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Experimental and Clinical Studies on Platelet Receptors in Cardiovascular Disease

Braun, Oscar LU (2007) In Lund University Faculty of Medicine Doctoral Dissertation Series
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... (More)
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. (Less)
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author
supervisor
opponent
  • Professor Hjemdahl, Paul, Enheten för klinisk farmakologi, Institutionen för medicin, Karolinska Universitetssjukhuset
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Medicin (människa och djur), Medicine (human and vertebrates), inflammation, athersosclerosis, platelets, thrombosis, Cardiovascular system, Kardiovaskulära systemet
in
Lund University Faculty of Medicine Doctoral Dissertation Series
pages
125 pages
publisher
Cardiology
defense location
Segerfalksalen Wallenberg Neurocentrum Sölvegatan 19, Lund
defense date
2007-11-02 09:15:00
ISSN
1652-8220
ISBN
978-91-85897-15-5
language
English
LU publication?
yes
additional info
Lingwei Wang, Oscar Braun, Anna-Karin Wihlborg, Henrik Brogren, Sverker Jern and David Erlinge. 2003. Quantification of ADP and ATP receptor expression in human platelets. Journal of thrombosis and haemostasis, vol 1 pp 330-336. Blackwell Pub
Oscar Braun, Anita Jagroop, Lingwei Wang, Dimitri Mikhailidis, Geoffrey Burnstock and David Erlinge. 2005. Increased platelet purinergic sensitivity in peripheral arterial disease--a pilot study. Platelets, vol 16 pp 261-267. Taylor & Francis
Oscar Braun, Stefan Amisten, Anna-Karin Wihlborg, Karen Hunting, David Nilsson and David Erlinge. 2007. Residual platelet ADP reactivity after clopidogrel treatment is dependent on activation of both the unblocked P2Y1 and the P2Y12 receptor and is correlated with protein expression of P2Y12. Purinergic Signalling, vol 3 pp 195-201. Springer
Oscar Braun, Matilda Johnell, Christoph Varenhorst, Stefan James, John Brandt, Joe Jakubowski, Kenneth Winters, Lars Wallentin, David Erlinge and Agneta Siegbahn. . Greater inhibition of platelet activation and platelet-monocyte complex formation by prasugrel compared to clopidogrel in patients with stable coronary artery disease (manuscript)
Oscar Braun, Jan Slotta, Michael Menger, David Erlinge and Henrik Thorlacius. . Primary and secondary capture of platelets onto inflamed femoral artery endothelium is dependent on P-selectin and PSGL-1. (submitted)
id
d6383f4a-d3a3-4129-9b91-e6f5edb3a3d1 (old id 599101)
date added to LUP
2016-04-01 16:51:12
date last changed
2019-05-21 21:55:56
@phdthesis{d6383f4a-d3a3-4129-9b91-e6f5edb3a3d1,
  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.}},
  author       = {{Braun, Oscar}},
  isbn         = {{978-91-85897-15-5}},
  issn         = {{1652-8220}},
  keywords     = {{Medicin (människa och djur); Medicine (human and vertebrates); inflammation; athersosclerosis; platelets; thrombosis; Cardiovascular system; Kardiovaskulära systemet}},
  language     = {{eng}},
  publisher    = {{Cardiology}},
  school       = {{Lund University}},
  series       = {{Lund University Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{Experimental and Clinical Studies on Platelet Receptors in Cardiovascular Disease}},
  year         = {{2007}},
}