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Targeting coagulation factor XII as a novel therapeutic option in brain trauma

Hopp, Sarah; Albert-Weissenberger, Christiane; Mencl, Stine; Bieber, Michael; Schuhmann, Michael K; Stetter, Christian; Nieswandt, Bernhard; Schmidt, Peter M; Monoranu, Camelia-Maria and Alafuzoff, Irina, et al. (2016) In Annals of Neurology 79(6). p.82-970
Abstract

OBJECTIVE: 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.

METHODS: We investigated the impact of genetic... (More)

OBJECTIVE: 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.

METHODS: 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.

RESULTS: 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.

INTERPRETATION: 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.

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publication status
published
keywords
Journal Article
in
Annals of Neurology
volume
79
issue
6
pages
82 - 970
publisher
John Wiley and Sons Inc.
external identifiers
  • scopus:84964687014
ISSN
1531-8249
DOI
10.1002/ana.24655
language
English
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no
id
a5e5d899-2b63-4dd6-a6c2-43d49ee8d098
date added to LUP
2016-12-09 15:57:10
date last changed
2017-11-14 09:53:47
@article{a5e5d899-2b63-4dd6-a6c2-43d49ee8d098,
  abstract     = {<p>OBJECTIVE: 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.</p><p>METHODS: 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.</p><p>RESULTS: 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.</p><p>INTERPRETATION: 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.</p>},
  author       = {Hopp, Sarah and Albert-Weissenberger, Christiane and Mencl, Stine and Bieber, Michael and Schuhmann, Michael K and Stetter, Christian and Nieswandt, Bernhard and Schmidt, Peter M and Monoranu, Camelia-Maria and Alafuzoff, Irina and Marklund, Niklas and Nolte, Marc W and Sirén, Anna-Leena and Kleinschnitz, Christoph},
  issn         = {1531-8249},
  keyword      = {Journal Article},
  language     = {eng},
  number       = {6},
  pages        = {82--970},
  publisher    = {John Wiley and Sons Inc.},
  series       = {Annals of Neurology},
  title        = {Targeting coagulation factor XII as a novel therapeutic option in brain trauma},
  url          = {http://dx.doi.org/10.1002/ana.24655},
  volume       = {79},
  year         = {2016},
}