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Feasibility and reproducibility of personalised antiplatelet therapy using short thrombelastography

Feasibility and reproducibility of personalised antiplatelet therapy using short thrombelastography
Feasibility and reproducibility of personalised antiplatelet therapy using short thrombelastography
This thesis is under permanent embargo and not available for download

Platelet activation and aggregation play a central role in atherothrombosis and, as a result, in the occurrence of cardiovascular disease (CVD). Inhibition of several pathways which lead to platelet activation has become the therapeutic target of antiplatelet therapy (APT). Therefore, APT has become a foundation of primary and secondary prevention in CVD. Routine APT after percutaneous coronary intervention (PCI) consists of aspirin in combination with a P2Y12 inhibitor. However, multiple studies to date have consistently shown variable individual response to these agents as determined by ex vivo platelet function tests (PFT). Furthermore, patients with high on treatment platelet reactivity (HTPR) are at enhanced risk of adverse, ischaemic events, including stent thrombosis (ST), and, by contrast, individuals with low on treatment platelet reactivity (LTPR) are at increased risk of bleeding. The consequences of a subtherapeutic response to APT are important. Considering a potential benefit of a therapeutic "sweet spot" for these agents which decreases the risk of thrombotic and haemorrhagic complications, it may be suboptimal that the assessment of individual responses to APT, is currently not performed routinely in clinical practice. Furthermore, providing personalised antiplatelet therapy based on results from point of care PFTs may have significant clinical benefits to patients. However, before this strategy could be implemented, several key questions remain outstanding.

The objectives of the studies presented in this thesis are as follows. Firstly, to investigate the inadequate response to various P2Y12 inhibitors and describe a case series of patients with HTPR to all three widely available APT agents. Secondly, to see if the response to aspirin vary in association with an intense model of "on/off" vascular inflammation and, in particular, to seek the evidence of an alternative, aspirin-independent pathway of AA- induced clotting. Thirdly, to validate a novel point of care (POC) PFT, called TEG 6s, using its predecessor, TEG 5000, as a reference. Finally, to investigate if short thrombelastography based on area under the curve at 15 minutes derived from TEG 6s is a viable and time saving option.

In chapter 3, I described three patients, who had experienced definite stent thrombosis and demonstrated HTPR on clopidgrel, prasugrel and ticagrelor, which may have important implications.
In chapter 4, I showed that blood clotting, varies during an acute vascular inflammation and that AA-induced platelet activation is modified despite effective aspirin activity at its primary pharmacological target. I also demonstrated, that AA- and ADP-mediated platelet reactivity dropped at initial stages post-surgery, but recovered at 3 months to higher levels than baseline. Finally, although AA-induced clotting showed dynamic variation, and thromboxane B2 levels were supressed throughout, there was no corresponding increase in the alternative AA-lipoxygenase metabolite, 12-HETE.
In chapter 5, I presented encouraging results and confirmed that TEG 6s possesses several key features which make it a potential tool that could be utilised in our daily clinical practice for monitoring individual responses to APT.
In the 6th chapter I showed that s-TEG 6s based on AUC15 is a viable and time-saving option.

The results of the studies described in this thesis highlight the ongoing importance of further research to establish APT in routine practice. Furthermore, the data offer insights into potential mechanisms of aspirin metabolism and provide an answer to a potential link between vascular inflammation and subsequent ischaemic events. Finally, these results present a new POC PFT, which has the potential to be utilised in a daily clinical practice. Collectively, these findings could act as a basis of large clinical trials, which may help to shape the future of APT in CVD.
University of Southampton
Olechowski, Bartosz, Marcin
b025b40b-f9fa-4b8e-8f57-310d47e57700
Olechowski, Bartosz, Marcin
b025b40b-f9fa-4b8e-8f57-310d47e57700
Curzen, Nicholas
70f3ea49-51b1-418f-8e56-8210aef1abf4

Olechowski, Bartosz, Marcin (2019) Feasibility and reproducibility of personalised antiplatelet therapy using short thrombelastography. University of Southampton, Doctoral Thesis, 357pp.

