Thromb Haemost 2019; 119(05): 735-743
DOI: 10.1055/s-0039-1683461
Cellular Haemostasis and Platelets
Georg Thieme Verlag KG Stuttgart · New York

Adrenaline Improves Platelet Reactivity in Ticagrelor-Treated Healthy Volunteers

Sukhi Singh
1  Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
,
Tor Damén
2  Department of Anaesthesiology and Intensive Care Medicine, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
3  Department of Cardiothoracic Anaesthesia and Intensive Care, Sahlgrenska University Hospital, Gothenburg, Sweden
,
Andreas Nygren
2  Department of Anaesthesiology and Intensive Care Medicine, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
3  Department of Cardiothoracic Anaesthesia and Intensive Care, Sahlgrenska University Hospital, Gothenburg, Sweden
,
Caroline Shams Hakimi
1  Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
,
Sofia Ramström
4  Cardiovascular Research Centre, School of Medical Sciences, Örebro University, Örebro, Sweden
5  Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
,
Mikael Dellborg
1  Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
,
Tomas L. Lindahl
5  Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
,
Camilla Hesse
6  Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
7  Regional Blood Bank, Sahlgrenska University Hospital, Gothenburg, Sweden
,
Anders Jeppsson
1  Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
8  Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden
› Author Affiliations
Funding 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.
Further Information

Publication History

08 December 2018

03 January 2019

Publication Date:
19 February 2019 (eFirst)

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.

Supplementary Material