Intracoronary shear-related up-regulation of platelet P-selectin and platelet-monocyte aggregation despite the use of aspirin and clopidogrel.
Recent in vitro studies have shown that shear stress can cause platelet activation by agonist-independent pathways. However, no studies have assessed the extent of shear-induced platelet activation within human coronary arteries. We sampled blood from the coronary arteries proximal and distal to coronary lesions and from the coronary sinus in humans with stable coronary disease who were taking both aspirin and clopidogrel. A novel, computationally based technique for estimating shear stress from 3-dimensional coronary angiographic images of these arteries was developed, and the effect of stenosis severity and calculated shear stress on in vivo platelet and related leukocyte activation pathways were determined. We provide evidence of intracoronary up-regulation of platelet P-selectin, platelet-monocyte aggregation, and monocyte CD11b without platelet glycoprotein IIb-IIIa activation or soluble P-selectin up-regulation. This correlates with intracoronary stenosis severity and calculated shear stress and occurs despite the concurrent use of aspirin and clopidogrel. Our results show for the first time shear-related platelet and monocyte activation in human coronary arteries and suggest this as a potential therapeutic target that is resistant to conventional antiplatelet agents.
Yong
Andy S C
AS
ANZAC Research Institute, University of Sydney, Sydney, Australia.
Pennings
Gabrielle J
GJ
Chang
Michael
M
Hamzah
Afiqah
A
Chung
Tommy
T
Qi
Miao
M
Brieger
David
D
Behnia
Masud
M
Krilis
Steven A
SA
Ng
Martin K C
MK
Lowe
Harry C
HC
Kritharides
Leonard
L
D000368:Aged; D001241:Aspirin / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D023921:Coronary Stenosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D005434:Flow Cytometry; D006801:Humans; D007962:Leukocytes / Q000187:drug effects / Q000473:pathology; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019007:P-Selectin / Q000378:metabolism*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015854:Up-Regulation
D039481:CD11b Antigen; C509295:ITGAM protein, human; D019007:P-Selectin; D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin