This Article Full Text Full Text (PDF) All Versions of this Article: 23/3/518    most recent 01.ATV.0000057809.32354.22v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by van Gestel, M. A. Articles by oude Egbrink, M. G.A. Search for Related Content PubMed PubMed Citation Articles by van Gestel, M. A. Articles by oude Egbrink, M. G.A. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB ADENOSINE 5'-PHOSPHATE CALCIUM COMPOUNDS CALCIUM, ELEMENTAL Related Collections Pacemaker Cardiovascular imaging agents/Techniques Smooth muscle proliferation and differentiation Pulmonary circulation and disease Other anticoagulants

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:518.)
© 2003 American Heart Association, Inc.

Thrombosis

In Vivo Blockade of Platelet ADP Receptor P2Y₁₂ Reduces Embolus and Thrombus Formation but Not Thrombus Stability

Miriam A. van Gestel; Johan W.M. Heemskerk; Dick W. Slaaf; Viviane V.T. Heijnen; Robert S. Reneman; Mirjam G.A. oude Egbrink

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.

Correspondence to M.G.A. oude Egbrink, Department of Physiology, Maastricht University, PO Box 616, 6200 MD Maastricht, Netherlands. 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

This article has been cited by other articles:

				D. A. Payne, C. I. Jones, P. D. Hayes, A. R. Naylor, and A. H. Goodall Therapeutic Benefit of Low-Dose Clopidogrel in Patients Undergoing Carotid Surgery Is Linked to Variability in the Platelet Adenosine Diphosphate Response and Patients' Weight Stroke, September 1, 2007; 38(9): 2464 - 2469. [Abstract] [Full Text] [PDF]

				W. A. Schumacher, J. S. Bostwick, M. L. Ogletree, A. B. Stewart, T. E. Steinbacher, J. Hua, L. A. Price, P. C. Wong, and R. P. Rehfuss Biomarker Optimization to Track the Antithrombotic and Hemostatic Effects of Clopidogrel in Rats J. Pharmacol. Exp. Ther., July 1, 2007; 322(1): 369 - 377. [Abstract] [Full Text] [PDF]

				J. M. E. M. Cosemans, I. C. A. Munnix, R. Wetzker, R. Heller, S. P. Jackson, and J. W. M. Heemskerk Continuous signaling via PI3K isoforms beta and {gamma} is required for platelet ADP receptor function in dynamic thrombus stabilization Blood, November 1, 2006; 108(9): 3045 - 3052. [Abstract] [Full Text] [PDF]

				R. T. Dorsam, S. Kim, S. Murugappan, S. Rachoor, H. Shankar, J. Jin, and S. P. Kunapuli Differential requirements for calcium and Src family kinases in platelet GPIIb/IIIa activation and thromboxane generation downstream of different G-protein pathways Blood, April 1, 2005; 105(7): 2749 - 2756. [Abstract] [Full Text] [PDF]