title: In vitro  and  in vivo  evaluation of the effect of elevated factor VIII on the thrombogenic process.
abstract: Factor VIII (FVIII), a procoagulant cofactor, plays a crucial role in the intrinsic coagulation cascade. A causal association between elevated FVIII levels and venous thrombosis incidence has been established; no such association has been confirmed with arterial thrombosis. The independent role of elevated FVIII levels in arteriolar thrombosis was evaluated in a mouse model to determine the thrombogenic potential of elevated levels of FVIII. The  in vitro  thrombogenic effect of elevated FVIII levels was examined using thrombin-antithrombin (TAT) complex generation and thromboelastography (TEG) assays. The thrombogenic potential of acute and extended elevation of circulating FVIII levels was assessed using ferric chloride induced injury of the cremaster arterioles. The rate of TAT complex formation, and the final concentration of TAT complexes, significantly increased as FVIII levels were elevated from 100% to 400% FVIII activity. TEG analysis of fibrin and clot formation showed that as FVIII levels were elevated, the time to initial fibrin formation decreased and the rate of fibrin formation increased. The acute elevation of circulating FVIII to 400% FVIII activity resulted in significantly decreased times to vessel occlusion. Prolonged elevation of FVIII activity did not significantly affect time to vessel occlusion. In conclusion, acute elevations in FVIII levels result in a non-linear thrombogenic effect, with non-significant increases in thrombogenic risk within the physiological range (FVIII levels up to 200%). Prolonged elevation of plasma FVIII did not further increase the thrombogenic potential of elevated FVIII levels.
authors.affiliation: Department of Pathology and Molecular Medicine, 201 Richardson Laboratory, Queen's University, Kingston, Ontario, K7L 3N6 Canada.
authors.forename: M
authors.initials: M
authors.lastname: Golder
authors.forename: J
authors.initials: J
authors.lastname: Mewburn
authors.forename: D
authors.initials: D
authors.lastname: Lillicrap
mesh_terms: D000818:Animals; D000990:Antithrombin III; D001777:Blood Coagulation / Q000235:genetics; D002712:Chlorides; D004195:Disease Models, Animal; D005169:Factor VIII / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D005290:Ferric Compounds; D006467:Hemophilia A / Q000097:blood / Q000150:complications* / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010447:Peptide Hydrolases / Q000097:blood; D013916:Thrombelastography; D013927:Thrombosis / Q000097:blood* / Q000139:chemically induced / Q000235:genetics; D013997:Time Factors; D015854:Up-Regulation; D057772:Vascular System Injuries / Q000097:blood* / Q000139:chemically induced / Q000235:genetics
chemical_list: D002712:Chlorides; D005290:Ferric Compounds; C046193:antithrombin III-protease complex; C078147:F8 protein, human; D000990:Antithrombin III; D005169:Factor VIII; D010447:Peptide Hydrolases; C024555:ferric chloride