ABSTRACT Microhemorrhages are an underestimated aspect in the pathophysiology of vulnerable plaques and aneurysms. Erythrocyte liberation within hemorrhages leads to extracellular hemoglobin accumulation and iron‐containing hemin generation. Hemin induces platelet activation, thrombosis, and ferroptosis‐mediated destruction of platelet membranes through GPVI/CLEC‐2 signaling. Hemin‐toxicity results in destruction of platelet membranes, which is caused by ferroptosis, a non‐apoptotic cell death. Antiplatelet drugs have limited effect on hemin‐induced activation. We evaluated the effect of hemin on platelet function using light transmission aggregometry and multipanel flow cytometry. We found that P2Y 12 and COX‐1 inhibition attenuates hemin‐induced aggregation only at low hemin concentrations (3.1/6.25 μM), whereas at higher concentrations (12.5/25 μM) no substantial inhibition was found. High hemin concentrations enhance phosphatidylserine exposure, procoagulant and microvesicle formation as well as ferroptosis, which was not attenuated in the presence of Src‐inhibitors, indicating that membrane‐disintegration is not primarily mediated via GPVI/CLEC‐2 receptor‐dependent ITAM‐signaling. In contrast, iron chelation by deferoxamine significantly reduced microvesicle and ROS generation, loss of mitochondrial membrane potential and lipid peroxidation. Soluble recombinant Fc‐GPVI scavenging of hemin protects against hemin‐induced platelet activation, plasma membrane disintegration and microvesicle formation. High hemin concentrations lead to plasma membrane disintegration and ferroptosis, inhibited by iron chelation and hemin scavenging via soluble Fc‐GPVI, but not by GPVI/CLEC‐2 receptor‐mediated ITAM signaling. We speculate that iron overload enables receptor‐independent ferroptosis induction by hemin and may represent a therapeutic target to prevent platelet‐driven thrombosis in microhemorrhages.
Laspa et al. (2026) studied this question.