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Platelet PAR1 receptor density-Correlation to platelet activation response and changes in exposure after platelet activation
Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.ORCID iD: 0000-0002-1920-3962
Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
Leicester Medical School University of Leicester, UK.
Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
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2008 (English)In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 121, no 5, 681-688 p.Article in journal (Refereed) Published
Abstract [en]

Introduction: A polymorphism (-14 A/T) affecting PAR1 expression on the platelet surface has recently been identified. A two-fold variation in receptor density, which correlated with the platelet response to PAR1-activating peptide (PAR1-AP), has been reported. Materials and methods: We used flow cytometry to measure the correlation between the number of PAR1 receptors and platelet activation. We also measured the changes in receptor exposure after platelet activation with PAR1-AP, ADP, PAR4-AP or a collagen-related peptide (CRP). Results: In our study, the PAR1 receptor number varied almost four-fold, from 547 to 2063 copies/platelet (mean ± S.D. 1276 ± 320, n = 70). The number of PAR1 receptors on resting platelets correlated to platelet fibrinogen binding and P-selectin expression following platelet activation with PAR1-AP (r2 = 0.30, p < 0.01 and r2 = 0.15, p < 0.05, respectively, n = 36). The correlation was not improved by exclusion of the ADP-component from the PAR1-AP-induced response. We found a trend, but no statistically significant differences in PAR1 receptor number and platelet reactivity between A/A individuals and T/A or T/T individuals. Ex vivo activation with PAR1-AP decreased PAR1 surface exposure to 71 ± 19% of the exposure on resting platelets (mean ± S.D., p < 0.01, n = 19), while activation by ADP, PAR4-AP or CRP significantly increased the exposure, to 151 ± 27%, 120 ± 21% and 138 ± 25%, respectively (n = 11, 11 and 10). Conclusions: This study shows a large variation in PAR1 receptor number in healthy individuals, a variation correlated to the platelet activation response. We found a significant reduction in PAR1 surface exposure after adding PAR1-AP, while activation with ADP, PAR4-AP or CRP increased the exposure.

Place, publisher, year, edition, pages
2008. Vol. 121, no 5, 681-688 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-43417DOI: 10.1016/j.thromres.2007.06.010Local ID: 73781OAI: oai:DiVA.org:liu-43417DiVA: diva2:264276
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13Bibliographically approved
In thesis
1. The role of platelet thrombin receptors PAR1 and PAR4 in platelet activation
Open this publication in new window or tab >>The role of platelet thrombin receptors PAR1 and PAR4 in platelet activation
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Platelets play a pivotal role in coagulation and haemostasis. Their most prominent task is to seal damaged blood vessels by the formation of a platelet plug at the damaged area. Once the injury is covered, platelets retract the coagulum to close the wound and allow the blood to flow freely in the vessel. Platelets are strongly activated by the essential enzyme thrombin, formed in the coagulation cascade. Activation of the platelet thrombin receptors PAR1 and PAR4 leads to shape change, secretion of granule content, and aggregation, all of which can be accomplished by each receptor individually. However more and more findings indicate that there are differences between the receptors and that they have different physiological functions.

This thesis presents studies performed to elucidate the relative role of PAR1 and PAR4 in platelet activation and coagulation.

We have studied the effects on platelet activation and coagulation, and revealed a possible physiological role for PAR4 in the stabilisation of the coagulum. We also investigated the relative role of PAR1 and PAR4 in the cross-talk between thrombin and epinephrine with and without inhibition of COX-1. We demonstrated that PAR4 interacts with adrenergic receptors and causes an aggregation of platelets dependent on released ATP and its receptor P2X1, thereby circumventing the inhibition by aspirin. Not only is this an interesting specific role for PAR4, but it may also be of clinical importance considering that COX-1 inhibition is the most common treatment for patients with cardiovascular disease to prevent thrombosis.

We show that the number of PAR1 receptors varied between donors and that this variation was correlated to the response on receptor activation. The number of PAR1 receptors on the platelet surface was decreased after PAR1 stimulation but increased after stimulation of other receptors.

In a final attempt to elucidate the nature of PAR1 and PAR4 we used mathematics to evaluate the effect of co-stimulation of the receptors. We found a strong synergistic effect for both platelet activation and aggregation. This indicates that PAR1 and PAR4 interact in a yet unknown way to regulate or amplify the effect of each other rather than merely transmitting the incoming signal the same way.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2009. 70 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1156
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-51935 (URN)978-91-7393-505-0 (ISBN)
Public defence
2009-12-04, Linden, Hälsouniversitetet, Campus US, Linköpings Universitet, Linköping, 13:00 (English)
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Available from: 2009-11-24 Created: 2009-11-24 Last updated: 2015-03-13Bibliographically approved

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Ramström, SofiaVretenbrant-Öberg, KarinEnström, CamillaLindahl, Tomas

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