A factor XIIa inhibitory antibody provides thromboprotection in extracorporeal circulation without increasing bleeding risk.
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.
Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, SE-171 76 Stockholm, Sweden.
Magnus
M
Larsson
Veronika
V
Rayzman
Marc W
MW
Nolte
Katrin F
KF
Nickel
Jenny
J
Björkqvist
Anne
A
Jämsä
Matthew P
MP
Hardy
Marion
M
Fries
Stefan
S
Schmidbauer
Patricia
P
Hedenqvist
Michael
M
Broomé
Ingo
I
Pragst
Gerhard
G
Dickneite
Michael J
MJ
Wilson
Andrew D
AD
Nash
Con
C
Panousis
Thomas
T
Renné
D000818:Animals; D000906:Antibodies / Q000494:pharmacology* / Q000627:therapeutic use*; D001166:Arteriovenous Shunt, Surgical; D001777:Blood Coagulation / Q000187:drug effects; D020134:Catalytic Domain; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018604:Epitope Mapping; D005112:Extracorporeal Circulation / Q000009:adverse effects*; D015956:Factor XIIa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006470:Hemorrhage / Q000188:drug therapy* / Q000209:etiology*; D006493:Heparin / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D011817:Rabbits; D012307:Risk Factors; D013045:Species Specificity; D013927:Thrombosis / Q000517:prevention & control*
D000906:Antibodies; D006493:Heparin; D015956:Factor XIIa