Antagonism of P2Y12 reduces physiological thromboxane levels

• Published in: Platelets (Edinburgh) 2010-12, Vol.21 (8), p.604-609
• Main Authors: Bhavaraju, Kamala, Georgakis, Alexander, Jin, Jianguo, Kent Gartner, Theodore, Tomiyama, Yoshiaki, Nurden, Alan, Nurden, Paquita, Kunapuli, Satya P.
• Format: Article
• Language: English
• Subjects: adenosine diphosphate (ADP); Adenosine Diphosphate - metabolism; Adolescent; Adult; Animals; antagonists; aspirin; Blood Platelets - drug effects; Blood Platelets - metabolism; coronary artery disease; Female; Humans; Male; Mice; Mice, Knockout; Middle Aged; P2Y; Pilot Projects; Piperazines; Platelet Aggregation Inhibitors - pharmacology; Prasugrel Hydrochloride; protease activated receptors (PARs); Purinergic P2Y Receptor Antagonists - pharmacology; Receptors, Purinergic P2Y12 - genetics; Receptors, Purinergic P2Y12 - metabolism; Serum thromboxane; Thiophenes; Thromboxanes - blood; Ticlopidine - analogs & derivatives; Young Adult
• ISSN: 0953-7104; 1369-1635
• DOI: 10.3109/09537104.2010.511684

Antiplatelet therapy for the management of patients with cardiovascular risks often includes a combination therapy of aspirin and clopidogrel, acting through inhibition of thromboxane generation and blockade of Gi-coupled P2Y12 receptor, respectively. We hypothesized that ADP acting through P2Y12 regulates physiological thromboxane levels. The serum thromboxane levels in mice (n = 3) dosed with clopidogrel and prasugrel were decreased by 83.1 ± 5.3% and 94.26 ± 1.75% respectively compared to untreated mice. Pre-treatment of human blood (n = 3) ex vivo with active metabolites of clopidogrel or prasugrel led to a reduction in thromboxane levels to 16.3 ± 3.2% and 4.9 ± 0.8% respectively, compared to untreated human serum. We also evaluated serum thromboxane levels in P2Y receptor null mice (n = 4). Whereas serum thromboxane levels in P2Y1 null mice were similar to those in wild type littermates, those in the P2Y12 null mice were inhibited by 83.15 ± 3.8%. Finally, in a pilot study, serum thromboxane levels were reduced by 76.05 ± 8.41% in healthy human volunteers (n = 6) upon dosing with clopidogrel, compared to the levels before dosing. In conclusion, P2Y12 antagonism alone can decrease physiological thromboxane levels. Thus, this study could pave way the for newer/modified treatment regimens for the management of patients with thrombotic complications who are allergic or non-responsive to aspirin.