Record type: Thesis (Doctoral)

Abstract

This thesis is under permanent embargo and not available for download

Platelet activation and aggregation play a central role in atherothrombosis and, as a result, in the occurrence of cardiovascular disease (CVD). Inhibition of several pathways which lead to platelet activation has become the therapeutic target of antiplatelet therapy (APT). Therefore, APT has become a foundation of primary and secondary prevention in CVD. Routine APT after percutaneous coronary intervention (PCI) consists of aspirin in combination with a P2Y12 inhibitor. However, multiple studies to date have consistently shown variable individual response to these agents as determined by ex vivo platelet function tests (PFT). Furthermore, patients with high on treatment platelet reactivity (HTPR) are at enhanced risk of adverse, ischaemic events, including stent thrombosis (ST), and, by contrast, individuals with low on treatment platelet reactivity (LTPR) are at increased risk of bleeding. The consequences of a subtherapeutic response to APT are important. Considering a potential benefit of a therapeutic "sweet spot" for these agents which decreases the risk of thrombotic and haemorrhagic complications, it may be suboptimal that the assessment of individual responses to APT, is currently not performed routinely in clinical practice. Furthermore, providing personalised antiplatelet therapy based on results from point of care PFTs may have significant clinical benefits to patients. However, before this strategy could be implemented, several key questions remain outstanding.

The objectives of the studies presented in this thesis are as follows. Firstly, to investigate the inadequate response to various P2Y12 inhibitors and describe a case series of patients with HTPR to all three widely available APT agents. Secondly, to see if the response to aspirin vary in association with an intense model of "on/off" vascular inflammation and, in particular, to seek the evidence of an alternative, aspirin-independent pathway of AA- induced clotting. Thirdly, to validate a novel point of care (POC) PFT, called TEG 6s, using its predecessor, TEG 5000, as a reference. Finally, to investigate if short thrombelastography based on area under the curve at 15 minutes derived from TEG 6s is a viable and time saving option.

In chapter 3, I described three patients, who had experienced definite stent thrombosis and demonstrated HTPR on clopidgrel, prasugrel and ticagrelor, which may have important implications.
In chapter 4, I showed that blood clotting, varies during an acute vascular inflammation and that AA-induced platelet activation is modified despite effective aspirin activity at its primary pharmacological target. I also demonstrated, that AA- and ADP-mediated platelet reactivity dropped at initial stages post-surgery, but recovered at 3 months to higher levels than baseline. Finally, although AA-induced clotting showed dynamic variation, and thromboxane B2 levels were supressed throughout, there was no corresponding increase in the alternative AA-lipoxygenase metabolite, 12-HETE.
In chapter 5, I presented encouraging results and confirmed that TEG 6s possesses several key features which make it a potential tool that could be utilised in our daily clinical practice for monitoring individual responses to APT.
In the 6th chapter I showed that s-TEG 6s based on AUC15 is a viable and time-saving option.

The results of the studies described in this thesis highlight the ongoing importance of further research to establish APT in routine practice. Furthermore, the data offer insights into potential mechanisms of aspirin metabolism and provide an answer to a potential link between vascular inflammation and subsequent ischaemic events. Finally, these results present a new POC PFT, which has the potential to be utilised in a daily clinical practice. Collectively, these findings could act as a basis of large clinical trials, which may help to shape the future of APT in CVD.

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Published date: December 2019

Identifiers

Local EPrints ID: 449843
URI: http://eprints.soton.ac.uk/id/eprint/449843
PURE UUID: f7e77322-3ac2-49ea-8a5f-81f13ca02846
ORCID for Nicholas Curzen: ORCID iD orcid.org/0000-0001-9651-7829

Catalogue record

Date deposited: 22 Jun 2021 16:30
Last modified: 11 May 2024 01:40

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Contributors

Author: Bartosz, Marcin Olechowski
Thesis advisor: Nicholas Curzen ORCID iD

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