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  • 1
    Online Resource
    Online Resource
    Spontaneous thrombosis in mice carrying the factor V Leiden mutation
    American Society of Hematology ; 2000
    In:  Blood Vol. 96, No. 13 ( 2000-12-15), p. 4222-4226
    Details
    In: Blood, American Society of Hematology, Vol. 96, No. 13 ( 2000-12-15), p. 4222-4226
    Abstract: A polymorphism in coagulation factor V, factor V Leiden (FVL), is the major known genetic risk factor for thrombosis in humans. Approximately 10% of mutation carriers experience clinically significant thrombosis in their lifetime. In a small subset of patients, thrombosis is associated with coinheritance of other prothrombotic gene mutations. However, the potential contribution of additional genetic risk factors in the majority of patients remains unknown. To gain insight into the molecular basis for the variable expressivity of FVL, mice were generated carrying the homologous mutation (R504Q [single-letter amino acid codes]) inserted into the endogenous murine Fv gene. Adult heterozygous (FvQ/+) and homozygous (FvQ/Q) mice are viable and fertile and exhibit normal survival. Compared with wild-type mice, adult FvQ/Q mice demonstrate a marked increase in spontaneous tissue fibrin deposition. No differences in fetal development or survival are observed among FvQ/Q,FvQ/+ or control littermates on the C57BL/6J genetic background. In contrast, on a mixed 129Sv-C57BL/6J genetic background,FvQ/Q mice develop disseminated intravascular thrombosis in the perinatal period, resulting in significant mortality shortly after birth. These results may explain the high degree of conservation of the R504/R506 activated protein C cleavage site within FV among mammalian species and suggest an important contribution of other genetic factors to the thrombosis associated with FVL in humans.
    Type of Medium: Online Resource
    ISSN: 1528-0020 , 0006-4971
    URL: Article
    DOI: 10.1182/blood.V96.13.4222
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2000
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 2
    Online Resource
    Online Resource
    Lethal Perinatal Thrombosis in Mice Resulting From the Interaction of Tissue Factor Pathway Inhibitor Deficiency and Factor V Leiden
    Ovid Technologies (Wolters Kluwer Health) ; 2002
    In:  Circulation Vol. 105, No. 18 ( 2002-05-07), p. 2139-2142
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 105, No. 18 ( 2002-05-07), p. 2139-2142
    Abstract: Background — Factor V Leiden (FVL) is a common genetic risk factor for thrombosis in humans. The incomplete penetrance of FVL suggests important contributions from other genetic or environmental modifying factors. Variation in the expression of tissue factor pathway inhibitor ( TFPI ) has also been proposed as a risk factor for venous thrombosis and has been shown to enhance the prothrombotic effect of FVL in vitro. Methods and Results — To examine the potential in vivo interaction between Tfpi and FvL , we analyzed crosses between mice carrying FvL and a deficiency of TFPI. The Fv Q/Q , Tfpi +/− genotype was nearly completely fatal in the early perinatal period. Increased fibrin deposition was observed in multiple organs from the Fv Q/Q , Tfpi +/− fetuses, suggesting disseminated thrombosis. Conclusions — These observations demonstrate the prothrombotic effect of modest variations in the level of TFPI expression and suggest that TFPI could be an important genetic modifier for the thrombosis associated with FVL in humans.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/01.CIR.0000017361.39256.82
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2002
    detail.hit.zdb_id: 1466401-X
    detail.hit.zdb_id: 80099-5
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  • 3
    Online Resource
    Online Resource
    Spontaneous thrombosis in mice carrying the factor V Leiden mutation
    American Society of Hematology ; 2000
    In:  Blood Vol. 96, No. 13 ( 2000-12-15), p. 4222-4226
    Details
    In: Blood, American Society of Hematology, Vol. 96, No. 13 ( 2000-12-15), p. 4222-4226
    Abstract: A polymorphism in coagulation factor V, factor V Leiden (FVL), is the major known genetic risk factor for thrombosis in humans. Approximately 10% of mutation carriers experience clinically significant thrombosis in their lifetime. In a small subset of patients, thrombosis is associated with coinheritance of other prothrombotic gene mutations. However, the potential contribution of additional genetic risk factors in the majority of patients remains unknown. To gain insight into the molecular basis for the variable expressivity of FVL, mice were generated carrying the homologous mutation (R504Q [single-letter amino acid codes]) inserted into the endogenous murine Fv gene. Adult heterozygous (FvQ/+) and homozygous (FvQ/Q) mice are viable and fertile and exhibit normal survival. Compared with wild-type mice, adult FvQ/Q mice demonstrate a marked increase in spontaneous tissue fibrin deposition. No differences in fetal development or survival are observed among FvQ/Q,FvQ/+ or control littermates on the C57BL/6J genetic background. In contrast, on a mixed 129Sv-C57BL/6J genetic background,FvQ/Q mice develop disseminated intravascular thrombosis in the perinatal period, resulting in significant mortality shortly after birth. These res ults may explain the high degree of conservation of the R504/R506 activated protein C cleavage site within FV among mammalian species and suggest an important contribution of other genetic factors to the thrombosis associated with FVL in humans.
