Enhanced platelet reactivity and thrombosis in Apoe-/- mice exposed to cigarette smoke is attenuated by P2Y12 antagonism

Thromb Res. 2010 Oct;126(4):e312-7. doi: 10.1016/j.thromres.2010.03.010. Epub 2010 May 10.


Introduction: Smoking increases the risk of acute arterial thrombosis, including myocardial infarction, likely due to multi-factorial effects on the vasculature. Heightened platelet reactivity may be among the adverse effects of smoke exposure.

Methods: To examine the effects of smoke exposure on platelet function in an atherosclerotic environment, Apoe-deficient female mice, maintained on a Western diet, were exposed (4 hrs/d, 5 d/wk) to sidestream cigarette smoke in a whole-body exposure chamber for 12 weeks. A separate group of wild type C57BL/6J mice were also exposed to smoke in an identical fashion.

Results: In comparison to control Apoe-/- mice exposed to filtered ambient air, smoke-exposed Apoe-/- mice displayed a 1.8±0.3 fold enhanced ADP-induced fibrinogen binding ex vivo (P<0.001) and had a shorter time to thrombotic occlusion following ferric chloride injury of the carotid artery (median time to thrombosis of 8 vs. 13 min; P=0.015). Administration of the direct-acting P2Y12 antagonist cangrelor blunted ex vivo fibrinogen binding and attenuated thrombosis (median time 20 min) in Apoe-/- mice exposed to sidestream smoke. The effects of smoke exposure required a proatherosclerotic background, as wild-type C57Bl/6J mice exposed to smoke displayed similar fibrinogen binding and thrombotic occlusion times as did control mice.

Conclusions: Our results demonstrate that exposure to smoke heightens platelet reactivity and thrombosis in Apoe-/- mice and implicate signaling through platelet P2Y12 receptor as a mediator of the adverse consequence of smoke exposure. These results may partially explain the recent observations that smokers derive greater clinical benefit from the P2Y12 antagonist clopidogrel than do non-smokers.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Monophosphate / analogs & derivatives
  • Adenosine Monophosphate / pharmacology
  • Animals
  • Apolipoproteins E / genetics*
  • Apolipoproteins E / metabolism
  • Blood Platelets / metabolism*
  • Chlorides
  • Female
  • Ferric Compounds
  • Fibrinogen / metabolism
  • Gene Deletion
  • Mice
  • Mice, Inbred C57BL
  • Purinergic P2Y Receptor Antagonists / pharmacology
  • Receptors, Purinergic P2Y12 / metabolism*
  • Thrombosis / chemically induced
  • Thrombosis / etiology*
  • Tobacco Smoke Pollution / adverse effects*


  • Apolipoproteins E
  • Chlorides
  • Ferric Compounds
  • P2ry12 protein, mouse
  • Purinergic P2Y Receptor Antagonists
  • Receptors, Purinergic P2Y12
  • Tobacco Smoke Pollution
  • Adenosine Monophosphate
  • cangrelor
  • Fibrinogen
  • ferric chloride