Experimental and Clinical Studies on Platelet Receptors in Cardiovascular Disease

Oscar Braun

Experimental and Clinical Studies on Platelet Receptors in Cardiovascular Disease

Cardiology

Research output: Thesis › Doctoral Thesis (compilation)

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.

Original language	English
Qualification	Doctor
Awarding Institution	Cardiology
Supervisors/Advisors	Erlinge, David, Supervisor
Award date	2007 Nov 2
Publisher	Cardiology
ISBN (Print)	978-91-85897-15-5
Publication status	Published - 2007

Bibliographical note

Defence details

Date: 2007-11-02
Time: 09:15
Place: Segerfalksalen Wallenberg Neurocentrum Sölvegatan 19, Lund

External reviewer(s)

Name: Hjemdahl, Paul
Title: Professor
Affiliation: Enheten för klinisk farmakologi, Institutionen för medicin, Karolinska Universitetssjukhuset

---

<div class="article_info">Lingwei Wang, Oscar Braun, Anna-Karin Wihlborg, Henrik Brogren, Sverker Jern and David Erlinge. <span class="article_issue_date">2003</span>. <span class="article_title">Quantification of ADP and ATP receptor expression in human platelets.</span> <span class="journal_series_title">Journal of thrombosis and haemostasis</span>, <span class="journal_volume">vol 1</span> <span class="journal_pages">pp 330-336</span>. <span class="journal_distributor">Blackwell Pub</span></div>
<div class="article_info">Oscar Braun, Anita Jagroop, Lingwei Wang, Dimitri Mikhailidis, Geoffrey Burnstock and David Erlinge. <span class="article_issue_date">2005</span>. <span class="article_title">Increased platelet purinergic sensitivity in peripheral arterial disease--a pilot study.</span> <span class="journal_series_title">Platelets</span>, <span class="journal_volume">vol 16</span> <span class="journal_pages">pp 261-267</span>. <span class="journal_distributor">Taylor & Francis</span></div>
<div class="article_info">Oscar Braun, Stefan Amisten, Anna-Karin Wihlborg, Karen Hunting, David Nilsson and David Erlinge. <span class="article_issue_date">2007</span>. <span class="article_title">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.</span> <span class="journal_series_title">Purinergic Signalling</span>, <span class="journal_volume">vol 3</span> <span class="journal_pages">pp 195-201</span>. <span class="journal_distributor">Springer</span></div>
<div class="article_info">Oscar Braun, Matilda Johnell, Christoph Varenhorst, Stefan James, John Brandt, Joe Jakubowski, Kenneth Winters, Lars Wallentin, David Erlinge and Agneta Siegbahn. <span class="article_issue_date"></span>. <span class="article_title">Greater inhibition of platelet activation and platelet-monocyte complex formation by prasugrel compared to clopidogrel in patients with stable coronary artery disease</span> (manuscript)</div>
<div class="article_info">Oscar Braun, Jan Slotta, Michael Menger, David Erlinge and Henrik Thorlacius. <span class="article_issue_date"></span>. <span class="article_title">Primary and secondary capture of platelets onto inflamed femoral artery endothelium is dependent on P-selectin and PSGL-1.</span> (submitted)</div>

Subject classification (UKÄ)

Cardiology and Cardiovascular Disease

Free keywords

Medicin (människa och djur)
Medicine (human and vertebrates)
inflammation
athersosclerosis
platelets
thrombosis
Cardiovascular system
Kardiovaskulära systemet

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Cite this

@phdthesis{d6383f4ad3a341299b91e6f5edb3a3d1,

title = "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.",

keywords = "Medicin (m{\"a}nniska och djur), Medicine (human and vertebrates), inflammation, athersosclerosis, platelets, thrombosis, Cardiovascular system, Kardiovaskul{\"a}ra systemet",

