Direct oral anticoagulants cause placental vascular abnormalities and epigenetic reprogramming in placenta and the offspring

Introduction Direct oral anticoagulants (DOACs) are increasingly used as antithrombotic agents in non-pregnant individuals. Their use is discouraged in pregnancy due to their potential teratogenic effects. Several reports ask for better monitoring and reporting in cases of inadvertent DOAC use during pregnancy questioning whether DOACs may be safe to use during pregnancy. In the current study we aimed to study whether DOAC exposure during pregnancy impairs placental function and may have long-lasting effects in the offspring.

Method To study the effect of DOACs during pregnancy, mice received factor IIa inhibitor (fIIai, dabigatran) alone or in combination with procoagulant extracellular vesicles (EVs, to induce placental thrombo-inflammation). Placenta was evaluated for morphological alterations (H&E) and expression of trophoblast differentiation marker GCM-1. In vitro, trophoblast cells were treated with fIIai to study trophoblast differentiation and epigenetic regulation. Similarly, placenta, neonatal brain and kidney were studied for global epigenetic marks (DNMT1, HDAC3, H3K9me3, H3K9ac) using immunoblotting.[1] [2] [3] [4] [5]

Results EV-induced pregnancy loss was prevented by fIIai treatment. However, the embryos showed growth restriction suggesting embryopathy. fIIai treatment on days 9.5 and 11.5 post-coitus resulted in altered placental morphology at day 13.5 post-coitus reflecting persistent impaired placental vascularization. fIIai reduced GCM-1 expression and altered epigenetic marks in vitro and in vivo. Remarkably, even neonatal brains and kidneys showed dysregulated epigenetic marks suggesting that fIIai, which can cross the placenta, can epigenetically re-program the offspring.

Conclusion These results suggest that fIIai, while preventing thrombo-inflammatory effects during pregnancy, has severe consequences on placental and embryonic development. These effects may be partially epigenetically programmed and can persist in the offspring. This may affect the offspring health. Further mechanistic studies are required to evaluate whether these effects are thrombin dependent, the mechanism underlying the altered epigenetic marks and their relevance. In line with current recommendations these results warrant caution regarding the use of fIIai in pregnancy.

Publikationsverlauf

Artikel online veröffentlicht:
20. Februar 2023

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