Homozygosity for Factor V Leiden Leads to Enhanced Thrombosis and Atherosclerosis in Mice

Eitzman, Daniel T.; Westrick, Randal J.; Shen, Yuechun; Bodary, Peter F.; Gu, Shufang; Manning, Sara L.; Dobies, Sarah L.; Ginsburg, David

doi:10.1161/01.cir.0000160854.75779.e8

Cited by 69 publications

(57 citation statements)

References 32 publications

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“…14 Eitzman et al report that the factor V Leiden mouse is abnormally susceptible to experimental thrombosis induced by photochemical injury of the carotid artery. 9 This finding is consistent with reports of accelerated thrombosis in mice with other genetic abnormalities of coagulation that lead to increased thrombin generation, such as deficiency of thrombomodulin 15 or heparin cofactor II. 16 Taken together, these observations demonstrate definitively that unregulated thrombin generation can contribute to arterial thrombosis, at least in mice.…”

Section: See P 1822supporting

confidence: 91%

“…7 An article by Eitzman et al in this issue of Circulation sheds new light on the influence of factor V Leiden in arterial disease. 9 Eitzman and colleagues use a murine model, the factor V Leiden mouse, to examine the effects of excessive thrombin generation on arterial thrombosis and the development of atherosclerosis. The factor V Leiden mouse carries the murine equivalent of human factor V Leiden, introduced by engineering a point mutation into the murine factor V gene.…”

Section: See P 1822mentioning

confidence: 99%

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Another Lesson From the Factor V Leiden Mouse

Lentz

2005

Circulation

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Section: See P 1822supporting

confidence: 91%

Section: See P 1822mentioning

confidence: 99%

Another Lesson From the Factor V Leiden Mouse

Lentz

2005

Circulation

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“…22,23 A mouse model carrying the homologous murine FV Leiden mutation (R504Q) showed enhanced venous thrombosis, consistent with an increased incidence of VTE in human FV Leiden carriers. 24,25 Thus, FV Leiden mice provide a valuable in vivo model of thrombosis-associated diseases in whites and have been studied under various stimulations or pathophysiologic conditions. [25][26][27] Recent guidelines for establishing pathogenic causality of rare genetic variants emphasize that the strongest evidence for causality comes from disruption of the candidate gene in a model organism (eg, a mouse) that recapitulates the pathology in humans.…”

Section: Introductionmentioning

confidence: 99%

Exacerbated venous thromboembolism in mice carrying a protein S K196E mutation

Banno

Kita

Fernández

et al. 2015

Blood

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Key Points• A protein S-K196E mutation reduced its activated protein C cofactor activity in recombinant murine protein S-K196E and in K196E mutant mice.• Mice carrying a protein S-K196E mutation or heterozygous protein S deficiency were more vulnerable to venous thrombosis than wild-type mice.Protein S (PS) acts as an anticoagulant cofactor for activated protein C in regulation of blood coagulation. The K196E mutation in PS is a race-specific genetic risk factor for venous thromboembolism with a prevalence of ∼2% within the Japanese population. To evaluate the thrombosis risk of the PS-K196E mutation, we generated PS-K196E knockin mice and heterozygous PS-deficient mice. We analyzed their thrombotic states, comparing with mice carrying the factor V Leiden mutation (FV-R504Q), a race-specific genetic risk for venous thrombosis in whites. PS-K196E mice grew normally but had decreased activated protein C cofactor activity in plasma. Purified recombinant murine PS-K196E showed the same decreased activated protein C cofactor activity. A deep vein thrombosis model of electrolytic inferior vena cava injury and pulmonary embolism models induced by infusion of tissue factor or polyphosphates revealed that PS-K196E mice, heterozygous PS-deficient mice, and FV-R504Q mice were much more susceptible to venous thrombosis compared with wild-type mice. Transient middle cerebral artery ischemiareperfusion injury model studies demonstrated that both PS-K196E mice and heterozygous PS-deficient mice had cerebral infarction similar to wild-type mice, consistent with human observations. Our in vitro and in vivo results support a causal relationship between the PS-K196E mutation and venous thrombosis and indicate that PS-K196E mice can provide an in vivo evaluation system to help uncovering racial differences in thrombotic

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“…Therefore, sP-selectin can prime leukocyte integrin activation and leukocyte adhesion during inflammation, 31 and this activity could explain the enhanced atherosclerotic lesion growth with elevated recruitment of monocytes to the lesion in the P-sel ⌬CT/⌬CT /apoE Ϫ/Ϫ mice. In addition, elevated procoagulant activity was shown to promote atherosclerosis 52,53 and may stimulate platelet activation that enhances lesion growth as well. 54,55 Our animal results are also in agreement with clinical studies showing that increased sP-selectin is associated with increased plasma LDL in hypercholesterolemic individuals.…”

Section: Increased Levels Of Sp-selectin Accelerate Atherosclerosismentioning

confidence: 99%

Elevated levels of soluble P-selectin in mice alter blood-brain barrier function, exacerbate stroke, and promote atherosclerosis

Kisucka

Chauhan

Zhao

et al. 2009

Blood

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Cerebrovascular and cardiovascular diseases are a major cause of morbidity and mortality. Soluble P-selectin (sP-selectin) is a biomarker for platelet/endothelial activation and is considered a risk factor for vascular disease. sP-selectin enhances procoagulant activity by inducing leukocyte-derived microparticle production and promotes activation of leukocyte integrins. However, it is not known whether it directly contributes to vascular complications. We investigated the effect of increased levels of sP-selectin on bloodbrain barrier (BBB) function, stroke outcome, and atherosclerosis by comparing wild-type mice with P-sel ⌬CT/⌬CT mice in which the endogenous P-selectin gene was replaced with a mutant that produces abnormally high plasma levels of sP-selectin. P-sel ⌬CT/⌬CT mice presented several abnormalities, including (1) higher BBB permeability, with 25% of the animals showing differential permeability between the right and left hemispheres;(2) altered social behavior with increased aggression; (3) larger infarcts in the middle cerebral artery occlusion ischemic stroke model; and (4) increased susceptibility to atherosclerotic, macrophage-rich lesion development in both male and female mice on the apoE ؊/؊ genetic background. Thus, elevated sP-selectin is not only a biomarker for vascular disease, but also may contribute directly to atherosclerosis and cerebrovascular complications. (Blood. 2009;113:6015-6022)

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Homozygosity for Factor V Leiden Leads to Enhanced Thrombosis and Atherosclerosis in Mice

Cited by 69 publications

References 32 publications

Another Lesson From the Factor V Leiden Mouse

Another Lesson From the Factor V Leiden Mouse

Exacerbated venous thromboembolism in mice carrying a protein S K196E mutation

Elevated levels of soluble P-selectin in mice alter blood-brain barrier function, exacerbate stroke, and promote atherosclerosis

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