Tissue Plasminogen Activator Induced Delayed Edema in Experimental Porcine Intracranial Hemorrhage: Reduction with Plasminogen Activator Inhibitor-1 Administration

Hematoma puncture and subsequent clot lysis with recombinant tissue plasminogen activator (rtPA) emerged as an alternative therapy for spontaneous intracerebral hemorrhage (ICH) and is associated with delayed edema possibly counteracting the beneficial effects of hematoma volume reduction. We hypothesized that immediate reversal of rtPA activity after clot lysis and hematoma drainage diminishes edema formation. To test this hypothesis, we administered plasminogen activator inhibitor (PAI)-1 after rtPA lysis of experimentally induced ICH. A right frontal ICH was placed through a twist drill burr hole and autologous blood injection. Following creation of the frontal ICH, pigs received no further treatment (n = 5), lysis with rtPA (n = 7), or lysis with rtPA followed by administration of PAI-1 (n = 6). Hematoma and edema volumes were assessed with magnetic resonance imaging on days 0, 4, and 10. The rtPA significantly reduced hematoma volume and contributed to edema on day 10 after experimentally induced ICH. Administration of PAI-1 attenuated the rtPA-induced edema volume on day 10, but the hematoma volume reduction was less pronounced. In conclusion, PAI-1 attenuated delayed cerebral edema after rtPA lysis of experimental ICH but also reduced the lytic activity of rtPA. The combination of rtPA clot lysis with PAI-1 might have the potential to further improve the effect of the lytic therapy of ICH, but additional studies to define the optimum time point for PAI-1 administration are required.