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Thromb Haemost 2013; 109(01): 53-60
DOI: 10.1160/TH12-05-0316
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

In vitro and in vivo evaluation of the effect of elevated factor VIII on the thrombogenic process

Mia Golder
1   Department of Pathology and Molecular Medicine, Richardson Laboratory, Queen’s University, Kingston, Ontario, Canada
*   Current address: Department of Pathology and Laboratory Medicine, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
,
Jeffrey Mewburn
2   Division of Cancer Biology and Genetics, Queen’s University Cancer Research Institute, Queen’s University, Kingston, Ontario, Canada
,
David Lillicrap
1   Department of Pathology and Molecular Medicine, Richardson Laboratory, Queen’s University, Kingston, Ontario, Canada
› Author Affiliations Financial support: This research was funded by the Heart and Stroke Foundation of Ontario (NA6386).
Further Information

Publication History

Received: 14 May 2012

Accepted after major revision: 09 October 2012

Publication Date:
25 November 2017 (online)

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Summary

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 nonlinear 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.

Keywords

Animal models - arterial thrombosis - factor VIII - intravital microscopy
 

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