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Assessment of Individual Responses to antiplatelet therapy in cardiovascular disease: insights with short thrombelastography

Assessment of Individual Responses to antiplatelet therapy in cardiovascular disease: insights with short thrombelastography
Assessment of Individual Responses to antiplatelet therapy in cardiovascular disease: insights with short thrombelastography
The pivotal role of platelets in atherogenesis and thrombosis is well established. Consequently, suppression of platelet function with antiplatelet therapy (APT) is an important therapeutic target for the prevention of cardiovascular events in high-risk populations, particularly in patients treated with percutaneous coronary intervention (PCI). Based on various ex vivo platelet function assays (PFAs), studies have consistently shown heterogeneity in responses to APT. This is especially important given that platelet reactivity has been associated with both atherothrombotic events and bleeding complications at opposite ends of the spectrum. Personalised APT based on assessing individual responses has therefore emerged as a logical solution to the dilemma of optimising clinical outcomes in PCI and CVD, however this has yet to be proven. Furthermore, a number of important questions regarding the delivery of this strategy remain outstanding before it can be implemented in clinical practice.

The studies presented in this thesis have universally employed Short Thrombelastography (s-TEG) to: (i) determine whether VerifyNow, a point of care PFA, overestimates the functional effects of clopidogrel compared to s-TEG, based on the inclusion of prostaglandin E1 as agonist; (ii) to evaluate whether responses to APT remain stable over time following hospital discharge thereby obviating the need for serial testing; and (iii) to compare the antiplatelet and anticoagulant effects of unfractionated heparin and bivalirudin, two adjunctive anticoagulant agents used commonly in the setting of primary PCI. Furthermore, there is anecdotal evidence suggesting that arachidonic acid (AA), a substrate of the cyclooxygenase-1 (COX-1) pathway blocked by aspirin, can stimulate clotting via alternative pathway(s). We therefore sought to investigate potential COX-1-independent mechanisms for AA-mediated clotting in a population of patients undergoing major vascular surgery on aspirin.

Studies in this thesis raise concerns about the stability of responses to APT over time and highlight the importance of an accurate and reliable assay of platelet function for the successful implementation of a personalised APT strategy. Furthermore, they offer important mechanistic insights into the contrasting pharmacodynamic effects of anticoagulant agents commonly used as adjuncts in PCI. Collectively, these studies could form the basis of larger clinical trials that may influence how these agents are prescribed in the future.
University of Southampton
Khanna, Vikram
17b557ad-b071-4d1a-84dd-3ba58470cee0
Khanna, Vikram
17b557ad-b071-4d1a-84dd-3ba58470cee0
Curzen, Nicholas
70f3ea49-51b1-418f-8e56-8210aef1abf4
Englyst, Nicola
f84399af-7265-4224-b556-102c3aa272b0

Khanna, Vikram (2016) Assessment of Individual Responses to antiplatelet therapy in cardiovascular disease: insights with short thrombelastography. University of Southampton, Doctoral Thesis, 288pp.

Record type: Thesis (Doctoral)

Abstract

The pivotal role of platelets in atherogenesis and thrombosis is well established. Consequently, suppression of platelet function with antiplatelet therapy (APT) is an important therapeutic target for the prevention of cardiovascular events in high-risk populations, particularly in patients treated with percutaneous coronary intervention (PCI). Based on various ex vivo platelet function assays (PFAs), studies have consistently shown heterogeneity in responses to APT. This is especially important given that platelet reactivity has been associated with both atherothrombotic events and bleeding complications at opposite ends of the spectrum. Personalised APT based on assessing individual responses has therefore emerged as a logical solution to the dilemma of optimising clinical outcomes in PCI and CVD, however this has yet to be proven. Furthermore, a number of important questions regarding the delivery of this strategy remain outstanding before it can be implemented in clinical practice.

The studies presented in this thesis have universally employed Short Thrombelastography (s-TEG) to: (i) determine whether VerifyNow, a point of care PFA, overestimates the functional effects of clopidogrel compared to s-TEG, based on the inclusion of prostaglandin E1 as agonist; (ii) to evaluate whether responses to APT remain stable over time following hospital discharge thereby obviating the need for serial testing; and (iii) to compare the antiplatelet and anticoagulant effects of unfractionated heparin and bivalirudin, two adjunctive anticoagulant agents used commonly in the setting of primary PCI. Furthermore, there is anecdotal evidence suggesting that arachidonic acid (AA), a substrate of the cyclooxygenase-1 (COX-1) pathway blocked by aspirin, can stimulate clotting via alternative pathway(s). We therefore sought to investigate potential COX-1-independent mechanisms for AA-mediated clotting in a population of patients undergoing major vascular surgery on aspirin.

Studies in this thesis raise concerns about the stability of responses to APT over time and highlight the importance of an accurate and reliable assay of platelet function for the successful implementation of a personalised APT strategy. Furthermore, they offer important mechanistic insights into the contrasting pharmacodynamic effects of anticoagulant agents commonly used as adjuncts in PCI. Collectively, these studies could form the basis of larger clinical trials that may influence how these agents are prescribed in the future.

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Vikram Khanna Thesis - Version of Record
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Published date: April 2016

Identifiers

Local EPrints ID: 415504
URI: http://eprints.soton.ac.uk/id/eprint/415504
PURE UUID: 3323a9dc-8143-415e-8e0a-2488c028e7ec
ORCID for Nicholas Curzen: ORCID iD orcid.org/0000-0001-9651-7829
ORCID for Nicola Englyst: ORCID iD orcid.org/0000-0003-0508-8323

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Date deposited: 13 Nov 2017 17:30
Last modified: 18 Feb 2021 17:04

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Contributors

Author: Vikram Khanna
Thesis advisor: Nicholas Curzen ORCID iD
Thesis advisor: Nicola Englyst ORCID iD

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