A Factor XIIa Inhibitory Antibody Provides Thromboprotection in Extracorporeal Circulation Without Increasing Bleeding Risk
| Autor: | Con Panousis, Anne Jämsä, Ingo Pragst, Patricia Hedenqvist, Marion Fries, Jenny Björkqvist, Matthew P. Hardy, Michael J. Wilson, Michael Broomé, Andrew D. Nash, Marc W. Nolte, Magnus Larsson, Katrin F. Nickel, Stefan Schmidbauer, Thomas Renné, Gerhard Dickneite, Veronika Rayzman |
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| Rok vydání: | 2014 |
| Předmět: |
Extracorporeal Circulation
medicine.medical_treatment Hemorrhage Factor XIIa Antibodies law.invention Mice Arteriovenous Shunt Surgical Species Specificity Risk Factors law Catalytic Domain medicine Extracorporeal membrane oxygenation Cardiopulmonary bypass Animals Humans Thrombus Blood Coagulation Factor XII Dose-Response Relationship Drug Heparin business.industry Extracorporeal circulation Thrombosis General Medicine medicine.disease 3. Good health Disease Models Animal Coagulation Anesthesia Rabbits business Epitope Mapping medicine.drug |
| Zdroj: | Science Translational Medicine. 6 |
| ISSN: | 1946-6242 1946-6234 |
| Popis: | Currently used anticoagulants prevent thrombosis but increase bleeding. We show an anticoagulation therapy without bleeding risk based on a plasma protease factor XII function-neutralizing antibody. We screened for antibodies against activated factor XII (FXIIa) using phage display and demonstrated that recombinant fully human antibody 3F7 binds into the FXIIa enzymatic pocket. 3F7 interfered with FXIIa-mediated coagulation, abolished thrombus formation under flow, and blocked experimental thrombosis in mice and rabbits. We adapted an extracorporeal membrane oxygenation (ECMO) cardiopulmonary bypass system used for infant therapy to analyze clinical applicability of 3F7 in rabbits. 3F7 provided thromboprotection as efficiently as heparin, and both drugs prevented fibrin deposition and thrombosis within the extracorporeal circuit. Unlike heparin, 3F7 treatment did not impair the hemostatic capacity and did not increase bleeding from wounds. These data establish that targeting of FXIIa is a safe mode of thromboprotection in bypass systems, and provide a clinically relevant anticoagulation strategy that is not complicated by excess bleeding. |
| Databáze: | OpenAIRE |
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