Carbamazepine Induces Platelet Apoptosis and Thrombocytopenia Through Protein Kinase A.

Weiling Xiao,Rong Yan,Kesheng Dai,Chenglin Sun,Jian Gu,Kangxi Zhou,Lan Dai,Mengnan Yang

doi:10.3389/fphar.2021.749930

Weiling Xiao, Rong Yan + Show 6 more

Open Access

https://doi.org/10.3389/fphar.2021.749930

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Abstract

Carbamazepine is extensively used worldwide to treat a wide range of disorders such as epilepsy, peripheral neuralgia and bipolar disorder. Thrombocytopenia and hemorrhage have been identified in multiple carbamazepine-treated patients. However, the underlying mechanism remains poorly understood. Here, we show that platelets undergo apoptosis after carbamazepine treatment. The apoptotic platelets induced by carbamazepine are rapidly removed in vivo, which accounts for thrombocytopenia. We found that carbamazepine treatment attenuates the phosphorylation level of bcl-xl/bcl-2-associated death promoter (BAD), vasodilator-associated stimulated phosphoprotein (VASP) and GPIbβ in platelets, indicating an inhibition effect on protein kinase A (PKA). We further demonstrated that carbamazepine reduced PKA activity through PI3K/Akt/PDE3A signaling pathway. Pharmacological activation of PKA or inhibition of PI3K/Akt/PDE3A protects platelets from apoptosis induced by carbamazepine. Importantly, PDE3A inhibitors or PKA activator ameliorates carbamazepine-mediated thrombocytopenia in vivo. These findings shed light on a possible mechanism of carbamazepine-induced thrombocytopenia, designating PDE3A/PKA as a potential therapeutic target in the treatment of carbamazepine-induced thrombocytopenia.

Highlights

Epilepsy, one of the most common neurological disorders, affects about 70 million people around the world (Hirtz et al, 2007; Cagnetti et al, 2014)
To investigate the pathogenesis of CBZ-induced isolated thrombocytopenia, we examined the biological role of CBZ in platelet apoptosis, since apoptosis determines the lifespan of platelets (Zhao et al, 2017; Wei and Harper, 2019)
We examined the role of platelet apoptosis in CBZ-induced thrombocytopenia and platelet clearance

Summary

Introduction

One of the most common neurological disorders, affects about 70 million people around the world (Hirtz et al, 2007; Cagnetti et al, 2014). Prolonged CBZ therapy is frequently associated with severe hematological alterations, including agranulocytosis (Kumari et al, 2011), thrombocytopenia (Ishikita et al, 1999) and even aplastic anemia (Tohen et al, 1995; Blackburn et al, 1998). Among these alterations, it should be noted that CBZ-induced isolated thrombocytopenia has been reported in clinical application (Kimura et al, 1995; Ishikita et al, 1999; Finsterer et al, 2001).

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