    Type of Medium: Online Resource
    ISSN: 1528-0020 , 0006-4971
    URL: Article
    DOI: 10.1182/blood.V96.13.4222.h8004222_4222_4226
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2000
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
    Online Resource
    Online Resource
    Deficiency of Tissue Factor Pathway Inhibitor Promotes Atherosclerosis and Thrombosis in Mice
    Ovid Technologies (Wolters Kluwer Health) ; 2001
    In:  Circulation Vol. 103, No. 25 ( 2001-06-26), p. 3044-3046
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 103, No. 25 ( 2001-06-26), p. 3044-3046
    Abstract: Background —Tissue factor initiates blood coagulation after atherosclerotic plaque disruption. Tissue factor pathway inhibitor (TFPI) inhibits tissue factor activity and may reduce thrombus formation in this setting. We evaluated the effect of heterozygous TFPI deficiency on the development of atherosclerosis and thrombosis in atherosclerosis-prone mice. Methods and Results —Mice with a combined heterozygous TFPI deficiency and homozygous apolipoprotein E deficiency (TFPI +/– /apoE –/– ) were generated by crossbreeding, and they were analyzed for atherosclerosis throughout the vascular tree. Compared with mice with a normal TFPI genotype (TFPI +/+ /apoE –/– ), mice with a TFPI deficiency exhibited a greater atherosclerotic burden involving the carotid and common iliac arteries. Staining for active tissue factor within the plaque revealed more activity in TFPI +/– /apoE –/– mice compared with TFPI +/+ /apoE –/– mice. Consistent with increased plaque tissue factor activity, the time to occlusive thrombosis after photochemical carotid plaque injury was significantly decreased in TFPI +/– /apoE –/– mice. Conclusions —These observations indicate that TFPI protects from atherosclerosis and is an important regulator of the thrombosis that occurs in the setting of atherosclerosis.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/hc2501.092492
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2001
    detail.hit.zdb_id: 1466401-X
    detail.hit.zdb_id: 80099-5
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  • 5
    Online Resource
    Online Resource
    Heparin cofactor II inhibits arterial thrombosis after endothelial injury
    American Society for Clinical Investigation ; 2002
    In:  Journal of Clinical Investigation Vol. 109, No. 2 ( 2002-1-15), p. 213-219
    Details
    In: Journal of Clinical Investigation, American Society for Clinical Investigation, Vol. 109, No. 2 ( 2002-1-15), p. 213-219
    Type of Medium: Online Resource
    ISSN: 0021-9738
    URL: Article
    DOI: 10.1172/JCI0213432
    Language: English
    Publisher: American Society for Clinical Investigation
    Publication Date: 2002
    detail.hit.zdb_id: 3067-3
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  • 6
    Online Resource
    Online Resource
    Hyperlipidemia Promotes Thrombosis After Injury to Atherosclerotic Vessels in Apolipoprotein E–Deficient Mice
    Ovid Technologies (Wolters Kluwer Health) ; 2000
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 20, No. 7 ( 2000-07), p. 1831-1834
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 20, No. 7 ( 2000-07), p. 1831-1834
    Abstract: Abstract —The increased risk of hyperlipidemia on the development of complications of atherosclerosis is well established. Cholesterol-lowering therapies lead to a decrease in the incidence of vascular thrombotic events that is out of proportion to the reduction in plaque size. This suggests that the occurrence of acute thrombosis overlying a disrupted plaque is influenced by changes in lipid levels. The influence of acute hyperlipidemia on the development of thrombosis overlying an atherosclerotic plaque in vivo has not been extensively studied. We used a murine model of vascular injury induced by a photochemical reaction to elicit thrombus formation overlying an atherosclerotic plaque. Fifteen apolipoprotein E–deficient mice were maintained on normal chow until the age of 30 weeks. Five days before the induction of thrombosis, 6 mice were started on a high fat diet, and 9 mice were continued on normal chow. Mice then underwent photochemical injury to the common carotid artery immediately proximal to the carotid bifurcation, where an atherosclerotic plaque is consistently present. Mice maintained on normal chow developed occlusive thrombi, determined by cessation of blood flow, 44±5 minutes (mean±SEM) after photochemical injury, whereas mice fed a high fat chow developed occlusive thrombosis at 27±3 minutes ( P 〈 0.02). Histological analysis confirmed the presence of acute thrombus formation overlying an atherosclerotic plaque. These studies demonstrate a useful model for assessing the determinants of thrombosis in the setting of atherosclerosis and show that acute elevations in plasma cholesterol facilitate thrombus formation at sites of atherosclerosis after vascular injury.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/01.ATV.20.7.1831
