title: Targeting coagulation factor XII as a novel therapeutic option in brain trauma.
abstract: Traumatic brain injury is a major global public health problem for which specific therapeutic interventions are lacking. There is, therefore, a pressing need to identify innovative pathomechanism-based effective therapies for this condition. Thrombus formation in the cerebral microcirculation has been proposed to contribute to secondary brain damage by causing pericontusional ischemia, but previous studies have failed to harness this finding for therapeutic use. The aim of this study was to obtain preclinical evidence supporting the hypothesis that targeting factor XII prevents thrombus formation and has a beneficial effect on outcome after traumatic brain injury.
  
  
  
  We investigated the impact of genetic deficiency of factor XII and acute inhibition of activated factor XII with a single bolus injection of recombinant human albumin-fused infestin-4 (rHA-Infestin-4) on trauma-induced microvascular thrombus formation and the subsequent outcome in 2 mouse models of traumatic brain injury.
  
  
  
  Our study showed that both genetic deficiency of factor XII and an inhibition of activated factor XII in mice minimize trauma-induced microvascular thrombus formation and improve outcome, as reflected by better motor function, reduced brain lesion volume, and diminished neurodegeneration. Administration of human factor XII in factor XII-deficient mice fully restored injury-induced microvascular thrombus formation and brain damage.
  
  
  
  The robust protective effect of rHA-Infestin-4 points to a novel treatment option that can decrease ischemic injury after traumatic brain injury without increasing bleeding tendencies. Ann Neurol 2016;79:970-982.
authors.affiliation: Department of Neurology, University Hospital of Würzburg, Würzburg, Germany.|Department of Neurosurgery, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hopp
authors.affiliation: Department of Neurology, University Hospital of Würzburg, Würzburg, Germany.|Department of Neurosurgery, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Albert-Weissenberger
authors.affiliation: Department of Neurology, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Stine
authors.initials: S
authors.lastname: Mencl
authors.affiliation: Department of Neurology, University Hospital of Würzburg, Würzburg, Germany.|Comprehensive Heart Failure Center (DZHI), University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Bieber
authors.affiliation: Department of Neurology, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Schuhmann
authors.affiliation: Department of Neurosurgery, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Stetter
authors.affiliation: Rudolf Virchow Center, German Research Society Research Center for Experimental Biomedicine, Julius Maximilian University, Würzburg, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt
authors.affiliation: CSL Limited, Bio21 Molecular Science and Biotechnology Institute, Parkville, Victoria, Australia.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Schmidt
authors.affiliation: Institute of Pathology, Department of Neuropathology, Comprehensive Cancer Center Mainfranken, Julius Maximilian University, Würzburg, Germany.
authors.forename: Camelia-Maria
authors.initials: CM
authors.lastname: Monoranu
authors.affiliation: Department of Immunology, Uppsala University, Uppsala, Sweden.|Department of Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Irina
authors.initials: I
authors.lastname: Alafuzoff
authors.affiliation: Department of Neuroscience, Neurosurgery, Uppsala University, Uppsala, Sweden.
authors.forename: Niklas
authors.initials: N
authors.lastname: Marklund
authors.affiliation: CSL Behring, Marburg, Germany.
authors.forename: Marc W
authors.initials: MW
authors.lastname: Nolte
authors.affiliation: Department of Neurosurgery, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Anna-Leena
authors.initials: AL
authors.lastname: Sirén
authors.affiliation: Department of Neurology, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kleinschnitz
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000188:drug therapy* / Q000503:physiopathology; D016022:Case-Control Studies; D004195:Disease Models, Animal; D005174:Factor XII / Q000235:genetics / Q000627:therapeutic use*; D015956:Factor XIIa / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D019476:Insect Proteins / Q000627:therapeutic use*; D020767:Intracranial Thrombosis / Q000188:drug therapy*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D059906:Neuroimaging; D010974:Platelet Aggregation / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D012709:Serum Albumin / Q000627:therapeutic use*; D000075462:Serum Albumin, Human; D055815:Young Adult
chemical_list: D019476:Insect Proteins; D011993:Recombinant Fusion Proteins; D012709:Serum Albumin; C000609004:rHA-infestin-4 protein; D005174:Factor XII; D015956:Factor XIIa; D000075462:Serum Albumin, Human