L. Hu (1), Z. Fan (2), H. Du (3), R. Ni (4), S. Zhang (1), K. Yin (1), J. Ye (1), Y. Zhang (1), X. Wei (2), X. Zhang (5), P. L. Gross (4), S. P. Kunapuli (6), Z. Ding (1)
(1) Key Laboratory of Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China; (2) Department of Chemistry, and Institutes of Biomedical Sciences, Fudan University, Shanghai, China; (3) College of Science, Beijing University of Chemical Technology, Beijing, China; (4) Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada; (5) Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; (6) Department of Physiology and the Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
The addition of phosphodiesterase (PDE) inhibitors has been reported to potentiate the antithrombotic effects of P2Y12 antagonists without increasing bleeding risk. In this study, we report that a potent antiplatelet agent, 2-ethylthio-6-phenethylaminoadenosine (BF061), inhibits platelet activation and thrombosis via P2Y12 antagonism and PDE inhibition. We explored the antiplatelet mechanism of BF061 by measuring cAMP, cGMP levels, PDE activity, and the interaction between ADP and P2Y12 using atomic force microscopy. The antithrombotic effect of BF061 was evaluated in mice using intravital microscopy in FeCl3-induced mesenteric and laser-induced cremasteric arterial thrombosis models. BF061 robustly inhibited platelet aggregation and ATP release induced by multiple platelet agonists via P2Y12 antagonism and PDE inhibition. Interestingly, despite being structurally similar to BF061, P2Y12 receptor antagonist AR-C69931MX had no effect on human platelet PDE. In FeCl3-induced mesenteric arterial thrombosis model, BF061 effectively prevented thrombus formation similarly to clopidogrel; it also reduced thrombus volume in laser-injured cremaster arteriole model. In contrast, BF061 induced dramatically less bleeding at an antithrombotic dose compared to clopidogrel. In summary, we developed a novel antiplatelet and antithrombotic agent targeting both P2Y12 and PDE. Given the prevalence of combined antiplatelet therapy in clinical practice, an antiplatelet agent bearing dual activities may have therapeutic advantage as a potential antithrombotic drug.
Antithrombotic, Antiplatelet, BF061, PDE inhibitor, P2Y12 receptor antagonist
Roberto J. C. Fonseca1, Stephan-Nicollas M. C. G. Oliveira1, Fábio R. Melo1, Maria G. Pereira2, Norma M. B. Benevides2, Paulo A. S. Mourão1
Thromb Haemost 2008 99 3: 539-545
Alexandre Fontayne1, Muriel Meiring2, Seb Lamprecht2, Jan Roodt2, Eddy Demarsin3, Philippe Barbeaux3, Hans Deckmyn1
Thromb Haemost 2008 100 4: 670-677
Alexandre Fontayne 1, Karen Vanhoorelbeke 1, Inge Pareyn 1, Isabel Van Rompaey 2, Muriel Meiring 3, Seb Lamprecht 3, Jan Roodt 3, Johan Desmet 4, Hans Deckmyn 1
Thromb Haemost 2006 96 11: 671-684
Patients receiving oral anticoagulants should be carefully managed to minimize the risk of bleeding...
Acquired haemophilia A (AHA) is a rare but often severe bleeding disorder caused by ...
Section III " Vitamin K antagonists in heart disease: Current status and perspectives" of...