24) pmol/10 9 platelets, respectively). Adding dexmedetomidine induced a moderate reduction in cAMP concentration compared with the combination of ADP and ticagrelor (61 (53-67) vs. 131 (97-150) pmol/10 9 platelets) whereas clonidine had only a faint effect (102 (88-104) vs. 131 (97-150) pmol/10 9 platelets).…”

“…So far studies performed with epinephrine are encouraging. Using a model of artery stenosis, Yao et al and Samama et al have reported in canines and pigs, respectively, that epinephrine infusion fully restored platelet thrombus formation abolished by clopidogrel [22,23] Singh et al recently confirmed that even low clinically-relevant doses of epinephrine infusion (0.15 µg/kg/min, leading to epinephrine concentration 20 nM) slightly improved platelet aggregation and clot formation in healthy volunteers receiving ticagrelor [24]. However, it is likely that higher epinephrine doses would be required to translate biological surrogates into clinically-relevant effects on bleeding control, exposing patients to hypertension and bleeding enhancement, and serious cerebral and cardiovascular adverse effects [25].…”

High-Dose Epinephrine Enhances Platelet Aggregation at the Expense of Procoagulant Activity

“…However, while most of the published studies investigated the aggregating endpoint of platelet activation 24,25,[32][33][34] or the ability of EPI to restore activation response of ticagrelor treated platelets, 32,35,36 to the best of our knowledge, only one publication 37 reported data on the role of EPI during the induction of the procoagulant activity of platelets.…”

Depression and Cardiovascular Disease: The Viewpoint of Platelets

“…In vivo infusion or in vitro exposure to EPI, enhances ADP-induced platelet aggregation and clot formation both in healthy subjects treated with ticagrelor and in ACS patients under acetylsalicylic acid and ticagrelor therapy [ 67 , 68 ] ( Table 1 ).…”

“…In vivo infusion or in vitro exposure to EPI, enhances ADP-induced platelet aggregation and clot formation both in healthy subjects treated with ticagrelor and in ACS patients under acetylsalicylic acid and ticagrelor therapy [67,68] (Table 1). Despite NE induces platelet activation by binding, like EPI, α2-adrenergic receptors, its action is two or three times less effective than EPI [52,60] (Table 1).…”