Platelet function and response to low-dose aspirin in pregnancy

Navaratnam, K
(2017) Platelet function and response to low-dose aspirin in pregnancy. PhD thesis, University of Liverpool.

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Pre-eclampsia is a serious multisystem disorder unique to pregnant women and associated with significant maternal and perinatal morbidity and mortality worldwide. Despite the investment of decades of basic science and clinical research, the pathophysiology of pre-eclampsia has been incompletely illustrated. In low doses, the cyclooxygenase inhibitor and antiplatelet, aspirin, can redress the thromboxane/prostacyclin imbalance observed in pregnancies affected by pre-eclampsia. Low-dose aspirin is currently recommended for high risk pregnancies in many countries, despite affording only modest overall risk reduction. It has been demonstrated that aspirin-treated individuals experience variable antiplatelet and clinical effects, with ‘non-responders’ having a preponderance for adverse clinical outcomes. The aim of this research was to investigate whether aspirin non-responsiveness exists in pregnant women at high risk of pre-eclampsia and assess whether platelet response to aspirin relates to markers of placental function and/or adverse clinical outcomes. An additional aim was to conduct an unbiased genome-wide assessment of genetic factors which may influence an individual’s response to aspirin. This was made possible by first establishing reference ranges for cyclooxygenase-selective platelet function in pregnancy and developing nuclear magnetic resonance and liquid chromatography mass spectrometry protocols to detect aspirin metabolites and determine adherence. Women at high risk of pre-eclampsia, according to National Institute of Health and Care Excellence criteria, were assessed longitudinally for adherence and platelet function. With exact adherence assessments and cyclooxygenase-selective platelet function testing, aspirin non-responsiveness could not be identified. Additionally, there were no significant associations between platelet response to aspirin, markers of placental function, genetic factors and adverse clinical outcomes. However, a significant proportion of women exhibited variable response to low-dose aspirin, changing their response status throughout their pregnancies. This variable response strongly suggests suboptimal aspirin adherence and/or suboptimal dosing in this population. With the recent findings of increased reduction in the risk of pre-eclampsia with higher doses of aspirin, there is now a valuable opportunity to deepen our understanding of the pharmacokinetics and pharmacodynamics of aspirin in pregnancy. Advances in technology available for genomics and access to biobanked maternal DNA from high-quality, well-phenotyped cohorts provide a strong foundation from which to examine pre-eclampsia disease genomics.

Item Type: Thesis (PhD)
Divisions: Faculty of Health and Life Sciences > Faculty of Health and Life Sciences
Depositing User: Symplectic Admin
Date Deposited: 19 Dec 2017 10:36
Last Modified: 19 Jan 2023 06:53
DOI: 10.17638/03009774