Spontaneous intracerebral hemorrhage (ICH) is a common and often fatal disease with no effective treatment. Edema plays an important role both in its morbidity and mortality. In a pig model of ICH, we have identified two pathophysiologically distinct types of edema in white matter adjacent to hematomas, i.e., a rapidly developing, early edema (by 1h) without increased barrier permeability and vasogenic edema developing 8 to 24 hours later. The early edema is marked (>10 percent increases in water content), is associated with serum protein accumulation in white matter (including hematoma-derived fibrinogen), and is visualized by magnetic resonance imaging (MRI). This edema is prolonged and damages the white matter causing by demyelination and gliosis. Our preliminary studies show this edema develops 1) following plasma, but not packed red cell, infusions into white matter and 2) only if a coagulation occurs. The delayed edema can be markedly reduced, even prevented, by early (4h) lysis of the clot with tissue plasminogen activator (tPA) followed by hematoma aspiration. These findings lead us to hypothesize that clot formation and fibrin deposition in the interstitial spaces of the white matter surrounding the hematoma are critical, mandatory steps for early white matter edema. We also hypothesize that the vasogenic edema is secondary, accentuates the edema and, if persistent, damages white matter. Finally, we hypothesize this sequence can be interrupted by early treatment with fibrinolytic agents that facilitate both primary clot removal and lysis of interstitial fibrin deposits (termed """"""""interstitial fibrinolysis""""""""). To test these hypotheses, we will evaluate the effectiveness of specific or modified blood components in producing white matter edema following infusion into the white matter. Outcomes will be determined by measuring the volumes of the white matter edema provoked and the permanent tissue injury induce using histologic, immunocytochemical and computer-assisted morphometric methods. Interstitial serum proteins, fibrin deposition and myelin damage will be measured immunohistochemically and biochemically. MR imaging will permit the relationships between perihemotomal edema development, white matter blood flow and changes in blood-brain-barrier permeability to be determined and correlated with neuropathologic outcomes. Finally, several fibrinolytic treatments will be examined to determine if such agents infused into the hematoma or hematoma cavity reduce/prevent ICH edema by """"""""interstitial fibrinolysis"""""""". These studies explore new pathophysiologic mechanisms that initiate brain injury from ICH, and derive novel therapeutic approaches to improve outcome by interrupting pathologic sequences before irreversible damage occurs.
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