Plasma kallikrein mediates brain hemorrhage and edema caused by tissue plasminogen activator therapy in mice after stroke

Fabrício Simão, Tuna Ustunkaya, Allen C. Clermont and Edward P. Feener

Key points

  • tPA activates the contact system and plasma kallikrein blockade enhances tPA-mediated thrombolysis.

  • Plasma kallikrein contributes to hemorrhagic transformation and cerebral edema in mice with acute stroke receiving tPA.


Thrombolytic therapy using tissue plasminogen activator (tPA) in acute stroke is associated with increased risks of cerebral hemorrhagic transformation and angioedema. While plasma kallikrein (PKal) has been implicated in contributing to both hematoma expansion and thrombosis in stroke, its role in the complications associated with the therapeutic use of tPA in stroke is not yet available. We investigated the effects of tPA on plasma prekallikrein (PPK) activation and the role of PKal on cerebral outcomes in a murine thrombotic stroke model treated with tPA. We show that tPA increases PKal activity in vitro in both murine and human plasma, via a FXII dependent mechanism. Intravenous administration of tPA increased circulating PKal activity in mice. In mice with thrombotic occlusion of the middle cerebral artery, tPA administration increased brain hemorrhage transformation, infarct volume and edema. These adverse effects of tPA were ameliorated in plasma prekallikrein (Klkb1)- and Factor XII (FXII)-deficient mice and in Wild-Type (WT) mice pretreated with a PKal inhibitor prior to tPA. tPA-induce brain hemisphere reperfusion after photothrombolic MCAO was increased in Klkb1-/- mice compared with WT mice. In addition, PKal inhibition reduced MMP-9 activity in brain following stroke and tPA therapy. These data demonstrate that tPA activates PPK in plasma and PKal inhibition reduces cerebral complications associated with tPA-mediated thrombolysis in stroke.

  • Submitted September 19, 2016.
  • Accepted January 9, 2017.