on January 23, 2003
Published online before print January 23, 2003, doi: 10.1161/01.ATV.0000057809.32354.22
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Submitted on December 3, 2002
Accepted on December 18, 2002
In Vivo Blockade of Platelet ADP Receptor P2Y12 Reduces Embolus and Thrombus Formation but Not Thrombus Stability
Miriam A. van Gestel ;
From the Departments of Physiology (M.A.v.G., V.V.T.H., R.S.R., M.G.A.o.E.), Biochemistry (J.W.M.H.), and Biophysics (D.W.S.), Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands, and the Department of Biomedical Engineering (D.W.S.), Eindhoven University of Technology, Eindhoven, the Netherlands.
* To whom correspondence should be addressed. E-mail: M.oudeEgbrink{at}fys.unimaas.nl.
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.
Methods and 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 µg · kg · 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.
Key words: vessel wall injury • in vivo thromboembolism • platelet activation • adenosine diphosphate • antithrombotic drugs
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