Factor XI-dependence of surface- and tissue factor-initiated thrombus propagation in primates.
Thrombin, generated through activation of factor XI (FXI) and/or tissue factor (TF)-factor VIIa, is essential for thrombosis and hemostasis. We investigated the role of FXI-dependent thrombus propagation under arterial flow conditions producing rapid thrombus growth that, after the initiation phase, could limit the availability of TF at the blood/thrombus interface. Thrombosis was initiated by knitted dacron or TF-presenting teflon grafts deployed into arteriovenous shunts in baboons treated with antihuman FXI antibody (aFXI). Although aFXI did not prevent thrombus initiation, it markedly reduced intraluminal thrombus growth on both surfaces. The antithrombotic effect of aFXI was comparable with that of heparin at doses that significantly prolonged the partial thromboplastin time (APTT), prothrombin time (PT), and bleeding time (BT). aFXI also prolonged the APTT, but the PT and BT were unaffected. Thus, antithrombotic targeting of FXI might inhibit thrombosis with relatively modest hemostatic impairment versus strategies targeting other coagulation factors.
Gruber
Andras
A
Department of Biomedical Engineering at Georgia Institute of Technology & Emory University School of Medicine, 1639 Pierce Dr, WMB Suite 2001, Atlanta, GA 30322-4600, USA. agruber@emory.edu
Hanson
Stephen R
SR
D000818:Animals; D000906:Antibodies / Q000494:pharmacology / Q000627:therapeutic use; D000910:Antibodies, Heterophile; D001166:Arteriovenous Shunt, Surgical / Q000009:adverse effects; D001780:Blood Coagulation Tests; D001792:Blood Platelets / Q000473:pathology; D005172:Factor XI / Q000276:immunology / Q000502:physiology*; D005337:Fibrin / Q000378:metabolism; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D010215:Papio; D011323:Primates; D013925:Thromboplastin / Q000502:physiology*; D013927:Thrombosis / Q000188:drug therapy / Q000209:etiology*
D000906:Antibodies; D000910:Antibodies, Heterophile; D005337:Fibrin; D006493:Heparin; D005172:Factor XI; D013925:Thromboplastin