Untersuchungen zur pharmakologischen Charakterisierung von Gerinnungsfaktor XIIa-Inhibitoren
Unter physiologischen Bedingungen limitiert die Hämostase nach einer Gefäßverletzung den Blutverlust. Dagegen fördern eine Plättchen-Aktivierung und die Blutgerinnung unter pathologischen Bedingungen die Entstehung einer Thrombose. Hierbei bewirkt der Kontakt zwischen Blut und Fremdoberflächen di...
Pharmakologie und Toxikologie
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- 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.