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Abstract: Autoimmune hemolysis is a condition characterized by platelet activation and thrombotic complications, offering limited treatment options. In recent years, the role of ferroptosis, a regulated cell death caused by lipid peroxidation and reactive oxygen species, has been investigated in platelets. It has been found that hemin, a byproduct of hemolysis, can trigger ferroptosis in platelets. Exploring the mechanisms behind ferroptosis in platelets and its connection to autoimmune hemolysis holds promising potential for developing targeted therapies to reduce thrombotic risk in affected patients. A key player in this context is the modulation of the cyclic guanosine monophosphate (cGMP) signaling pathway. In the experiments conducted with platelets from patients and healthy controls, it was observed that plasma samples from patients exhibited increased platelet aggregation, particularly under ADP stimulation. Treatment with cGMP modulators reduced aggregation in patient platelets, emphasizing the importance of cGMP modulation in reducing platelet activation in hemolytic plasma. Direct treatment of platelets with hemin resulted in enhanced platelet activation, manifested by increased surface expression of P-selectin, fibrinogen binding, ATP release, and morphological changes. cGMP modulation significantly attenuated these effects. Additionally, it was found that cGMP regulates hemin-induced ferroptosis in platelets, as demonstrated by phosphatidylserine exposure, ROS activity, and reduced mitochondrial membrane potential. Examination of the platelet lipidome revealed concentration-dependent changes due to hemin and the modulating effect of DEA/NO and riociguat on platelet lipidome. Analysis of ferroptosis-related lipids underscores their central role in the ferroptosis signaling pathway. The study provides insights into the prothrombotic properties of hemolytic plasma and the interaction of hemin, platelet activation, and cGMP modulation. Modulation of the cGMP signaling pathway shows promising inhibitory effects on platelet activation in autoimmune hemolysis. Further research is needed to clarify the underlying mechanisms and explore clinical applications of cGMP modulation.