Abstract Number: PB1823
Meeting: ISTH 2020 Congress
Background: Thrombomodulin (TM) deficiency causes platelet-mediated embryonic lethality in mice. Procoagulant extracellular vesicles (EVs) activate maternal platelets resulting in inflammasome activation in the trophoblast and preeclampsia (PE). We speculated that loss of trophoblast TM-expression unleashes platelet-dependent placental inflammasome activation, promoting embryonic lethality.
Aims: We investigated the interaction and functional relevance of EV-mediated thrombo-inflammation in placenta and placental thrombomodulin expression.
Methods: Inflammasome inhibition was conducted in TM-null placenta. Procoagulant EVs were injected into C57/Bl6 pregnant mice. Placental-TM expression and trophoblast proliferation was studied using immunoblotting and Ki-67 staining respectively. Differentiated mouse trophoblast stem cells were treated with EVs or IL-1β to study inflammasome associated loss of TM and proliferation. TM was restored in EV-injected pregnant mice using soluble TM (solulin) or transgenic TM expression to establish causality. Analysis of human PE placentae and trophoblast cells was conducted to scrutinize translational relevance.
Results: Genetic (NLRP3-/-) or pharmaceutical (anakinra) inflammasome inhibition did not rescue the TM-null embryos from lethality, establishing that the inflammasome activation does not cause lethality of TM-null embryos. However, treatment of mouse or human trophoblast cells with exogenous IL-1β reduced TM expression indicating that loss of TM is a consequence of inflammasome activation. Furthermore, EV treatment reduced TM expression and trophoblast proliferation in-vivo and in-vitro. Importantly, anakinra restored these effects. In human PE placentae, TM expression was negatively correlated with IL-1β expression and positively correlated with platelet counts and proliferation. Solulin treatment or transgenic expression of TM in placenta ameliorated the PE-like phenotype in mice, prevented thrombo-inflammation and restored proliferation.
Conclusions: These results establish a unidirectional relation of inflammasome activation and reduced trophoblast TM-expression, which contributes to the placental defect and embryonic demise in PE. Restoring TM levels may be a safe therapy in thrombo-inflammatory placental defects associated with excess platelet activation and placental inflammasome activation, as observed in PE.
To cite this abstract in AMA style:Kohli S, Gupta D, Gupta A, Rana R, Elwakiel A, Isermann B. Platelet and Extracellular Vesicle Mediated Inflammasome Activation Impairs Embryonic Survival by Reducing Placental Thrombomodulin Expression [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/platelet-and-extracellular-vesicle-mediated-inflammasome-activation-impairs-embryonic-survival-by-reducing-placental-thrombomodulin-expression/. Accessed May 6, 2021.
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