title: Evolution of intracerebral hemorrhage after intravenous tPA: reversal of harmful effects with mast cell stabilization.
abstract: Thrombolysis with tissue plasminogen activator (tPA) traditionally demands baseline imaging to rule out intracerebral hemorrhage (ICH), which causes delays in treatment. Preventing possible adverse effects of tPA on ICH would allow rapid on-site thrombolysis in patients with presumed acute ischemic stroke, reducing onset-to-treatment times. We examined how intravenous tPA alters ICH evolution during an extended follow-up, and how mast cell stabilization affects this process. Intracerebral hemorrhage was induced in rats by collagenase injection. Rats received either saline (n=10), tPA (n=13), tPA+low-dose cromoglycate (n=10), or tPA+high-dose cromoglycate (n=10). Magnetic resonance imaging was performed at 24, 48, and 72 hours after ICH induction, together with neurologic evaluations. During 72 hours of follow-up, tPA administration did not significantly increase hematoma volume (mean±s.d. 83.5±14.3 versus 66.7±14.7 μL; P=0.256) or hemispheric expansion (14.5±5.0 versus 11.5±5.0%; P=0.457) compared with saline. However, tPA-treated animals had worse neurologic outcomes (P<0.05), and mortality (8/13 versus 3/10). Combining tPA with high-dose cromoglycate mitigated hemispheric expansion (7.4±1.7 versus 14.5±5.0%; P=0.01), improved neurologic outcome (P<0.001) and decreased mortality (1/10; P<0.05) compared with tPA alone. Our results suggest tPA increases neurologic deficit in ICH, an effect that was abolished by concomitant mast cell stabilization. Further studies are needed to establish the clinical relevance of these findings.
authors.affiliation: 1] Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland [2] Experimental MRI Laboratory, Biomedicum, Helsinki, Finland.
authors.forename: Ivan
authors.initials: I
authors.lastname: Marinkovic
authors.affiliation: Molecular Neurology, Research Programs Unit, and Department of Clinical Neurosciences, University of Helsinki, Helsinki, Finland.
authors.forename: Olli S
authors.initials: OS
authors.lastname: Mattila
authors.affiliation: 1] Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland [2] Experimental MRI Laboratory, Biomedicum, Helsinki, Finland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Strbian
authors.affiliation: 1] Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland [2] Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Atte
authors.initials: A
authors.lastname: Meretoja
authors.affiliation: 1] Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland [2] Experimental MRI Laboratory, Biomedicum, Helsinki, Finland.
authors.forename: Shashank
authors.initials: S
authors.lastname: Shekhar
authors.affiliation: Molecular Neurology, Research Programs Unit, and Department of Clinical Neurosciences, University of Helsinki, Helsinki, Finland.
authors.forename: Jani
authors.initials: J
authors.lastname: Saksi
authors.affiliation: 1] Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland [2] Experimental MRI Laboratory, Biomedicum, Helsinki, Finland.
authors.forename: Usama
authors.initials: U
authors.lastname: Abo-Ramadan
authors.affiliation: Genome-Scale Biology Program, University of Helsinki, Helsinki, Finland.
authors.forename: Ville
authors.initials: V
authors.lastname: Rantanen
authors.affiliation: 1] Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland [2] Molecular Neurology, Research Programs Unit, and Department of Clinical Neurosciences, University of Helsinki, Helsinki, Finland.
authors.forename: Perttu J
authors.initials: PJ
authors.lastname: Lindsberg
authors.affiliation: 1] Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland [2] Experimental MRI Laboratory, Biomedicum, Helsinki, Finland.
authors.forename: Turgut
authors.initials: T
authors.lastname: Tatlisumak
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D006406:Hematoma / Q000473:pathology / Q000517:prevention & control; D007275:Injections, Intravenous; D053208:Kaplan-Meier Estimate; D008279:Magnetic Resonance Imaging; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000473:pathology; D008833:Microcirculation / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator