Experimental and Clinical Studies on Platelet Receptors in Cardiovascular Disease
Abstract: The crucial role of platelets in maintaining primary hemostais has been evident for a long time and there is now also mounting evidence for their involvement in inflammation. In combination with aspirin, inhibition of the platelet P2Y12 ADP receptor with clopidogrel has become a cornerstone in the antiplatelet in acute coronary syndromes. Recently, several studies have indicated that a considerable number of patients treated with clopidogrel show poor responsiveness to the drug. In this thesis we investigate possible variables explaining the mechanisms behind variation to clopidogrel. We also investigate the effects of a novel P2Y12 receptor antagonist, prasugrel, in comparison to clopidogrel. In the last paper we investigate the mechanisms behind platelet-endothelial cell interactions in a mouse model of arterial inflammation. To study platelet function we mainly used flow cytometry based techniques. We used real-time RT-PCR and quantitative western blots to study mRNA and protein expression levels in human platelets. To study platelet interactions in vivo in mice we used fluorescent intravital microscopy. We could confirm the expression of three P2 receptors in human platelets and exclude expression of additional P2 receptors. In hyperactive platelets from patients with peripheral arterial disease we could not detect increased P2 receptor expression as compared to healthy controls. In a subsequent study we could correlate decreased response to clopidogrel to increased protein expression of the P2Y12 receptor in patients with coronary artery disease. We could conclude that prasugrel inhibits several markers of platelet activation and the formation of platelet-leukocyte aggregates more efficiently than clopidogrel. Furthermore, in a moue model of arterial inflammation we found that P-selectin is responsible for a significant part of the platelet-leukocyte interactions. In conclusion, this thesis presents experimental and clinical knowledge to better understand aspects of existent antiplatelet treatments and the studies also provide inputs to the development of future treatment modalities.
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