Homozygosity for factor V Leiden leads to enhanced thrombosis and atherosclerosis in mice.
BACKGROUND
Activated protein C resistance due to factor V Leiden (FVL) is a common genetic risk factor for venous thrombosis in humans. Although the impact of FVL on the development of venous thrombosis is well established, its effect on arterial thrombosis and atherosclerosis is controversial.


RESULTS
To determine the effect of the FVL mutation on arterial thrombosis in the mouse, wild-type (Fv+/+), heterozygous FVL (FvQ/+), and homozygous FVL (FvQ/Q) mice underwent photochemical carotid arterial injury to induce occlusive thrombosis. FvQ/Q mice formed occlusive thromboses 27+/-3 minutes (n=7) after the onset of injury, which was significantly shorter than that observed for Fv+/+ mice (56+/-7 minutes, n=9, P<0.01), whereas FvQ/+ mice (41+/-7 minutes, n=5) were intermediate (P=0.5, compared with Fv+/+). To determine the source of FVL relevant to the enhanced vascular thrombosis, bone marrow transplantation experiments were performed between Fv+/+ and FvQ/Q mice. FvQ/Q mice transplanted with Fv+/+ bone marrow formed occlusive thromboses at 35+/-5 minutes (n=7, P<0.05 compared with Fv+/+ mice), whereas Fv+/+ mice transplanted with FvQ/Q bone marrow occluded at 59+/-7 minutes (n=6, P<0.001 compared with FvQ/Q mice). To assess the effect of the FVL mutation on the development of atherosclerosis, FvQ/Q mice were crossed with the atherosclerosis-prone apolipoprotein E (ApoE)-deficient strain (ApoE-/-) to generate FvQ/Q,ApoE-/- mice. By 52 weeks of age, FvQ/Q,ApoE-/- mice (n=8) had developed more aortic atherosclerosis (40+/-6% lesion area) compared with Fv+/+,ApoE-/- mice (15+/-3% lesion area; n=12, P<0.02).


CONCLUSIONS
In conclusion, homozygosity for the FVL mutation in mice leads to enhanced arterial thrombosis and atherosclerosis. The source of the FVL leading to accelerated thrombosis appears to be circulating, non-platelet-derived plasma FVL.
Eitzman
Daniel T
DT
Division of Cardiology, University of Michigan Medical Center, Ann Arbor 48109-0644, USA. deitzman@umich.edu
Westrick
Randal J
RJ
Shen
Yuechun
Y
Bodary
Peter F
PF
Gu
Shufang
S
Manning
Sara L
SL
Dobies
Sarah L
SL
Ginsburg
David
D
D000818:Animals; D001018:Aortic Diseases / Q000209:etiology; D001161:Arteriosclerosis / Q000209:etiology*; D016026:Bone Marrow Transplantation; D020212:Carotid Artery Injuries; D002341:Carotid Artery Thrombosis / Q000209:etiology; D004195:Disease Models, Animal; D005165:Factor V / Q000235:genetics*; D005340:Fibrinogen / Q000096:biosynthesis; D006720:Homozygote; D051379:Mice; D008817:Mice, Mutant Strains; D010777:Photochemistry; D013917:Thrombin / Q000096:biosynthesis; D013927:Thrombosis / Q000209:etiology*
C095381:factor V Leiden; D005165:Factor V; D005340:Fibrinogen; D013917:Thrombin