Plasma Kallikrein Mediates Brain Hemorrhage and Edema Caused by Tissue Plasminogen Activator Therapy in Mice After Stroke

Blood. 2017 Apr 20;129(16):2280-2290. doi: 10.1182/blood-2016-09-740670. Epub 2017 Jan 27.

Abstract

Thrombolytic therapy using tissue plasminogen activator (tPA) in acute stroke is associated with increased risks of cerebral hemorrhagic transformation and angioedema. Although 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 factor XII (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 PPK (Klkb1)-deficient and FXII-deficient mice and in wild-type (WT) mice pretreated with a PKal inhibitor prior to tPA. tPA-induced brain hemisphere reperfusion after photothrombolic middle cerebral artery occlusion was increased in Klkb1-/- mice compared with WT mice. In addition, PKal inhibition reduced matrix metalloproteinase-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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Intravenous
  • Angioedema / blood
  • Angioedema / chemically induced*
  • Angioedema / genetics
  • Animals
  • Cerebral Hemorrhage / blood
  • Cerebral Hemorrhage / chemically induced*
  • Cerebral Hemorrhage / genetics
  • Disease Models, Animal
  • Factor XII / genetics
  • Factor XII / metabolism
  • Fibrinolytic Agents / adverse effects*
  • Gene Expression
  • Humans
  • Infarction, Middle Cerebral Artery / blood
  • Infarction, Middle Cerebral Artery / drug therapy
  • Infarction, Middle Cerebral Artery / genetics
  • Infarction, Middle Cerebral Artery / pathology
  • Male
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Mice, Knockout
  • Plasma Kallikrein / genetics
  • Plasma Kallikrein / metabolism*
  • Stroke / blood
  • Stroke / drug therapy*
  • Stroke / genetics
  • Stroke / pathology
  • Thrombolytic Therapy
  • Thrombosis / blood
  • Thrombosis / drug therapy*
  • Thrombosis / genetics
  • Thrombosis / pathology
  • Tissue Plasminogen Activator / adverse effects*

Substances

  • Fibrinolytic Agents
  • Factor XII
  • Plasma Kallikrein
  • Tissue Plasminogen Activator
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse