Differential involvement of the P2Y1 and P2Y12 receptors in platelet procoagulant activity

被引:106
作者
Léon, C [1 ]
Ravanat, C [1 ]
Freund, M [1 ]
Cazenave, JP [1 ]
Gachet, C [1 ]
机构
[1] EFS Alsace, INSERM, U311, F-67065 Strasbourg, France
关键词
P2; receptor; ADP; thrombin generation; thrombosis; platelets;
D O I
10.1161/01.ATV.0000092127.16125.E6
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective - In vivo, activated platelets contribute to the initiation of thrombin generation through the exposure of phosphatidylserine to form a procoagulant catalytic surface and through platelet - leukocyte interactions, which lead to the exposure of leukocyte tissue factor (TF). On the basis of observations that the platelet P2Y(1) and P2Y(12) receptors both contribute to thrombosis and thrombin formation in an in vivo model of TF-induced thromboembolism, we further characterized the role of these receptors in thrombin generation. Methods and Results - By using the selective P2 antagonists MRS2179 and AR-C69931MX, the P2Y(12) receptor was found to be involved in thrombin-induced exposure of PS on isolated platelets and consequently in TF-induced thrombin formation in platelet-rich plasma. By contrast, the P2Y1 receptor was not involved in phosphatidylserine exposure nor in thrombin generation in platelet-rich plasma. In addition, both receptors were found to contribute to the interactions between platelets and leukocytes mediated by platelet P-selectin exposure, which result in TF exposure at the surface of leukocytes. Conclusions - Overall, these results point to a differential involvement of the 2 platelet ADP receptors in the generation of thrombin and provide further evidence for the relevance of molecules targeting these receptors as antithrombotic agents.
引用
收藏
页码:1941 / 1947
页数:7
相关论文
共 36 条
[1]   In vivo demonstration of an antithrombin effect of Abciximab [J].
Ambrose, JA ;
Hawkey, M ;
Badimon, JJ ;
Coppola, J ;
Geagea, JP ;
Rentrop, KP ;
Domiguez, A ;
Duvvuri, S ;
Elmquist, T ;
Arias, J ;
Doss, R ;
Dangas, G .
AMERICAN JOURNAL OF CARDIOLOGY, 2000, 86 (02) :150-152
[2]  
Amirkhosravi A, 1996, THROMB HAEMOSTASIS, V75, P87
[3]   Scientific and therapeutic advances in antiplatelet therapy [J].
Bhatt, DL ;
Topol, EJ .
NATURE REVIEWS DRUG DISCOVERY, 2003, 2 (01) :15-28
[4]   Alternatively spliced human tissue factor: a circulating, soluble, thrombogenic protein [J].
Bogdanov, VY ;
Balasubramanian, V ;
Hathcock, J ;
Vele, O ;
Lieb, M ;
Nemerson, Y .
NATURE MEDICINE, 2003, 9 (04) :458-462
[5]   Antiplatelet agents in tissue factor-induced blood coagulation [J].
Butenas, S ;
Cawthern, KM ;
van't Veer, C ;
DiLorenzo, ME ;
Lock, JB ;
Mann, KG .
BLOOD, 2001, 97 (08) :2314-2322
[6]  
CAZENAVE JP, 1983, ANN BIOL CLIN-PARIS, V41, P167
[7]   P-SELECTIN INDUCES THE EXPRESSION OF TISSUE FACTOR ON MONOCYTES [J].
CELI, A ;
PELLEGRINI, G ;
LORENZET, R ;
DEBLASI, A ;
READY, N ;
FURIE, BC ;
FURIE, B .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (19) :8767-8771
[8]  
Chattaraj S C, 2001, Curr Opin Investig Drugs, V2, P250
[9]   Administration of abciximab during percutaneous coronary intervention reduces both ex vivo platelet thrombus formation and fibrin deposition - Implications for a potential anticoagulant effect of abciximab [J].
Dangas, G ;
Badimon, JJ ;
Coller, BS ;
Fallon, JT ;
Sharma, SK ;
Hayes, RM ;
Meraj, P ;
Ambrose, JA ;
Marmur, JD .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 1998, 18 (08) :1342-1349
[10]  
DIMINNO G, 1983, J PHARMACOL EXP THER, V225, P57