Background: Thrombocytopenia is common among patients with hepatitis B virus (HBV) infection, limiting the anti-viral therapy. Eltrombopag (EP), a thrombopoietin receptor (TPO-R) agonist and potent iron chelator, is being evaluated in clinical trials for treatment of patients with hepatitis B-related immunologic thrombocytopenia (HBV-ITP). Pro-inflammatory S100A8/9 as danger-associated molecular patterns activate Toll-like receptor 4 (TLR4). Because monocytes have a critical role in development of both ITP and chronic hepatitis, we explored the contribution of monocyte subsets in control of inflammatory immunity in patients with HBV-ITP. How the activity of monocytes is regulated by EP to avoid excessive inflammatory response is not fully understood.

Aims: This study aims to assess the inhibitory effect of EP on TLR4 signaling, which contributes to diminishment of inflammation in monocytes, and elucidates the underlying mechanisms of EP as an iron chelator for the treatment of patients with HBV-ITP.

Methods: S100A8/9 levels in the plasma of HBV-ITP patients were analyzed by ELISA. EP inhibition of S100A8/9-induced TLR4 pathway activation and pro-inflammatory cytokine expression in monocytes sorted from human PBMCs were evaluated by Western Blot, qPCR, flow cytometry and ELISA. TLR4 signaling was also measured in murine bone marrow-derived monocytes after LPS and S100A8/9 stimulation. Reactive oxygen species (ROS) generation was observed by flow cytometry.

Results: S100A8/9 in the plasma of HBV-ITP patients showed a marked increase compared with healthy controls(Fig1. a), and EP inhibited TLR4-triggered inflammation in human monocytes(Fig1. b-d). Iron deprivation caused decreased expression of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) and repression of TLR4 pathway (p-ERK, p-JNK, p-STAT1) in monocytes from both human and mice(Fig. e-g). Moreover, our study demonstrated a reduction of ROS production after exogenous administration of EP(Fig1. h).

Conclusions: These results reveal the iron chelation of EP in the treatment of HBV-ITP patients, and labile iron is a critical mediator of excessive inflammation and oxidative stress.

[Fig 1. EP suppresses excessive inflammation in HBV-ITP through inhibition of TLR4 signaling pathway.]

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/eltrombopag-suppresses-excessive-inflammation-in-hepatitis-b-related-immunologic-thrombocytopenia-through-inhibition-of-toll-like-receptor-4-signaling-pathway/