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

Citation
Simao, F., et al. “Plasma Kallikrein Mediates Brain Hemorrhage And Edema Caused By Tissue Plasminogen Activator Therapy In Mice After Stroke.”. Blood, pp. 2280-2290.
Center Joslin Diabetes Center
Author Fabricio Simao, Tuna Ustunkaya, Allen C Clermont, Edward P Feener
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.

Year of Publication
2017
Journal
Blood
Volume
129
Issue
16
Number of Pages
2280-2290
Date Published
12/2017
ISSN Number
1528-0020
DOI
10.1182/blood-2016-09-740670
Alternate Journal
Blood
PMID
28130211
PMCID
PMC5399481
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