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2000
    detail.hit.zdb_id: 1221433-4
    detail.hit.zdb_id: 1494427-3
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  • 7
    Online Resource
    Online Resource
    Homozygosity for Factor V Leiden Leads to Enhanced Thrombosis and Atherosclerosis in Mice
    Ovid Technologies (Wolters Kluwer Health) ; 2005
    In:  Circulation Vol. 111, No. 14 ( 2005-04-12), p. 1822-1825
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 111, No. 14 ( 2005-04-12), p. 1822-1825
    Abstract: 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. Methods and Results— To determine the effect of the FVL mutation on arterial thrombosis in the mouse, wild-type ( Fv +/+ ), heterozygous FVL ( Fv Q /+ ), and homozygous FVL ( Fv Q/Q ) mice underwent photochemical carotid arterial injury to induce occlusive thrombosis. Fv Q/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 Fv Q /+ 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 Fv Q/Q mice. Fv Q/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 Fv Q/Q bone marrow occluded at 59±7 minutes (n=6, P 〈 0.001 compared with Fv Q/Q mice). To assess the effect of the FVL mutation on the development of atherosclerosis, Fv Q/Q mice were crossed with the atherosclerosis-prone apolipoprotein E (ApoE)–deficient strain ( ApoE −/− ) to generate Fv Q/Q ,ApoE −/− mice. By 52 weeks of age, Fv Q/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.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/01.CIR.0000160854.75779.E8
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2005
    detail.hit.zdb_id: 1466401-X
    detail.hit.zdb_id: 80099-5
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  • 8
    Online Resource
    Online Resource
    Plasminogen activator inhibitor-1 deficiency protects against atherosclerosis progression in the mouse carotid artery
    American Society of Hematology ; 2000
    In:  Blood Vol. 96, No. 13 ( 2000-12-15), p. 4212-4215
    Details
    In: Blood, American Society of Hematology, Vol. 96, No. 13 ( 2000-12-15), p. 4212-4215
    Abstract: Dissolution of the fibrin blood clot is regulated in large part by plasminogen activator inhibitor-1 (PAI-1). Elevated levels of plasma PAI-1 may be an important risk factor for atherosclerotic vascular disease and are associated with premature myocardial infarction. The role of the endogenous plasminogen activation system in limiting thrombus formation following atherosclerotic plaque disruption is unknown. This study found that genetic deficiency for PAI-1, the primary physiologic regulator of tissue-type plasminogen activator (tPA), prolonged the time to occlusive thrombosis following photochemical injury to carotid atherosclerotic plaque in apolipoprotein E-deficient (apoE−/−) mice. However, anatomic analysis revealed a striking difference in the extent of atherosclerosis at the carotid artery bifurcation between apoE−/− mice and mice doubly deficient for apoE and PAI-1 (PAI-1−/−/apoE−/−). Consistent with a previous report, PAI-1+/+/apoE−/−and PAI-1−/−/apoE−/− mice developed similar atherosclerosis in the aortic arch. The marked protection from atherosclerosis progression at the carotid bifurcation conferred by PAI-1 deficiency suggests a critical role for PAI-1 in the pathogenesis of atherosclerosis at sites of turbulent flow, potentially through the inhibition of fibrin clearance. Consistent with this hypothesis, intense fibrinogen/fibrin staining was observed in atherosclerotic lesions at the carotid bifurcation compared to the aortic arch. These observations identify significant differences in the pathogenesis of atherosclerosis at varying sites in the vascular tree and suggest a previously unappreciated role for the plasminogen activation system in atherosclerosis progression at sites of turbulent flow.
