title: Hematoma expansion in experimental intracerebral hemorrhage is not altered by peracute treatment with recombinant tissue plasminogen activator.
abstract: Recombinant tissue-type plasminogen activator (rt-PA) is the mainstay of acute stroke treatment and the only approved medical therapy so far. Because of its fibrinolytic action, it is presumed to aggravate intracerebral hemorrhage (ICH). Since clinical features do not discriminate between ischemic stroke and ICH, brain imaging is strictly required before the initiation of thrombolysis. A recent study has shown that rt-PA does not worsen (primary) ICH in two different experimental mouse models. Here, we further explored this surprising finding and examined hematoma expansion and long-term outcome after rt-PA treatment in a murine model of ICH. We induced ICH by collagenase injection into the right basal ganglia of C57BL/6 mice. At 30 min, 90 min or 4h after ICH induction, respectively, mice were treated with vehicle or 10mg/kg rt-PA. In parallel, we administered the vascular tracer Evans Blue (EB) and sacrificed the mice 2h after injection to assess EB extravasation as a marker of ongoing bleeding and rt-PA induced rebleeding. Additionally, we observed mice which were treated with vehicle or rt-PA 30 min after ICH induction for 72 h and quantified functional outcome and hematoma volume. EB extravasation was highest in the groups that were treated after 30 min and decreased thereafter according to a cessation of active bleeding. At all three time points covering the early phase of ICH, treatment with rt-PA did not increase EB extravasation. In the 72 h observation, there was also no difference in functional outcome and hematoma volume. In our experimental study, we were not able to demonstrate that peracute rt-PA treatment in (primary) ICH has detrimental effects on hematoma expansion, hematoma volume or functional outcome. This finding needs careful consideration in future translational studies.
authors.affiliation: Goethe University Hospital, Department of Neurology, Frankfurt am Main, Germany. Electronic address: w.pfeilschifter@med.uni-frankfurt.de.
authors.forename: W
authors.initials: W
authors.lastname: Pfeilschifter
authors.forename: S
authors.initials: S
authors.lastname: Kashefiolasl
authors.forename: A
authors.initials: A
authors.lastname: Lauer
authors.forename: H
authors.initials: H
authors.lastname: Steinmetz
authors.forename: C
authors.initials: C
authors.lastname: Foerch
mesh_terms: D000818:Animals; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D017364:Collagenases; D003627:Data Interpretation, Statistical; D005070:Evans Blue; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D005456:Fluorescent Dyes; D006406:Hematoma / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009422:Nervous System Diseases / Q000209:etiology / Q000503:physiopathology; D011994:Recombinant Proteins / Q000627:therapeutic use; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D005343:Fibrinolytic Agents; D005456:Fluorescent Dyes; D011994:Recombinant Proteins; D005070:Evans Blue; D010959:Tissue Plasminogen Activator; D017364:Collagenases
keywords: BBB; EB; Evans Blue; ICH; blood–brain barrier; intracerebral hemorrhage; recombinant tissue-type plasminogen activator; rt-PA; stroke; thrombolysis; tissue plasminogen activator