Abstract 4013

Poster Board III-949

Anti-platelet therapy is a widely accepted treatment regimen for the management of patients with cardiovascular risks. In clinics, many patients with cardiovascular diseases are managed on a combination therapy with Aspirin and Clopidogrel. Aspirin, being a COX-1 inhibitor blocks thromboxane generation and Clopidogrel metabolite antagonizes the P2Y12 receptor (ADP receptor). Thus these drugs block the two most important platelet positive feedback mediators and prevent amplification of platelet responses. The molecular mechanism of P2Y12 receptor antagonism on impairment of serum thromboxane is not understood to-date. Understanding this mechanism will clarify the molecular effects of P2Y12 antagonists when aspirin is clinically contraindicated in patients.

Hypothesis

We hypothesized that P2Y12 antagonism would lead to a decrease in serum thromboxane generation. We tested our hypothesis by employing both pharmacological and molecular genetic approaches.

Methods and Results

Serum thromboxane levels are a cogent marker for platelet hyperreactivity. It is produced when thrombin, which is generated during coagulation cascades, acts on PAR receptors on platelets. Serum was collected from non-anticoagulated blood after clot formation, following which serum thromboxane levels were measured with ELISA. The serum thromboxane levels in mice dosed with clopidogrel (n=4) (30 mg/kg body weight) were inhibited 88.04% compared to untreated mice. In human blood treated with the active metabolites of clopidogrel (R138727) or prasugrel (R361015) (n=3) were inhibited by 83.7% and 95.1%, respectively, compared to untreated human serum (100%). We also evaluated serum thromboxane levels in P2Y receptor null mice (n=4). Where as serum thromboxane levels in P2Y1 null mice were similar to those in wild type littermates, those in the P2Y12 null mice were inhibited by 78.9%. Furthermore serum thromboxane levels in P2Y12 deficient patients previously described in France and Japan were reduced to 25.3% and 11.7%, respectively, compared to normal volunteers (100%). We had one patient who was only on clopidogrel whose serum thromboxane levels were inhibited by 92.1%, compared to normal volunteers. In a pilot study, we recruited healthy volunteers (n=6), who were given clopidogrel for a week. Serum thromboxane levels were measured before and after the administration of clopidogrel. On an average, the serum thromboxane levels in these volunteers were inhibited by 72.3% after receiving clopidogrel.

Conclusions

In conclusion, P2Y12 receptor antagonism alone could lead to decrease in serum thromboxane levels. Hence in future novel P2Y12 antagonists alone might offer better protection without an additional need for aspirin.

Disclosures:

No relevant conflicts of interest to declare.

Topics:
aspirin, combined modality therapy, receptors, purinergic p2y12, thromboxane, clopidogrel, antagonists, metabolites, antiplatelet agents, cardiovascular diseases, prasugrel

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2009 by The American Society of Hematology
2009
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