The Road to Low-Dose Aspirin Therapy for the Prevention of Preeclampsia Began with the Placenta

Abstract

The road to low-dose aspirin therapy for the prevention of preeclampsia began in the 1980s with the discovery that there was increased thromboxane and decreased prostacyclin production in placentas of preeclamptic women. At the time, low-dose aspirin therapy was being used to prevent recurrent myocardial infarction and other thrombotic events based on its ability to selectively inhibit thromboxane synthesis without affecting prostacyclin synthesis. With the discovery that thromboxane was increased in preeclamptic women, it was reasonable to evaluate whether low-dose aspirin would be effective for preeclampsia prevention. The first clinical trials were very promising, but then two large multi-center trials dampened enthusiasm until meta-analysis studies showed aspirin was effective, but with caveats. Low-dose aspirin was most effective when started <16 weeks of gestation and at doses >100 mg/day. It was effective in reducing preterm preeclampsia, but not term preeclampsia, and patient compliance and patient weight were important variables. Despite the effectiveness of low-dose aspirin therapy in correcting the placental imbalance between thromboxane and prostacyclin and reducing oxidative stress, some aspirin-treated women still develop preeclampsia. Alterations in placental sphingolipids and hydroxyeicosatetraenoic acids not affected by aspirin, but with biologic actions that could cause preeclampsia, may explain treatment failures. Consideration should be given to aspirin's effect on neutrophils and pregnancy-specific expression of protease-activated receptor 1, as well as additional mechanisms of action to prevent preeclampsia.

Keywords: eicosanoids; isoprostanes; low-dose aspirin; neutrophils; placenta; preeclampsia; prostacyclin; protease-activated receptor 1; sphingolipids; thromboxane.

Figure 1

Production of prostacyclin and thromboxane in normal and preeclamptic placentas.

Figure 2

Significant reduction in preeclampsia.

Figure 3

Modest reduction in preeclampsia.

Figure 4

Importance of compliance for low-dose aspirin therapy.

Figure 5

Placental production of cyclooxygenase metabolites and isoprostanes in women with severe preeclampsia receiving low-dose aspirin, * p < 0.05.

Figure 6

Mechanism for selective inhibition of placental thromboxane (TX) by low-dose aspirin (ASA). Prostacyclin (PGI2).

Figure 7

Mechanism for inhibition of isoprostanes by aspirin (ASA).

Figure 8

Increases in HETEs related to the development of preeclampsia, ** p < 0.01, *** p < 0.001.

Figure 9

Interconversion of sphingolipids. (DAG, diacylglycerol; PKC, protein kinase C).

Figure 10

Increases in sphingolipids related to the development of preeclampsia, * p < 0.05, ** p < 0.01.

Figure 11

Neutrophils (brown) in omental fat arteries.

Figure 12

Expression of PAR-1 in omental vessels.

Figure 13

Confocal images of TET2 and p65 immuno-fluorescence staining in neutrophils of normal pregnant women. Nuclear localization induced by protease treatment was prevented by inhibition of PAR-1. Images were taken with a Zeiss LSM 700 using x63 lens and then cropped.

Figure 14

TET2 in omental vessels (A–D).

Figure 15

Molecular mechanism for protease activation of pregnancy neutrophils.

Figure 16

Expression of PAR-1 in syncytiotrophoblasts and macrophages in the placenta (dark brown staining).

Figure 17

Clinical manifestations of preeclampsia that can be explained by protease activation of PAR-1.