Abstract 2322: Mechanisms of Cold-Induced Platelet Dysfunction: P2Y12 Receptor Blockade Protects Platelets during Hypothermia as Employed in Clinical Settings
Hypothermia is employed in cardiac surgery to inhibit ischemia-related organ damage. However, hypothermia causes platelet dysfunction, which can result in deleterious bleeding as well as thrombotic complications. In an ex vivo flow chamber model and in a static spreading assay platelet function on different surfaces [collagen, von Willebrand factor (vWF), fibrinogen] was investigated at normothermia (37°C), hypothermia and after rewarming. ADP levels were determined with a bioluminometric assay. In vivo platelet thrombus formation in murine mesenteric arteries at 37°C and 28°C was examined with the FeCl3 thrombosis model via intravital microscopy, comparing thrombus size and thrombus stability. All data are given for hypothermia (18 –28°C) in comparison to values observed at 37°C. The following findings define hypothermia-associated mechanisms of haemostasis defects: Under ex vivo flow conditions, hypothermia reversibly inhibits platelet-collagen adhesion up to 15-fold (p < 0.001) as well as platelet-vWF adhesion 1.5-fold (p < 0.001). Hypothermia causes an irreversible platelet-spreading defect characterised by a 1.4-fold decrease (p < 0.001) of the platelet surface. Correlating with these ex vivo effects, tail-tip bleeding times are 1.9-fold prolonged in mice (p < 0.01). In contrast to the above, the following hypothermia-associated prothrombotic mechanisms could be defined: Platelet adhesion on fibrinogen under flow conditions is 2.2-fold increased (p < 0.001) indicating platelet receptor GP IIb/IIIa activation. At hypothermia, ADP degradation is 1.9-fold decreased (p < 0.0011), consecutively causing platelet activation. Platelet thrombi formed in vivo at hypothermia are 2.2-fold larger (p < 0.001) and dissagregate 5 times less (p < 0.001). Hypothermia-induced thrombus formation is reversed by in vivo administration of a platelet ADP receptor P2Y12 antagonist (2-MeSAMP). Platelet dysfunction at hypothermia is characterized by decreased haemostasis, which is mostly reversible on rewarming, in co-existence with a prothrombotic state. The latter clinically prominent problem may be preventable by pharmacological P2Y12 inhibition during cardiac surgery.