18880
2016
eng
970-982
6
79
article
1
2019-10-15
--
--
Targeting coagulation factor XII as a novel therapeutic option in brain trauma
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.
Annals of Neurology
10.1002/ana.24655
urn:nbn:de:bvb:20-opus-188800
Annals of Neurology (2016) 79:6, 970-982. https://doi.org/10.1002/ana.24655
291840
false
true
CC BY-NC-ND: Creative-Commons-Lizenz: Namensnennung, Nicht kommerziell, Keine Bearbeitungen 4.0 International
Sarah Hopp
Christiane Albert-Weissenberger
Stine Mencl
Michael Bieber
Michael K. Schuhmann
Christian Stetter
Bernhard Nieswandt
Peter M. Schmidt
Camelia-Maria Monoranu
Irina Alafuzoff
Niklas Marklund
Marc W. Nolte
Anna-Leena Sirén
Christoph Kleinschnitz
eng
uncontrolled
Molecular-weight heparin
eng
uncontrolled
Thrombus formation
eng
uncontrolled
Cerebral-ischemia
eng
uncontrolled
in-vivo
eng
uncontrolled
Intravascular coagulation
eng
uncontrolled
Hemodynamic depression
eng
uncontrolled
Head-injury
eng
uncontrolled
Rats
eng
uncontrolled
Model
eng
uncontrolled
Mice
Biowissenschaften; Biologie
Medizin und Gesundheit
open_access
Neurochirurgische Klinik und Poliklinik
Neurologische Klinik und Poliklinik
Rudolf-Virchow-Zentrum
OpenAIRE
Deutsches Zentrum für Herzinsuffizienz (DZHI)
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/18880/Hopp_AnnalsOfNeurology_2016.pdf
11926
2014
eng
269
8
article
1
2015-09-29
--
--
C1-Inhibitor protects from focal brain trauma in a cortical cryolesion mice model by reducing thrombo-inflammation
Traumatic brain injury (TBI) induces a strong inflammatory response which includes blood-brain barrier damage, edema formation and infiltration of different immune cell subsets. More recently, microvascular thrombosis has been identified as another pathophysiological feature of TBI. The contact-kinin system represents an interface between inflammatory and thrombotic circuits and is activated in different neurological diseases. C1-Inhibitor counteracts activation of the contact-kinin system at multiple levels. We investigated the therapeutic potential of C1-Inhibitor in a model of TBI. Male and female C57BL/6 mice were subjected to cortical cryolesion and treated with C1-Inhibitor after 1 h. Lesion volumes were assessed between day 1 and day 5 and blood-brain barrier damage, thrombus formation as well as the local inflammatory response were determined post TBI. Treatment of male mice with 15.0 IU C1-Inhibitor, but not 7.5 IU, 1 h after cryolesion reduced lesion volumes by ~75% on day 1. This protective effect was preserved in female mice and at later stages of trauma. Mechanistically, C1-Inhibitor stabilized the blood-brain barrier and decreased the invasion of immune cells into the brain parenchyma. Moreover, C1-Inhibitor had strong antithrombotic effects. C1-Inhibitor represents a multifaceted anti-inflammatory and antithrombotic compound that prevents traumatic neurodegeneration in clinically meaningful settings.
Frontiers in Cellular Neuroscience
10.3389/fncel.2014.00269
1662-5102
25249935
urn:nbn:de:bvb:20-opus-119263
Frontiers in Cellular Neuroscience 8:269. doi: 10.3389/fncel.2014.00269
Christiane Albert-Weissenberger
Stine Mencl
Michael K. Schuhmann
Irmak Salur
Eva Göb
Friederike Langhauser
Sarah Hopp
Nelli Hennig
Sven G. Meuth
Marc W. Nolte
Anna-Leena Sirén
Christoph Kleinschnitz
eng
uncontrolled
thrombosis
eng
uncontrolled
traumatic brain injury
eng
uncontrolled
C1-inhibitor
eng
uncontrolled
blood-brain barrier
eng
uncontrolled
contact-kinin system
eng
uncontrolled
edema
eng
uncontrolled
inflammation
Medizin und Gesundheit
open_access
Neurochirurgische Klinik und Poliklinik
Neurologische Klinik und Poliklinik
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/11926/025_Albert_Weissenberger_Frontiers_in_Ceööuöar_Neuroscience.pdf
16550
2016
eng
11626
7
article
1
2018-07-24
--
--
Blood coagulation factor XII drives adaptive immunity during neuroinflammation via CD87-mediated modulation of dendritic cells
Aberrant immune responses represent the underlying cause of central nervous system (CNS) autoimmunity, including multiple sclerosis (MS). Recent evidence implicated the crosstalk between coagulation and immunity in CNS autoimmunity. Here we identify coagulation factor XII (FXII), the initiator of the intrinsic coagulation cascade and the kallikrein–kinin system, as a specific immune cell modulator. High levels of FXII activity are present in the plasma of MS patients during relapse. Deficiency or pharmacologic blockade of FXII renders mice less susceptible to experimental autoimmune encephalomyelitis (a model of MS) and is accompanied by reduced numbers of interleukin-17A-producing T cells. Immune activation by FXII is mediated by dendritic cells in a CD87-dependent manner and involves alterations in intracellular cyclic AMP formation. Our study demonstrates that a member of the plasmatic coagulation cascade is a key mediator of autoimmunity. FXII inhibition may provide a strategy to combat MS and other immune-related disorders.
