title: 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(2)Y(12) plays a pivotal role in platelet activation. This experimental study tested P(2)Y(12) receptor blockade as an approach to protect platelets during ECC.
  
  
  METHODS
  Human blood was treated with the short-acting P(2)Y(12) blocker cangrelor (1 µM, t(1/2)<5 min) or the P(2)Y(12) 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 P(2)Y(12) blockade on platelet function was evaluated by cangrelor infusion (0.075 µg kg(-1) min(-1)).
  
  
  RESULTS
  During ex vivo hypothermic ECC, P(2)Y(12) 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
  P(2)Y(12) 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.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, University of Tübingen, Tübingen, Germany. krajewski@thg-lab.de
authors.forename: S
authors.initials: S
authors.lastname: Krajewski
authors.forename: J
authors.initials: J
authors.lastname: Kurz
authors.forename: B
authors.initials: B
authors.lastname: Neumann
authors.forename: T O
authors.initials: TO
authors.lastname: Greiner
authors.forename: A
authors.initials: A
authors.lastname: Stolz
authors.forename: B
authors.initials: B
authors.lastname: Balkau
authors.forename: K
authors.initials: K
authors.lastname: Peter
authors.forename: K
authors.initials: K
authors.lastname: Unertl
authors.forename: H P
authors.initials: HP
authors.lastname: Wendel
authors.forename: A
authors.initials: A
authors.lastname: Straub
mesh_terms: D000244:Adenosine Diphosphate / Q000097:blood; D000249:Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000990:Antithrombin III / Q000378:metabolism; D001778:Blood Coagulation Disorders / Q000517:prevention & control*; D001792:Blood Platelets / Q000187:drug effects* / Q000502:physiology; D002315:Cardiopulmonary Bypass; D003594:Cytoplasmic Granules / Q000187:drug effects; D005112:Extracorporeal Circulation; D006801:Humans; D007036:Hypothermia, Induced; D010447:Peptide Hydrolases / Q000378:metabolism; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000187:drug effects / Q000502:physiology; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000032:analysis; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology*; D013552:Swine
chemical_list: D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019038:Platelet Glycoprotein GPIb-IX Complex; D058921:Purinergic P2Y Receptor Antagonists; C046193:antithrombin III-protease complex; D000249:Adenosine Monophosphate; D000244:Adenosine Diphosphate; C117446:cangrelor; D000990:Antithrombin III; D010447:Peptide Hydrolases