TY  - JOUR
A1  - Göb, Vanessa
A1  - Voll, Maximilian G.
A1  - Zimmermann, Lena
A1  - Hemmen, Katharina
A1  - Stoll, Guido
A1  - Nieswandt, Bernhard
A1  - Schuhmann, Michael K.
A1  - Heinze, Katrin G.
A1  - Stegner, David
T1  - Infarct growth precedes cerebral thrombosis following experimental stroke in mice
JF  - Scientific Reports
N2  - Ischemic stroke is among the leading causes of disability and death worldwide. In acute ischemic stroke, successful recanalization of occluded vessels is the primary therapeutic aim, but even if it is achieved, not all patients benefit. Although blockade of platelet aggregation did not prevent infarct progression, cerebral thrombosis as cause of secondary infarct growth has remained a matter of debate. As cerebral thrombi are frequently observed after experimental stroke, a thrombus-induced impairment of the brain microcirculation is considered to contribute to tissue damage. Here, we combine the model of transient middle cerebral artery occlusion (tMCAO) with light sheet fluorescence microscopy and immunohistochemistry of brain slices to investigate the kinetics of thrombus formation and infarct progression. Our data reveal that tissue damage already peaks after 8 h of reperfusion following 60 min MCAO, while cerebral thrombi are only observed at later time points. Thus, cerebral thrombosis is not causative for secondary infarct growth during ischemic stroke.
KW  - cerebrovascular disorders
KW  - thrombosis
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265791
VL  - 11
IS  - 1
ER  - 
TY  - JOUR
A1  - Beck, Sarah
A1  - Stegner, David
A1  - Loroch, Stefan
A1  - Baig, Ayesha A.
A1  - Göb, Vanessa
A1  - Schumbutzki, Cornelia
A1  - Eilers, Eva
A1  - Sickmann, Albert
A1  - May, Frauke
A1  - Nolte, Marc W.
A1  - Panousis, Con
A1  - Nieswandt, Bernhard
T1  - Generation of a humanized FXII knock-in mouse-A powerful model system to test novel anti-thrombotic agents
JF  - Journal of Thrombosis and Haemostasis
N2  - 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.
KW  - hemostasis,
KW  - blood coagulation
KW  - factor XII
KW  - animal models
KW  - thrombosis
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259567
VL  - 19
IS  - 11
ER  -