Short-acting P2Y12 blockade to reduce platelet dysfunction and coagulopathy during experimental extracorporeal circulation and hypothermia

Abstract

Background. Extracorporeal circulation (ECC) and hypothermia are routinely used in cardiac surgery to maintain stable circulatory parameters and to increase the ischaemic tolerance of the patient. However, ECC and hypothermia cause platelet activation and dysfunction possibly followed by a devastating coagulopathy. Stimulation of the adenosinediphosphate (ADP) receptor P 2Y12 plays a pivotal role in platelet activation. This experimental study tested P2Y12 receptor blockade as an approach to protect platelets during ECC. Methods. Human blood was treated with the short-acting P2Y12 blocker cangrelor (1 μM, t 1/2<5 min) or the P2Y12 inhibitor 2-MeSAMP (100 μM) and circulated in an ex vivo ECC model at normothermia (37°C) and hypothermia (28°C). Before and after circulation, markers of platelet activation and of coagulation (thrombinantithrombin complex generation) were analysed. During hypothermic ECC in pigs, the effect of reversible P 2Y12 blockade on platelet function was evaluated by cangrelor infusion (0.075 μg kg-1 min-1). Results. During ex vivo hypothermic ECC, P2Y12 blockade inhibited platelet granule release (P<0.01), plateletgranulocyte binding (P<0.05), and platelet loss (P<0.001), whereas no effects on plateletECC binding, platelet CD42bα expression, glycoprotein IIb/IIIa activation, or thrombinantithrombin complex generation were observed. During hypothermic ECC in pigs, cangrelor inhibited plateletfibrinogen binding (P<0.05) and ADP-induced platelet aggregation (P<0.001). Platelet function was rapidly restored after termination of cangrelor infusion. Conclusions. P 2Y12 blockade by cangrelor prevents platelet activation during ECC and hypothermia. Owing to its short half-life, platelet inhibition can be well controlled, thus potentially reducing bleeding complications. This novel pharmacological strategy has the potential to reduce complications associated with ECC and hypothermia. © 2012 The Author. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.