Prostaglandin Control of Platelet Behaviour in Healthy and Hypertensive Pregnancy

Horn, Elizabeth Helen (1993) Prostaglandin Control of Platelet Behaviour in Healthy and Hypertensive Pregnancy. MD thesis, University of Glasgow.

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Platelet activation in vivo is a feature of normal pregnancy and occurs to a greater degree in pre-eclampsia, a hypertensive disorder of pregnancy. Furthermore, there is increasing evidence that platelet activation plays a key role in the pathophysiology of pre-eclampsia. Increased platelet reactivity in vitro has been previously reported in healthy pregnancy, but variable results have been obtained by different investigators conducting in vitro studies of platelet reactivity in pre-eclampsia. Platelet behaviour is controlled by a complex interaction of regulatory mechanisms, some of which promote and some of which inhibit platelet activation. Prostaglandins are involved in both stimulatory and inhibitory regulatory pathways. This thesis has examined platelet responses to inhibitory and pro- aggregatory prostaglandins in healthy pregnancy and pre-eclampsia, with an emphasis on the effects on platelets of inhibitory prostanoids. These studies have shown that during healthy pregnancy, platelets were less sensitive, compared with those from non pregnant women, to the inhibitory effects in vitro of a wide range of prostaglandins including prostacyclin, prostaglandin D2 and prostaglandin E1. This was associated with a reduction in accumulation in platelets of the inhibitory second messenger cyclic AMP, in response to these agents. The data presented are consistent with a reduction in platelet adenylate cyclase activity during healthy pregnancy. Longitudinal studies suggested changes in platelet cyclic AMP responses occurred early in the first trimester of pregnancy. Platelets from primigravid women with established pre-eclampsia showed reductions both in platelet sensitivity to the inhibitory effects of prostaglandins and in platelet cyclic AMP accumulation, of a similar degree to those demonstrated in platelets from healthy pregnant women. On the other hand, women with a previous history of pre-eclampsia, when studied longitudinally during a subsequent pregnancy, showed a more marked loss of platelet sensitivity to such prostaglandins, and this was accompanied by lower stimulated cyclic AMP levels compared with those in platelets from healthy pregnant women studied in parallel. In contrast with the loss of sensitivity to inhibitory prostaglandins, platelet aggregation was increased during healthy pregnancy, compared with that in non pregnant women, in response to an agonist at the thromboxane receptor (U46619). This was not due to enhanced endogenous thromboxane synthesis, as differences were maintained between pregnant and non pregnant women in the extent of U46619 induced aggregation in blood incubated with aspirin in vitro. Furthermore, platelet thromboxane B2 production was not increased during pregnancy, when measured either following spontaneous clotting of whole blood in vitro or in response to arachidonic acid in platelet rich plasma. It was therefore concluded that enhanced sensitivity of platelets to thromboxane is likely to contribute to increased reactivity of platelets in vitro, during pregnancy, particularly in response to weak agonists. The simultaneous reduction in platelet responses to inhibitory prostaglandins and increase in platelet sensitivity to pro-aggregatory prostaglandins are likely to interact to play a substantial role in platelet activation in vivo in healthy pregnancy. Further platelet activation in vivo in pre-eclampsia is readily explicable by the well established changes in balance of in vivo biosynthesis of pro-aggregatory and inhibitory prostanoids in pregnancy induced hypertension, on the background of physiological, pregnancy associated, alterations in responses to these prostaglandins which have been demonstrated in this thesis. Intrinsic differences in platelet behaviour in women at risk of preeclampsia, may, however, also promote in vivo platelet activation in this condition.

Item Type: Thesis (MD)
Qualification Level: Doctoral
Additional Information: Adviser: Peter Rubin
Keywords: Medicine, Obstetrics
Date of Award: 1993
Depositing User: Enlighten Team
Unique ID: glathesis:1993-74802
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 13 Nov 2019 15:58
Last Modified: 13 Nov 2019 15:58

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