Counteraction of unconjugated bilirubin against heme-induced toxicity in platelets.

Platelets are essential for normal hemostasis and thrombosis but become hyperactive in hemolytic disorders. Cell-free heme is known to be toxic to platelets and endothelial cells, playing a significant role in the progression of pathological complications in various hemolytic conditions. The abnormal activation of circulatory platelets results in micro/macrovascular thrombosis and clot formation in the lungs, worsening the disease. This work aimed to establish the potent bioactive molecule that can regulate the heme-induced toxicity in platelets. We found that unconjugated bilirubin (UCB), an endogenous antioxidant and a byproduct of heme degradation, exhibited a higher protective effect against hemin-induced platelet aggregation and activation. This protective effect could mainly be due to reducing ROS and lipid peroxidation-mediated ferroptosis in hemin-treated platelets. Further experiments suggested that by blocking the interaction between hemin and the CLEC-2 receptor, UCB regulates the downstream Syk phosphorylation, a key event in hemin-induced platelet toxicity. Thus, UCB is emerging as a natural regulatory molecule that mitigates hemin-induced platelet toxicity and holds promise as an adjunctive therapy for managing platelet-associated complications, particularly in hemolytic disorders.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)