The role of complement system in hemorrhagic stroke

Hemorrhagic stroke, including subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), and intraventricular hemorrhage (IVH), is associated with high morbidity and mortality driven by secondary injury processes such as neuroinflammation, blood-brain barrier disruption, and oxidative stress. Increasing evidence identifies the complement system as a central mediator of these responses. Following hemorrhage, exposure of blood components and damaged tissue rapidly activates the classical, lectin, and alternative complement pathways, converging on C3 and leading to generation of anaphylatoxins and terminal effector complexes. In SAH, complement activation is early and compartmentalized, contributing to early brain injury, delayed cerebral ischemia, and vascular dysfunction. In ICH, complement exhibits dual roles, promoting inflammatory injury and edema while also facilitating hematoma clearance. In IVH, emerging data implicate complement in hydrocephalus development, white matter injury, and long-term neurological deficits, particularly via C3-mediated inflammation and membrane attack complex-driven hemolysis. Complement-coagulation crosstalk further amplifies injury through reciprocal activation pathways. Although complement-targeted therapies show promise in preclinical and early clinical studies, translation is limited by the dynamic and context-dependent nature of complement signaling. Future work should focus on biomarker development and precision therapeutic strategies.