OC 51.1 - Direct oral anticoagulants cause placental vascular abnormalities and epigenetic reprogramming in placenta and the offspring

Tuesday, July 12, 2022

10:45 AM – 11:00 AM

Location: ExCel Center, S11A

Presentation Format: In-Person

Co-Author(s)

KS

Kunal Singh

PhD student
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University hospital Leipzig, Leipzig, Germany
Leipzig, Sachsen, Germany
AG

Anubhuti Gupta

PhD student
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University hospital Leipzig, Leipzig, Germany
Leipzig, Sachsen, Germany
RY

Ruaa Younis

PhD student
Institute for Laboratory Medicine, Leipzig University
Leipzig, Sachsen, Germany
HM

Han Mai

PhD student
Institute for Laboratory Medicine, Leipzig University
Leipzig, Sachsen, Germany
Khurrum Shahzad

Group leader
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University hospital Leipzig, Leipzig, Germany
Leipzig, Sachsen, Germany
Berend Isermann, PhD MD

Institute director
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University hospital Leipzig, Leipzig, Germany
Leipzig, Sachsen, Germany

Presenting Author(s)

SK

Shrey Kohli, PhD

Group leader
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University hospital Leipzig, Leipzig, Germany
Leipzig, Sachsen, Germany

Background: 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.

Aims: We aim to study whether DOAC exposure during pregnancy impairs placental function and may have long-lasting effects in the offspring.

Methods: 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 incude 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.

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 kidney showed dysregulated epigenetic marks suggesting that fIIai, which can cross the placenta, can epigenetically re-program the offspring.

Conclusion(s): 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.