Nature Communications
10.1038/ncomms11626
urn:nbn:de:bvb:20-opus-165503
Nature Communications, 2015, 7:11626. DOI: 10.1038/ncomms11626
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Kerstin Göbel
Susann Pankratz
Chloi-Magdalini Asaridou
Alexander M. Herrmann
Stefan Bittner
Monika Merker
Tobias Ruck
Sarah Glumm
Friederike Langhauser
Peter Kraft
Thorsten F. Krug
Johanna Breuer
Martin Herold
Catharina C. Gross
Denise Beckmann
Adelheid Korb-Pap
Michael K. Schuhmann
Stefanie Kuerten
Ioannis Mitroulis
Clemens Ruppert
Marc W. Nolte
Con Panousis
Luisa Klotz
Beate Kehrel
Thomas Korn
Harald F. Langer
Thomas Pap
Bernhard Nieswandt
Heinz Wiendl
Triantafyllos Chavakis
Christoph Kleinschnitz
Sven G. Meuth
eng
uncontrolled
blood coagulation
eng
uncontrolled
factor XII
eng
uncontrolled
neuroinflammation
eng
uncontrolled
dendric cells
Biowissenschaften; Biologie
Medizin und Gesundheit
open_access
Institut für Anatomie und Zellbiologie
Neurologische Klinik und Poliklinik
Rudolf-Virchow-Zentrum
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/16550/Goebel_Nature_Communications.pdf
15749
2017
eng
39
14
article
1
2018-02-12
--
--
Alleviation of secondary brain injury, posttraumatic inflammation, and brain edema formation by inhibition of factor XIIa
Background:
Traumatic brain injury (TBI) is a devastating neurological condition and a frequent cause of permanent disability. Posttraumatic inflammation and brain edema formation, two pathological key events contributing to secondary brain injury, are mediated by the contact-kinin system. Activation of this pathway in the plasma is triggered by activated factor XII. Hence, we set out to study in detail the influence of activated factor XII on the abovementioned pathophysiological features of TBI.
Methods:
Using a cortical cryogenic lesion model in mice, we investigated the impact of genetic deficiency of factor XII and inhibition of activated factor XII with a single bolus injection of recombinant human albumin-fused Infestin-4 on the release of bradykinin, the brain lesion size, and contact-kinin system-dependent pathological events. We determined protein levels of bradykinin, intracellular adhesion molecule-1, CC-chemokine ligand 2, and interleukin-1β by enzyme-linked immunosorbent assays and mRNA levels of genes related to inflammation by quantitative real-time PCR. Brain lesion size was determined by tetrazolium chloride staining. Furthermore, protein levels of the tight junction protein occludin, integrity of the blood-brain barrier, and brain water content were assessed by Western blot analysis, extravasated Evans Blue dye, and the wet weight-dry weight method, respectively. Infiltration of neutrophils and microglia/activated macrophages into the injured brain lesions was quantified by immunohistological stainings.
Results:
We show that both genetic deficiency of factor XII and inhibition of activated factor XII in mice diminish brain injury-induced bradykinin release by the contact-kinin system and minimize brain lesion size, blood-brain barrier leakage, brain edema formation, and inflammation in our brain injury model.
Conclusions:
Stimulation of bradykinin release by activated factor XII probably plays a prominent role in expanding secondary brain damage by promoting brain edema formation and inflammation. Pharmacological blocking of activated factor XII could be a useful therapeutic principle in the treatment of TBI-associated pathologic processes by alleviating posttraumatic inflammation and brain edema formation.
Journal of Neuroinflammation
10.1186/s12974-017-0815-8
urn:nbn:de:bvb:20-opus-157490
Journal of Neuroinflammation (2017) 14:39. DOI: 10.1186/s12974-017-0815-8
680966
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Sarah Hopp
Marc W. Nolte
Christian Stetter
Christoph Kleinschnitz
Anna-Leena Sirén
Christiane Albert-Weissenberger
eng
uncontrolled
factor XII
eng
uncontrolled
focal brain lesion
eng
uncontrolled
brain edema
Medizin und Gesundheit
open_access
Neurochirurgische Klinik und Poliklinik
Neurologische Klinik und Poliklinik
OpenAIRE
Förderzeitraum 2017
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/15749/Hopp_Journal_of_Neuroinflammation.pdf
25956
2021
eng
2835–2840
11
19
article
1
--
--
--
Generation of a humanized FXII knock-in mouse-A powerful model system to test novel anti-thrombotic agents
Background
Effective inhibition of thrombosis without generating bleeding risks is a major challenge in medicine. Accumulating evidence suggests that this can be achieved by inhibition of coagulation factor XII (FXII), as either its knock-out or inhibition in animal models efficiently reduced thrombosis without affecting normal hemostasis. Based on these findings, highly specific inhibitors for human FXII(a) are under development. However, currently, in vivo studies on their efficacy and safety are impeded by the lack of an optimized animal model expressing the specific target, that is, human FXII.
