Spontaneous intracerebral hemorrhage (ICH) is a common and often fatal stroke subtype. If the patient survives the ictus, the resulting hematoma within the brain parenchyma triggers a series of events leading to secondary insults and severe neurological deficits. After an ICH, lysis of erythrocytes in the hematoma and the mass itself result in brain swelling, neuronal death and neurological deficits. The hematoma can be removed by surgery or naturally by microglia/ macrophages. Our previous studies demonstrated that surgical clot removal with tissue plasminogen activator (tPA) reduces acute perihematomal edema in pigs. Recent studies found that enhancing microglia/ macrophage-mediated hematoma clearance reduces ICH-induced brain edema and improves functional outcome. CD47, also called integrin-associated protein, is expressed on erythrocytes and other cells regulating target cell phagocytosis. The role of CD47 in ICH has not been well studied. In preliminary studies, we found: 1) CD47 is expressed in rodent and pig erythrocytes; 2) erythrophagocytosis occurs in the perihematomal area and in the clot in both mouse and pig ICH models; 3) hematoma clearance is faster when the ICH is formed using CD47 knockout blood in mice; 4) the injection of CD47 knockout blood causes less brain swelling and neurological deficits than wild-type blood; and 5) co-injection of clodronate liposomes depletes M2 microglia/macrophages and causes more brain swelling and less hematoma clearance. These results suggest that CD47 inhibition is a target for reducing ICH-induced brain injury. Recently, there has been considerable interest in the cancer field in targeting CD47 with blocking antibodies to enhance phagocytosis and that approach is currently in clinical trial. In this application, we propose to test the following specific aims: 1) To examine whether CD47 levels in the hematoma are associated with infiltration of macrophages/microglia into the clot and clot clearance; 2) To examine whether modifying erythrocyte CD47 levels in the clot or blocking CD47 will affect hematoma clearance and ICH-induced brain injury in aged mice and in pigs; and 3) To determine whether blocking CD47 plus surgical clot removal with tPA will significantly reduce ICH-induced white matter injury. The long-term goal of our studies is to limit brain damage following ICH.