In vivo blockade of platelet ADP receptor P2Y12 reduces embolus and thrombus formation but not thrombus stability.
OBJECTIVE
ADP is a key platelet agonist in thromboembolism. One of the receptors involved in ADP-induced platelet activation is the P2Y12 receptor, which is a target for antithrombotic drugs.


RESULTS
Here, we present first evidence for a differential role of this receptor in thrombus and embolus formation in vivo. Anesthetized rabbits were treated with the selective P2Y12 antagonists AR-C69931 MX (3 microg x kg x min(-1) IV) or clopidogrel (25 mg/kg orally). Efficacy of these treatments was monitored by aggregation and thrombin generation measurements in blood samples ex vivo. Mesenteric arterioles were mechanically injured; thrombus growth and subsequent embolus formation were visualized by real-time intravital microscopy. AR-C69931 MX and clopidogrel significantly (P<0.05) reduced the total duration of embolization (by 52% and 36%, respectively), and fewer and smaller emboli were produced. The size of the initial thrombus was significantly reduced (P<0.005), but its stability was unaffected: plug formation was still effective.


CONCLUSIONS
These findings demonstrate that ADP and its P2Y12 receptor are involved in thrombus growth and especially in the formation of emboli on the downstream side of the initial thrombus. This may explain the beneficial effects of P2Y12 receptor antagonists in secondary prevention of ischemic events in patients with arterial thrombosis.
van Gestel
Miriam A
MA
Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
Heemskerk
Johan W M
JW
Slaaf
Dick W
DW
Heijnen
Viviane V T
VV
Reneman
Robert S
RS
oude Egbrink
Mirjam G A
MG
D000249:Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D000077144:Clopidogrel; D005260:Female; D008297:Male; D008565:Membrane Proteins; D015539:Platelet Activation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D058919:Purinergic P2 Receptor Antagonists; D011817:Rabbits; D058925:Receptors, Purinergic P2Y12; D013917:Thrombin / Q000096:biosynthesis; D013923:Thromboembolism / Q000188:drug therapy* / Q000378:metabolism*; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology
D008565:Membrane Proteins; D058919:Purinergic P2 Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D000249:Adenosine Monophosphate; C117446:cangrelor; D000077144:Clopidogrel; D013917:Thrombin; D013988:Ticlopidine; D002118:Calcium