Untersuchungen zur pharmakologischen Charakterisierung von Gerinnungsfaktor XIIa-Inhibitoren
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Philipps-Universität Marburg
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Abstract
While hemostasis involving platelet activation and blood coagulation is crucial to limit posttraumatic
blood loss, under pathological conditions it can also contribute to thrombosis. Furthermore, in clinical
scenarios where blood becomes exposed to anionic foreign surfaces like in extracorporeal membrane
oxygenation (ECMO) the intrinsic pathway of coagulation is initiated via activation of factor XII (FXII).
Consequently, these patients require a robust anticoagulative therapy, which is, however, associated
with an increased bleeding risk. Recent studies in rodents and primates have demonstrated that
deficiency or inhibition of FXIIa provided a reliable antithrombotic effect in several thrombosis
models. Most notably, physiological hemostasis was not affected in these animals. Therefore, the
first aim of the present thesis was to evaluate the antithrombotic efficacy of two specific FXIIainhibitors,
i.e. rHA-Infestin-4, a recombinant protein derived from the hematophagous insect
Triatoma infestans, and a fully human monoclonal antibody directed against FXIIa (anti-FXIIa MAb
3F7). Both FXIIa-inhibitors were tested in different thrombosis models and revealed a profound
antithrombotic efficacy (e. g. when thrombus formation was triggered by foreign surfaces in the
arteriovenous shunt model in mice and rabbits).
The second aim of this thesis was to investigate the neuroprotective effect of FXIIa-inhibition in a
murine ischemic stroke model with reperfusion injury (R/I). Recent stroke studies showed an improved
outcome in neurofunctional behavior and a reduced infarct volume in FXII-deficient mice,
probably due to a reduced R/I. An additional study confirmed the neuroprotective efficacy of prophylactic
FXIIa-inhibition by applying rHA-Infestin-4. Therefore, the efficacy of a prophylactic treatment
with anti-FXIIa MAb 3F7 was studied in this model of murine ischemic stroke in the present
thesis. Moreover, rHA-Infestin-4 was applied in a therapeutic approach. The best neuroprotection
was observed in the prophylactic approach, since the therapeutic rHA-Infestin-4 application could not
improve the disease outcome. In line with these results, the prophylactic FXIIa-inhibition ameliorated
the R/I-associated inflammatory reactions, microthrombosis and dramatically reduced mortality at 24
hours after reperfusion. Notably, the risk for intracranial hemorrhage was not increased.
Taken together, this thesis supports the assumption that targeting FXIIa may exert a potent antithrombotic
approach in clinical scenarios involving contact activation at foreign surfaces like ECMO
without interfering with physiological hemostasis. Additionally, inhibiting FXIIa prophylactically
significantly improved the disease outcome after ischemic stroke in mice.
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Dates
Created: 2015Issued: 2016-01-26
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
Keywords
Coagulation
DFG-subjects
Koagulation
DDC-Numbers
610
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Fries, Marion: Untersuchungen zur pharmakologischen Charakterisierung von Gerinnungsfaktor XIIa-Inhibitoren. : Philipps-Universität Marburg 2016-01-26. DOI: https://doi.org/10.17192/z2015.0319.
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This item has been published with the following license: In Copyright