Objective
The primary objective of this study is to develop and functionally characterize a humanized FXII mouse model.
Methods
A humanized FXII mouse model was generated by replacing the murine with the human F12 gene (genetic knock-in) and tested it in in vitro coagulation assays and in in vivo thrombosis models.
Results
These hF12\(^{KI}\) mice were indistinguishable from wild-type mice in all tested assays of coagulation and platelet function in vitro and in vivo, except for reduced expression levels of hFXII compared to human plasma. Targeting FXII by the anti-human FXIIa antibody 3F7 increased activated partial thromboplastin time dose-dependently and protected hF12\(^{KI}\) mice in an arterial thrombosis model without affecting bleeding times.
Conclusion
These data establish the newly generated hF12\(^{KI}\) mouse as a powerful and unique model system for in vivo studies on anti-FXII(a) biologics, supporting the development of efficient and safe human FXII(a) inhibitors.
Journal of Thrombosis and Haemostasis
10.1111/jth.15488
urn:nbn:de:bvb:20-opus-259567
publish
Journal of Thrombosis and Haemostasis 2021, 19(11):2835–2840. DOI: 10.1111/jth.15488
false
true
CC BY-NC: Creative-Commons-Lizenz: Namensnennung, Nicht kommerziell 4.0 International
Sarah Beck
David Stegner
Stefan Loroch
Ayesha A. Baig
Vanessa Göb
Cornelia Schumbutzki
Eva Eilers
Albert Sickmann
Frauke May
Marc W. Nolte
Con Panousis
Bernhard Nieswandt
eng
uncontrolled
hemostasis,
eng
uncontrolled
blood coagulation
eng
uncontrolled
factor XII
eng
uncontrolled
animal models
eng
uncontrolled
thrombosis
Medizin und Gesundheit
open_access
Rudolf-Virchow-Zentrum
Institut für Experimentelle Biomedizin
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/25956/Beck_Thrombosis.pdf
16737
2016
eng
e0146783
1
11
article
1
2018-08-27
--
--
The Coagulation Factor XIIa Inhibitor rHA-Infestin-4 Improves Outcome after Cerebral Ischemia/Reperfusion Injury in Rats
Background and Purpose
Ischemic stroke provokes severe brain damage and remains a predominant disease in industrialized countries. The coagulation factor XII (FXII)-driven contact activation system plays a central, but not yet fully defined pathogenic role in stroke development. Here, we investigated the efficacy of the FXIIa inhibitor rHA-Infestin-4 in a rat model of ischemic stroke using both a prophylactic and a therapeutic approach.
Methods
For prophylactic treatment, animals were treated intravenously with 100 mg/kg rHA-Infestin-4 or an equal volume of saline 15 min prior to transient middle cerebral artery occlusion (tMCAO) of 90 min. For therapeutic treatment, 100 mg/kg rHA-Infestin-4, or an equal volume of saline, was administered directly after the start of reperfusion. At 24 h after tMCAO, rats were tested for neurological deficits and blood was drawn for coagulation assays. Finally, brains were removed and analyzed for infarct area and edema formation.
Results
Within prophylactic rHA-Infestin-4 treatment, infarct areas and brain edema formation were reduced accompanied by better neurological scores and survival compared to controls. Following therapeutic treatment, neurological outcome and survival were still improved although overall effects were less pronounced compared to prophylaxis.
Conclusions
With regard to the central role of the FXII-driven contact activation system in ischemic stroke, inhibition of FXIIa may represent a new and promising treatment approach to prevent cerebral ischemia/reperfusion injury.
PLoS ONE
10.1371/journal.pone.0146783
urn:nbn:de:bvb:20-opus-167370
PLoS ONE 11(1):e0146783 (2016). DOI: 10.1371/journal.pone.0146783
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Jennifer Krupka
Frauke May
Thomas Weimer
Ingo Pragst
Christoph Kleinschnitz
Guido Stoll
Con Panousis
Gerhard Dickneite
Marc W. Nolte
eng
uncontrolled
coagulation factor XIIa
eng
uncontrolled
ischemic stroke
eng
uncontrolled
contact activation system
eng
uncontrolled
FXIIa inhibitor rHA-Infestin
Medizin und Gesundheit
open_access
Neurologische Klinik und Poliklinik
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/16737/Krupka_PLoS_ONE.PDF