Ironside et al Perihematomal Edema and ICH 1627 common pathway of the coagulation cascade. 39 Thrombin can also induce PHE formation independent of fibrinogen, which suggests that a pathophysiological mechanism exists that is distinct from the effects mediated by clot retraction. 8 Direct thrombin infusion has been associated with pronounced inflammatory responses in experimental ICH models, including mitosis induction, leukocyte chemotaxis, platelet aggregation, and cytokine release. 40, 41 Furthermore, thrombin alters endothelial cell-cell and cell-matrix interactions, and therefore, it could mediate opening of the blood-brain barrier. 26, 35, 42 Following blood-brain barrier disruption, activation of the complement cascade in the perihematomal parenchyma has been independently associated with PHE formation. 9, 43 Anaphylotoxins C3a and C5a serve as chemoattractants by activating endothelial cells and enhancing microglia infiltration, thereby amplifying the inflammatory response. 9 Complement inhibition by N-acetylheparin attenuates thrombin-induced PHE and improves neurological function in rat ICH models. 44 Furthermore, thrombin-specific inhibition is associated with a reduction in cerebral edema that is independent of hematoma volume. 8, 45 Therefore, thrombin-induced PHE formation is likely to result from the culmination of multiple coordinated mechanisms that are responsible for secondary brain injury. Finally, in the late phase of PHE evolution (ie,> 72 hours after hematoma formation), hematoma resolution occurs by a combination of erythrocyte lysis and erythophagocytosis. 2, 46 Although erythrophagocytosis is believed to accelerate ICH recovery, erythrocyte lysis is cytotoxic. 9, 46, 47 Depletion of intracellular energy reserve and formation of the complement membrane attack complex in erythrocytes results in subsequent cell lysis, leading to hemoglobin accumulation in the surrounding parenchyma. 2, 39, 46, 48 Hemoglobin inhibits Na+/K+ adenosine triphosphatase activity, generates hydroxyl radicals, stimulates lipid peroxidation, and causes neuronal death. 27, 48, 49 Elevated hemoglobin levels can be detected in the cerebrospinal fluid during the first several days after ICH. 50 In a rat ICH model, Xi et al10 observed marked brain edema 24 hours after intracerebral infusion with lysed autologous erythrocytes. In contrast, brain edema was delayed in rats infused intracerebrally with packed erythrocytes, implicating hemoglobin in edema formation. 10 In addition, intraparenchymal infusion of lysed erythrocytes increases blood-brain barrier permeability without affecting cerebral blood flow, which suggests an underlying vasogenic mechanism. 51, 52 In preclinical ICH models, administration of deferoxamine, an iron chelator, is associated with reductions in edema formation, white matter injury, and neuronal cell death. 53 Deferoxamine is also associated with decreased erythrocyte lysis and erythrophagocytosis in porcine ICH models. 47 Therefore, the precise relationships among hematoma clearance, PHE formation, and ICH recovery remain incompletely defined.