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

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 P₂Y₁₂ 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 (thrombin–antithrombin complex generation) were analysed. During hypothermic ECC in pigs, the effect of reversible P₂Y₁₂ 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), platelet–granulocyte binding (P<0.05), and platelet loss (P<0.001), whereas no effects on platelet–ECC binding, platelet CD42bα expression, glycoprotein IIb/IIIa activation, or thrombin–antithrombin complex generation were observed. During hypothermic ECC in pigs, cangrelor inhibited platelet–fibrinogen binding (P<0.05) and ADP-induced platelet aggregation (P<0.001). Platelet function was rapidly restored after termination of cangrelor infusion.

Conclusions

P₂Y₁₂ 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.