title: Selective factor XIIa inhibition attenuates silent brain ischemia: application of molecular imaging targeting coagulation pathway.
abstract: OBJECTIVE
  The purpose of this study was use molecular imaging targeting coagulation pathway and inflammation to better understand the pathophysiology of silent brain ischemia (SBI) and monitor the effects of factor XIIa inhibition.
  
  
  BACKGROUND
  SBI can be observed in patients who undergo invasive vascular procedures. Unlike acute stroke, the diffuse nature of SBI and its less tangible clinical symptoms make this disease difficult to diagnose and treat.
  
  
  METHODS
  We induced SBI in mice by intra-arterial injection of fluorescently labeled microbeads or fractionated clot into the carotid artery. After SBI induction, diffusion-weighted magnetic resonance imaging was performed to confirm the presence of microinfarcts in asymptomatic mice. Molecular imaging targeting the downstream factor XIII activity (single-photon emission computed tomography/computed tomography) at 3 h and myeloperoxidase activity (magnetic resonance imaging) on day 3 after SBI induction were performed, without and with the intravenous administration of a recombinant selective factor XIIa inhibitor derived from the hematophagous insect Triatoma infestans (rHA-Infestin-4). Statistical comparisons between 2 groups were evaluated by the Student t test or Mann-Whitney U test.
  
  
  RESULTS
  In SBI-induced mice, we found abnormal activation of the coagulation cascade (factor XIII activity) and increased inflammation (myeloperoxidase activity) close to where emboli lodge in the brain. rHA-Infestin-4 administration significantly reduced ischemic damage (53% to 85% reduction of infarct volume, p < 0.05) and pathological coagulation (35% to 39% reduction of factor XIII activity, p < 0.05) without increasing hemorrhagic frequency. Myeloperoxidase activity, when normalized to the infarct volume, did not significantly change with rHA-Infestin-4 treatment, suggesting that this treatment does not further decrease inflammation other than that resulting from the reduction in infarct volume.
  
  
  CONCLUSIONS
  Focal intracerebral clotting and inflammatory activity are part of the pathophysiology underlying SBI. Inhibiting factor XIIa with rHA-Infestin-4 may present a safe and effective treatment to decrease the morbidity of SBI.
authors.affiliation: Center for Systems Biology, Boston, Massachusetts 02114, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Chen
authors.forename: Jose-Luiz
authors.initials: JL
authors.lastname: Figueiredo
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Wojtkiewicz
authors.forename: Cory
authors.initials: C
authors.lastname: Siegel
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Iwamoto
authors.forename: Dong-Eog
authors.initials: DE
authors.lastname: Kim
authors.forename: Marc W
authors.initials: MW
authors.lastname: Nolte
authors.forename: Gerhard
authors.initials: G
authors.lastname: Dickneite
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.forename: Matthias
authors.initials: M
authors.lastname: Nahrendorf
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D058070:Asymptomatic Diseases; D001777:Blood Coagulation / Q000187:drug effects*; D001798:Blood Proteins / Q000494:pharmacology*; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002544:Cerebral Infarction / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D038524:Diffusion Magnetic Resonance Imaging; D004195:Disease Models, Animal; D005176:Factor XIII / Q000378:metabolism; D015956:Factor XIIa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D019476:Insect Proteins / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D057054:Molecular Imaging / Q000379:methods; D064847:Multimodal Imaging; D009195:Peroxidase / Q000378:metabolism; D049268:Positron-Emission Tomography; D011994:Recombinant Proteins / Q000494:pharmacology; D013997:Time Factors; D014057:Tomography, X-Ray Computed
chemical_list: D000925:Anticoagulants; D001798:Blood Proteins; D018836:Inflammation Mediators; D019476:Insect Proteins; D011994:Recombinant Proteins; C053635:factor XIIa inhibitor; C467902:infestin protein, Triatoma infestans; D005176:Factor XIII; D009195:Peroxidase; D015956:Factor XIIa