A factor XIIa inhibitory antibody provides thromboprotection in extracorporeal circulation without increasing bleeding risk
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A factor XIIa inhibitory antibody provides thromboprotection in extracorporeal circulation without increasing bleeding risk. / Larsson, Magnus; Rayzman, Veronika; Nolte, Marc W; Nickel, Katrin F; Björkqvist, Jenny; Jämsä, Anne; Hardy, Matthew P; Fries, Marion; Schmidbauer, Stefan; Hedenqvist, Patricia; Broomé, Michael; Pragst, Ingo; Dickneite, Gerhard; Wilson, Michael J; Nash, Andrew D; Panousis, Con; Renné, Thomas.
in: SCI TRANSL MED, Jahrgang 6, Nr. 222, 05.02.2014, S. 222ra17.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - A factor XIIa inhibitory antibody provides thromboprotection in extracorporeal circulation without increasing bleeding risk
AU - Larsson, Magnus
AU - Rayzman, Veronika
AU - Nolte, Marc W
AU - Nickel, Katrin F
AU - Björkqvist, Jenny
AU - Jämsä, Anne
AU - Hardy, Matthew P
AU - Fries, Marion
AU - Schmidbauer, Stefan
AU - Hedenqvist, Patricia
AU - Broomé, Michael
AU - Pragst, Ingo
AU - Dickneite, Gerhard
AU - Wilson, Michael J
AU - Nash, Andrew D
AU - Panousis, Con
AU - Renné, Thomas
PY - 2014/2/5
Y1 - 2014/2/5
N2 - 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.
AB - 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.
U2 - 10.1126/scitranslmed.3006804
DO - 10.1126/scitranslmed.3006804
M3 - SCORING: Journal article
C2 - 24500405
VL - 6
SP - 222ra17
JO - SCI TRANSL MED
JF - SCI TRANSL MED
SN - 1946-6234
IS - 222
ER -