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Introduction and Hypothesis: Tissue plasminogen activator (tPA) remains the only approved treatment for acute ischemic stroke, but its use is limited by serious risk of hemorrhage transformation over time resulting in enhanced brain injury. Plasma kallikrein (PK) has been implicated in both ischemic and hemorrhagic stroke, however its role during tPA-mediated thrombosis is not yet available. We hypothesized that plasma kallikrein inhibition could increase the safety of tPA thrombolysis in stroke.Methods: Male C57Bl6 mice were subjected to middle cerebral artery occlusion (MCAO) by photothrombotic laser, and then treated with tPA (10 mg/kg; via jugular vein) at 2 h in the absence or presence of pretreatment with the selective PK inhibitor BCBPC (1-Benzyl-N-(4-carbamimidoylbenzyl)-1H-pyrazole-4-carboxamide) at doses of 1, 3, 10, 20 mg/kg administered for 15 min before tPA. Male PK-deficient (Klkb1-/-) mice were used to further evaluate the role of PK in tPA-induced brain injury following MCAO. Mice were sacrificed at 24 h post-stroke and brains perfused with saline for evaluation of infarct size, edema and cerebral hemorrhage. Western blot was used to evaluate levels and the cleavage of the PK substrate high molecular weight kininogen (HK).Results: Acute tPA administration at 2 hours post MCAO increased infarct volume (2.1 fold), edema (1.8 fold) and hemorrhage transformation (2.7 fold) when compared with the untreated stroke group (p<0.05). Pretreatment of mice with BCBPC decreased tPA-induced infarct volume, edema and hemorrhage to 1.7 fold, 2.7 fold and 2.1 fold, respectively, in a dose dependent manner (p<0.05). Klkb1-/- mice with MCAO were also protected from tPA-induced brain infarct volume by 39% (P<0.05) and hemorrhage by 41% (P<0.05) when compared with wild-type mice subjected to both MCAO and tPA. Cleaved HK levels were higher in WT mice with stroke plus tPA compared with Klkb1-/- mice with stroke plus tPA.Conclusions: Plasma kallikrein contributes to the adverse effects of thrombolytic therapy with tPA on infarct volume, edema, and hemorrhagic transformation during ischemic stroke. Co-administration of a plasma kallikrein inhibitor with tPA may improve safety and efficacy of thrombolysis.