title: Lack of TAFI increases brain damage and microparticle generation after thrombolytic therapy in ischemic stroke.
abstract: BACKGROUND
  Thrombin-activatable fibrinolysis inhibitor (TAFI) plays an important role in coagulation and fibrinolysis. Whereas TAFI deficiency may lead to a haemorrhagic tendency, data from TAFI knockout mice (TAFI-/-) are controversial and no differences have been reported in these animals after ischemic stroke. There are also no data regarding the role of circulating microparticles (MPs) in TAFI-/-.
  
  
  OBJECTIVE
  to examine the effect of tPA on the rate of intracranial haemorrhage (ICH) and on MPs generated in a model of ischemic stroke in TAFI-/- mice.
  
  
  METHODS
  Thrombin was injected into the middle cerebral artery (MCA) to analyse the effect of tPA (10mg/Kg) on the infarct size and haemorrhage in the absence of TAFI. Immunofluorescence for Fluoro-Jade C was performed on frozen brain slides to analyse neuronal degeneration after ischemia. MPs were isolated from mouse blood and their concentrations calculated by flow cytometry.
  
  
  RESULTS
  Compared with saline, tPA significantly increased the infarct size in TAFI-/- mice (p<0.05). Although plasma fibrinolytic activity (fibrin plate assay) was higher in these animals, no macroscopic or microscopic ICH was detected. A positive signal for apoptosis and degenerating neurons was observed in the infarct area, being significantly higher in tPA treated TAFI-/- mice (p<0.05). Interestingly, higher numbers of MPs were found in TAFI-/- plasma as compared to wild type, after stroke (p<0.05).
  
  
  CONCLUSIONS
  TAFI deficiency results in increased brain damage in a model of thrombolysis after ischemic stroke, which was not associated with bleeding but with neuronal degeneration and MP production.
authors.affiliation: Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, CIMA-University of Navarra, Navarra Institute for Health Research (IdiSNA), Pamplona, Spain. Electronic address: josuneor@unav.es.
authors.forename: J
authors.initials: J
authors.lastname: Orbe
authors.affiliation: Pathophysiology and Pharmacology Department, Institute of Cellular Biology and Pathology 'Nicolae Simionescu' of Romanian Academy, Bucharest, Romania.
authors.forename: N
authors.initials: N
authors.lastname: Alexandru
authors.affiliation: Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, CIMA-University of Navarra, Navarra Institute for Health Research (IdiSNA), Pamplona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Roncal
authors.affiliation: Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, CIMA-University of Navarra, Navarra Institute for Health Research (IdiSNA), Pamplona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Belzunce
authors.affiliation: Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, CIMA-University of Navarra, Navarra Institute for Health Research (IdiSNA), Pamplona, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Bibiot
authors.affiliation: Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, CIMA-University of Navarra, Navarra Institute for Health Research (IdiSNA), Pamplona, Spain.
authors.forename: J A
authors.initials: JA
authors.lastname: Rodriguez
authors.affiliation: Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, the Netherlands; Department of Plasma Proteins, Sanquin Research, Amsterdam, the Netherlands.
authors.forename: J C M
authors.initials: JC
authors.lastname: Meijers
authors.affiliation: Pathophysiology and Pharmacology Department, Institute of Cellular Biology and Pathology 'Nicolae Simionescu' of Romanian Academy, Bucharest, Romania.
authors.forename: A
authors.initials: A
authors.lastname: Georgescu
authors.affiliation: Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, CIMA-University of Navarra, Navarra Institute for Health Research (IdiSNA), Pamplona, Spain.
authors.forename: J A
authors.initials: JA
authors.lastname: Paramo
mesh_terms: D000818:Animals; D025901:Carboxypeptidase B2 / Q000235:genetics / Q000378:metabolism*; D055252:Cell-Derived Microparticles / Q000187:drug effects / Q000378:metabolism*; D005343:Fibrinolytic Agents / Q000009:adverse effects / Q000627:therapeutic use; D020300:Intracranial Hemorrhages / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020521:Stroke / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism*; D015912:Thrombolytic Therapy / Q000009:adverse effects; D010959:Tissue Plasminogen Activator / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D005343:Fibrinolytic Agents; D025901:Carboxypeptidase B2; C585365:Cpb2 protein, mouse; D010959:Tissue Plasminogen Activator
keywords: Circulating cell-derived microparticles; Fibrinolysis; Inflammation; TAFI; Thrombolytic therapy