author = "Oscar Braun",

note = "Defence details Date: 2007-11-02 Time: 09:15 Place: Segerfalksalen Wallenberg Neurocentrum S{\"o}lvegatan 19, Lund External reviewer(s) Name: Hjemdahl, Paul Title: Professor Affiliation: Enheten f{\"o}r klinisk farmakologi, Institutionen f{\"o}r medicin, Karolinska Universitetssjukhuset --- <div class={"}article_info{"}>Lingwei Wang, Oscar Braun, Anna-Karin Wihlborg, Henrik Brogren, Sverker Jern and David Erlinge. <span class={"}article_issue_date{"}>2003</span>. <span class={"}article_title{"}>Quantification of ADP and ATP receptor expression in human platelets.</span> <span class={"}journal_series_title{"}>Journal of thrombosis and haemostasis</span>, <span class={"}journal_volume{"}>vol 1</span> <span class={"}journal_pages{"}>pp 330-336</span>. <span class={"}journal_distributor{"}>Blackwell Pub</span></div> <div class={"}article_info{"}>Oscar Braun, Anita Jagroop, Lingwei Wang, Dimitri Mikhailidis, Geoffrey Burnstock and David Erlinge. <span class={"}article_issue_date{"}>2005</span>. <span class={"}article_title{"}>Increased platelet purinergic sensitivity in peripheral arterial disease--a pilot study.</span> <span class={"}journal_series_title{"}>Platelets</span>, <span class={"}journal_volume{"}>vol 16</span> <span class={"}journal_pages{"}>pp 261-267</span>. <span class={"}journal_distributor{"}>Taylor & Francis</span></div> <div class={"}article_info{"}>Oscar Braun, Stefan Amisten, Anna-Karin Wihlborg, Karen Hunting, David Nilsson and David Erlinge. <span class={"}article_issue_date{"}>2007</span>. <span class={"}article_title{"}>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.</span> <span class={"}journal_series_title{"}>Purinergic Signalling</span>, <span class={"}journal_volume{"}>vol 3</span> <span class={"}journal_pages{"}>pp 195-201</span>. <span class={"}journal_distributor{"}>Springer</span></div> <div class={"}article_info{"}>Oscar Braun, Matilda Johnell, Christoph Varenhorst, Stefan James, John Brandt, Joe Jakubowski, Kenneth Winters, Lars Wallentin, David Erlinge and Agneta Siegbahn. <span class={"}article_issue_date{"}></span>. <span class={"}article_title{"}>Greater inhibition of platelet activation and platelet-monocyte complex formation by prasugrel compared to clopidogrel in patients with stable coronary artery disease</span> (manuscript)</div> <div class={"}article_info{"}>Oscar Braun, Jan Slotta, Michael Menger, David Erlinge and Henrik Thorlacius. <span class={"}article_issue_date{"}></span>. <span class={"}article_title{"}>Primary and secondary capture of platelets onto inflamed femoral artery endothelium is dependent on P-selectin and PSGL-1.</span> (submitted)</div>",

year = "2007",

language = "English",

isbn = "978-91-85897-15-5",

series = "Lund University Faculty of Medicine Doctoral Dissertation Series ",

publisher = "Cardiology",

type = "Doctoral Thesis (compilation)",

school = "Cardiology",

}

TY - THES

T1 - Experimental and Clinical Studies on Platelet Receptors in Cardiovascular Disease

AU - Braun, Oscar

N1 - Defence details Date: 2007-11-02 Time: 09:15 Place: Segerfalksalen Wallenberg Neurocentrum Sölvegatan 19, Lund External reviewer(s) Name: Hjemdahl, Paul Title: Professor Affiliation: Enheten för klinisk farmakologi, Institutionen för medicin, Karolinska Universitetssjukhuset --- <div class="article_info">Lingwei Wang, Oscar Braun, Anna-Karin Wihlborg, Henrik Brogren, Sverker Jern and David Erlinge. <span class="article_issue_date">2003</span>. <span class="article_title">Quantification of ADP and ATP receptor expression in human platelets.</span> <span class="journal_series_title">Journal of thrombosis and haemostasis</span>, <span class="journal_volume">vol 1</span> <span class="journal_pages">pp 330-336</span>. <span class="journal_distributor">Blackwell Pub</span></div> <div class="article_info">Oscar Braun, Anita Jagroop, Lingwei Wang, Dimitri Mikhailidis, Geoffrey Burnstock and David Erlinge. <span class="article_issue_date">2005</span>. <span class="article_title">Increased platelet purinergic sensitivity in peripheral arterial disease--a pilot study.</span> <span class="journal_series_title">Platelets</span>, <span class="journal_volume">vol 16</span> <span class="journal_pages">pp 261-267</span>. <span class="journal_distributor">Taylor & Francis</span></div> <div class="article_info">Oscar Braun, Stefan Amisten, Anna-Karin Wihlborg, Karen Hunting, David Nilsson and David Erlinge. <span class="article_issue_date">2007</span>. <span class="article_title">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.</span> <span class="journal_series_title">Purinergic Signalling</span>, <span class="journal_volume">vol 3</span> <span class="journal_pages">pp 195-201</span>. <span class="journal_distributor">Springer</span></div> <div class="article_info">Oscar Braun, Matilda Johnell, Christoph Varenhorst, Stefan James, John Brandt, Joe Jakubowski, Kenneth Winters, Lars Wallentin, David Erlinge and Agneta Siegbahn. <span class="article_issue_date"></span>. <span class="article_title">Greater inhibition of platelet activation and platelet-monocyte complex formation by prasugrel compared to clopidogrel in patients with stable coronary artery disease</span> (manuscript)</div> <div class="article_info">Oscar Braun, Jan Slotta, Michael Menger, David Erlinge and Henrik Thorlacius. <span class="article_issue_date"></span>. <span class="article_title">Primary and secondary capture of platelets onto inflamed femoral artery endothelium is dependent on P-selectin and PSGL-1.</span> (submitted)</div>

PY - 2007

Y1 - 2007

N2 - 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.

AB - 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.

KW - Medicin (människa och djur)

KW - Medicine (human and vertebrates)

KW - inflammation

KW - athersosclerosis

KW - platelets

KW - thrombosis

KW - Cardiovascular system

KW - Kardiovaskulära systemet

M3 - Doctoral Thesis (compilation)

SN - 978-91-85897-15-5

T3 - Lund University Faculty of Medicine Doctoral Dissertation Series

PB - Cardiology

ER -

Experimental and Clinical Studies on Platelet Receptors in Cardiovascular Disease

Abstract

Bibliographical note

Subject classification (UKÄ)

Free keywords

UN SDGs

Fingerprint

Cite this