title: Enhancement of rabbit jugular vein thrombolysis by neutralization of factor XI. In vivo evidence for a role of factor XI as an anti-fibrinolytic factor.
abstract: Recent in vitro studies have shown that fibrinolytic activity may be attenuated by a thrombin-activatable fibrinolysis inhibitor (TAFI), which is activated by thrombin, generated via the intrinsic pathway of coagulation in a factor XI-dependent way. Thus factor XI may play a role in the regulation of endogenous fibrinolysis. The aim of this study was to investigate the effect of in vivo inhibition of factor XI and TAFI in an experimental thrombosis model in rabbits. Incorporation of anti-factor XI antibodies in jugular vein thrombi resulted in an almost twofold increase in endogenous thrombolysis compared with a control antibody. A similar effect was observed when the anti-factor XI antibody was administered systemically. Inhibition of TAFI activity also resulted in a twofold increase in clot lysis whereas inhibition of both factor XI and TAFI activity had no additional effect. Thus, we provide the first in vivo evidence for enhanced thrombolysis through inhibition of clotting factor XI, demonstrating a novel role for the intrinsic pathway of coagulation. Furthermore we demonstrate that inhibition of TAFI had a similar effect on thrombolysis. We postulate that inhibition of factor XI activity enhances thrombolysis because of diminished indirect activation of TAFI.
authors.affiliation: Center for Hemostasis, Thrombosis, Atherosclerosis and Inflammation Research, Central Laboratory of The Netherlands Red Cross Blood Transfusion Service, 1100 DE, Amsterdam, The Netherlands.
authors.forename: M C
authors.initials: MC
authors.lastname: Minnema
authors.forename: P W
authors.initials: PW
authors.lastname: Friederich
authors.forename: M
authors.initials: M
authors.lastname: Levi
authors.forename: P A
authors.initials: PA
authors.lastname: von dem Borne
authors.forename: L O
authors.initials: LO
authors.lastname: Mosnier
authors.forename: J C
authors.initials: JC
authors.lastname: Meijers
authors.forename: B J
authors.initials: BJ
authors.lastname: Biemond
authors.forename: C E
authors.initials: CE
authors.lastname: Hack
authors.forename: B N
authors.initials: BN
authors.lastname: Bouma
authors.forename: H
authors.initials: H
authors.lastname: ten Cate
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D025901:Carboxypeptidase B2; D002268:Carboxypeptidases / Q000008:administration & dosage / Q000502:physiology; D005172:Factor XI / Q000502:physiology*; D005342:Fibrinolysis / Q000502:physiology*; D007601:Jugular Veins / Q000503:physiopathology*; D009500:Neutralization Tests; D010940:Plant Proteins / Q000008:administration & dosage; D011817:Rabbits; D011198:Solanum tuberosum; D013927:Thrombosis / Q000503:physiopathology*
chemical_list: D000906:Antibodies; D010940:Plant Proteins; D005172:Factor XI; D002268:Carboxypeptidases; D025901:Carboxypeptidase B2