title: Intravenous tPA therapy does not worsen acute intracerebral hemorrhage in mice.
abstract: Tissue plasminogen activator (tPA) is the only FDA-approved treatment for reperfusing ischemic strokes. But widespread use of tPA is still limited by fears of inadvertently administering tPA in patients with intracerebral hemorrhage (ICH). Surprisingly, however, the assumption that tPA will worsen ICH has never been biologically tested. Here, we assessed the effects of tPA in two models of ICH. In a mouse model of collagenase-induced ICH, hemorrhage volumes and neurological deficits after 24 hrs were similar in saline controls and tPA-treated mice, whereas heparin-treated mice had 3-fold larger hematomas. In a model of laser-induced vessel rupture, tPA also did not worsen hemorrhage volumes, while heparin did. tPA is known to worsen neurovascular injury by amplifying matrix metalloproteinases during cerebral ischemia. In contrast, tPA did not upregulate matrix metalloproteinases in our mouse ICH models. In summary, our experimental data do not support the assumption that intravenous tPA has a deleterious effect in acute ICH. However, due to potential species differences and the inability of models to fully capture the dynamics of human ICH, caution is warranted when considering the implications of these findings for human therapy.
authors: Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. foerch@em.uni-frankfurt.de
authors: Christian
authors: C
authors: Foerch
authors: Nathanael L
authors: NL
authors: Rosidi
authors: Frieder
authors: F
authors: Schlunk
authors: Arne
authors: A
authors: Lauer
authors: Flor A
authors: FA
authors: Cianchetti
authors: Emiri
authors: E
authors: Mandeville
authors: Ken
authors: K
authors: Arai
authors: Kazim
authors: K
authors: Yigitkanli
authors: Xiang
authors: X
authors: Fan
authors: Xiaoying
authors: X
authors: Wang
authors: Klaus
authors: K
authors: van Leyen
authors: Helmuth
authors: H
authors: Steinmetz
authors: Chris B
authors: CB
authors: Schaffer
authors: Eng H
authors: EH
authors: Lo
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D002543:Cerebral Hemorrhage / Q000473:pathology*; D008297:Male; D051379:Mice; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*
chemical_list: D010959:Tissue Plasminogen Activator