BACKGROUND: Thrombus formation through the activation of tissue factor (TF) and factor (F) XI is a critical event in the onset of cardiovascular disease. TF expressed in atherosclerotic plaques and circulating blood is an important determinant of thrombogenicity that contributes to fibrin-rich thrombus formation after plaque disruption. However, the contribution of FXI to thrombus formation on disrupted plaques remains unclear. METHODS: A mouse monoclonal antibody against FXI and activated FXI (FXIa) (XI-5108) was generated by immunization with activated human FXI. Prothrombin time (PT), activated partial thromboplastin time (APTT), bleeding time, and ex vivo platelet aggregation in rabbits were measured before and after an intravenous bolus injection of XI-5108. We investigated the role of FXI upon arterial thrombus growth in the rabbit iliac artery in the presence of repeated balloon injury. RESULTS: The XI-5108 antibody reacted to the light chain of human and rabbit FXI/FXIa, and inhibited FXIa-initiated FXa and FXIa generation. Fibrin-rich thrombi developed on the injured neointima that was obviously immunopositive for glycoprotein IIb-IIIa, fibrin, TF, and FXI. Intravenous administration of XI-5108 (3.0 mg kg(-1)) remarkably reduced thrombus growth, and the APTT was significantly prolonged. However, PT, bleeding time and platelet aggregation were not affected. CONCLUSIONS: These results indicate that plasma FXI plays a potent role in thrombus growth on the injured neointima. Inhibition of plasma FXI activity might help to reduce thrombus growth on ruptured plaques without prolonging bleeding time.
BACKGROUND:Thrombus formation through the activation of tissue factor (TF) and factor (F) XI is a critical event in the onset of cardiovascular disease. TF expressed in atherosclerotic plaques and circulating blood is an important determinant of thrombogenicity that contributes to fibrin-rich thrombus formation after plaque disruption. However, the contribution of FXI to thrombus formation on disrupted plaques remains unclear. METHODS: A mouse monoclonal antibody against FXI and activated FXI (FXIa) (XI-5108) was generated by immunization with activated human FXI. Prothrombin time (PT), activated partial thromboplastin time (APTT), bleeding time, and ex vivo platelet aggregation in rabbits were measured before and after an intravenous bolus injection of XI-5108. We investigated the role of FXI upon arterial thrombus growth in the rabbit iliac artery in the presence of repeated balloon injury. RESULTS: The XI-5108 antibody reacted to the light chain of human and rabbit FXI/FXIa, and inhibited FXIa-initiated FXa and FXIa generation. Fibrin-rich thrombi developed on the injured neointima that was obviously immunopositive for glycoprotein IIb-IIIa, fibrin, TF, and FXI. Intravenous administration of XI-5108 (3.0 mg kg(-1)) remarkably reduced thrombus growth, and the APTT was significantly prolonged. However, PT, bleeding time and platelet aggregation were not affected. CONCLUSIONS: These results indicate that plasma FXI plays a potent role in thrombus growth on the injured neointima. Inhibition of plasma FXI activity might help to reduce thrombus growth on ruptured plaques without prolonging bleeding time.
Authors: Philberta Y Leung; Sawan Hurst; Michelle A Berny-Lang; Norah G Verbout; David Gailani; Erik I Tucker; Ruikang K Wang; Owen J T McCarty; András Gruber Journal: Transl Stroke Res Date: 2012-09 Impact factor: 6.829
Authors: Jeffrey R Crosby; Ulla Marzec; Alexey S Revenko; Chenguang Zhao; Dacao Gao; Anton Matafonov; David Gailani; A Robert MacLeod; Erik I Tucker; Andras Gruber; Stephen R Hanson; Brett P Monia Journal: Arterioscler Thromb Vasc Biol Date: 2013-04-04 Impact factor: 8.311