title: Evidence of platelet activation at medically used hypothermia and mechanistic data indicating ADP as a key mediator and therapeutic target.
abstract: OBJECTIVE
  Hypothermia is used in various clinical settings to inhibit ischemia-related organ damage. However, prothrombotic effects have been described as potential side effects. This study aimed to elucidate the mechanism of hypothermia-induced platelet activation and subsequent prothrombotic events and to develop preventative pharmacological strategies applicable during clinically used hypothermia.
  
  
  RESULTS
  Platelet function was investigated ex vivo and in vivo at clinically used hypothermia (28°C/18°C). Hypothermic mice demonstrated increased expression of platelet activation marker P-selectin, platelet-leukocyte aggregate formation, and thrombocytopenia. Intravital microscopy of FeCl(3)-injured murine mesenteric arteries revealed increased platelet thrombus formation with hypothermia. Ex vivo flow chamber experiments indicated increased platelet-fibrinogen adhesion under hypothermia. We show that hypothermia results in reduced ADP hydrolysis via reduction of CD39 (E-NTPDase1) activity, resulting in increased levels of ADP and subsequent augmented primary and secondary platelet activation. In vivo administration of ADP receptor P(2)Y(12) antagonists and recombinant soluble CD39 prevented hypothermia-induced thrombus formation and thrombocytopenia, respectively.
  
  
  CONCLUSIONS
  The platelet agonist ADP plays a key role in hypothermia-induced platelet activation. Inhibition of receptor binding or hydrolysis of ADP has the potential to protect platelets against hypothermia-induced activation. Our findings provide a rational basis for further evaluation of novel antithrombotic strategies in clinically applied hypothermia.
authors.affiliation: Atherothrombosis and Vascular Biology, Baker IDI Heart and Diabetes Institute, PO Box 6492 St Kilda Rd Central, Melbourne, Victoria 8008, Australia. anstraub@me.com
authors.forename: Andreas
authors.initials: A
authors.lastname: Straub
authors.forename: Stefanie
authors.initials: S
authors.lastname: Krajewski
authors.forename: Jan David
authors.initials: JD
authors.lastname: Hohmann
authors.forename: Erik
authors.initials: E
authors.lastname: Westein
authors.forename: Fu
authors.initials: F
authors.lastname: Jia
authors.forename: Nicole
authors.initials: N
authors.lastname: Bassler
authors.forename: Carly
authors.initials: C
authors.lastname: Selan
authors.forename: Julia
authors.initials: J
authors.lastname: Kurz
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Wendel
authors.forename: Shala
authors.initials: S
authors.lastname: Dezfouli
authors.forename: Yuping
authors.initials: Y
authors.lastname: Yuan
authors.forename: Harshal
authors.initials: H
authors.lastname: Nandurkar
authors.forename: Shaun
authors.initials: S
authors.lastname: Jackson
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hickey
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Peter
mesh_terms: D000244:Adenosine Diphosphate / Q000097:blood*; D000704:Analysis of Variance; D000818:Animals; D015703:Antigens, CD / Q000097:blood / Q000494:pharmacology; D001081:Apyrase / Q000097:blood / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006801:Humans; D006868:Hydrolysis; D007036:Hypothermia, Induced / Q000009:adverse effects; D007970:Leukopenia / Q000097:blood / Q000209:etiology; D008562:Membrane Glycoproteins / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D019007:P-Selectin / Q000097:blood; D015539:Platelet Activation / Q000187:drug effects*; D010973:Platelet Adhesiveness / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019038:Platelet Glycoprotein GPIb-IX Complex; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology; D058472:Receptors, Purinergic P2Y1 / Q000097:blood / Q000187:drug effects; D058925:Receptors, Purinergic P2Y12 / Q000097:blood / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D013921:Thrombocytopenia / Q000097:blood / Q000209:etiology; D013927:Thrombosis / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D005343:Fibrinolytic Agents; D008562:Membrane Glycoproteins; D019007:P-Selectin; D010975:Platelet Aggregation Inhibitors; D019038:Platelet Glycoprotein GPIb-IX Complex; D058921:Purinergic P2Y Receptor Antagonists; D058472:Receptors, Purinergic P2Y1; D058925:Receptors, Purinergic P2Y12; D011994:Recombinant Proteins; C094990:adhesion receptor; D014841:von Willebrand Factor; D000244:Adenosine Diphosphate; D005340:Fibrinogen; D001081:Apyrase; C067869:CD39 antigen