Abstract
AbstractThrombolytic 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.
Highlights
plasma kallikrein (PKal) contributes to activity in vitro in both murine and human plasma, via a factor XII (FXII)–dependent hemorrhagic transformation mechanism
To investigate the factors that may contribute to type plasminogen activator (tPA)-mediated PKal activity, we incubated tPA (360 nM) with normal human plasma and with plasma-depleted in plasminogen or FXII
We show that plasminogen deficiency and FXII deficiency decreased tPA-induced kallikrein-like-activity by ;38% (P, .01)
Summary
Recombinant tissue-type plasminogen activator (tPA) is the only approved pharmacological therapy for thrombotic stroke in the acute phase.[1]. The KKS can exert prothrombotic effects mediated by the generation of FXIIa, which activates FXI and the intrinsic coagulation cascade.[10] In addition, we have previously shown that PKal impairs hemostasis by interfering with collagen-mediated platelet activation, which contributes to hematoma expansion in an experimental model of hemorrhagic stroke.[11] The role of the KKS on vascular leakage, inflammation, and thrombosis has been demonstrated in animal models of acute stroke.[12,13,14,15] the clinical significance of PKal and bradykinin in stroke and its cerebral complications is not yet available, these factors have been identified as clinically significant mediators of vasogenic edema associated with hereditary angioedema.[16,17] In addition, the KKS has been implicated in orolingual angioedema that is associated with tPA-mediated thrombolysis.[18,19,20]. Solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734
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