Objective: Hypothermia is employed in cardiac surgery to inhibit ischemia-related organ damage. However, hypothermia causes platelet activation and dysfunction, which can result in bleeding as well as thrombotic complications.
Methods: Platelet adhesion and spreading on different physiologically relevant surfaces was investigated at normothermia (37°C), hypothermia (18-28°C) and after rewarming under ex vivo flow and static conditions. In mice with body temperatures of 37°C and 28°C tail bleeding times were assessed and platelet aggregation in mesenteric arteries examined using intravital microscopy. Platelet agonist ADP levels and ADPase CD39 activity were determined using bioluminometry and thin layer chromatography.
Results: Bleeding times as well as platelet-collagen and platelet-vWF adhesion at physiological flow are reversibly prolonged by hypothermia. Furthermore, hypothermia causes a partially reversible platelet spreading defect.
In contrast, platelet thrombi formed in vivo at hypothermia are 2.2-fold larger (p<0.001) and dissagregate 5-fold less (p<0.001) compared to normothermia. This is paralleled by a 2.2-fold increase of platelet-fibrinogen adhesion (p<0.001).
Hypothermia reduces CD39-activity, subsequently impairing ADP degradation and increasing ADP-mediated platelet activation. Administration of platelet ADP receptor P2Y12 antagonists reverses hypothermia-induced platelet thrombus formation in vivo.
Conclusions: Most hypothermia induced platelet function-inhibiting effects are reversible on rewarming. Hypothermia-induced platelet activation can be explained by the observed reduction of CD39 ADP-metabolising activity. We present a novel concept of platelet protection against activation during hypothermia, which is based on P2Y12 inhibition. Because short-acting intravenously applicable P2Y12-blockers may soon be clinically available further clinical studies demonstrating the transferability of our concept into clinical practice are warranted.