    Type of Medium: Online Resource
    ISSN: 1528-0020 , 0006-4971
    URL: Article
    DOI: 10.1182/blood.V96.13.4212
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2000
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 9
    Online Resource
    Online Resource
    Plasminogen activator inhibitor-1 and vitronectin promote vascular thrombosis in mice
    American Society of Hematology ; 2000
    In:  Blood Vol. 95, No. 2 ( 2000-01-15), p. 577-580
    Details
    In: Blood, American Society of Hematology, Vol. 95, No. 2 ( 2000-01-15), p. 577-580
    Abstract: Occlusive thrombosis depends on the net balance between platelets, coagulation, and fibrinolytic factors. Epidemiologic information suggests that plasminogen activator inhibitor-1 (PAI-1), a central regulator of the fibrinolytic system, plays an important role in determining the overall risk for clinically significant vascular thrombosis. Vitronectin (VN), an abundant plasma and matrix glycoprotein, binds PAI-1 and stabilizes its active conformation. This study assessed the role of PAI-1 and VN expression in the formation of occlusive vascular thrombosis following arterial or venous injury. The common carotid arteries of 17 wild-type (WT) mice and 8 mice deficient in PAI-1 were injured photochemically while blood flow was continuously monitored. WT mice developed occlusive thrombi at 52.0 ± 3.8 minutes (mean ± SEM) following injury; mice deficient in PAI-1 developed occlusive thrombosis at 127 ± 15 minutes (P  & lt; .0001). Mice deficient in VN (n = 12) developed vascular occlusion 77 ± 11 minutes after injury, intermediate between the values observed for WT mice (P  & lt; .03) and mice deficient in PAI-1 (P  & lt; .01). PAI-1 and VN also affected the time to occlusion after injury to the jugular vein. Three WT mice developed occlusive venous thrombosis an average of 39.7 ± 1 minutes following the onset of injury, whereas the jugular veins of 4 mice deficient in PAI-1 and 4 deficient in VN occluded 56.7 ± 5 and 58.7 ± 2 minutes, respectively, following injury (P  & lt; .04 andP  & lt; .01 compared to WT mice). These results suggest that endogenous fibrinolysis and its regulation by PAI-1 and VN have important roles in the development of occlusive vascular thrombosis after vascular injury.
    Type of Medium: Online Resource
    ISSN: 1528-0020 , 0006-4971
    URL: Article
    DOI: 10.1182/blood.V95.2.577
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2000
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 10
    Online Resource
    Online Resource
    Plasminogen activator inhibitor-1 deficiency protects against atherosclerosis progression in the mouse carotid artery
    American Society of Hematology ; 2000
    In:  Blood Vol. 96, No. 13 ( 2000-12-15), p. 4212-4215
    Details
    In: Blood, American Society of Hematology, Vol. 96, No. 13 ( 2000-12-15), p. 4212-4215
    Abstract: Dissolution of the fibrin blood clot is regulated in large part by plasminogen activator inhibitor-1 (PAI-1). Elevated levels of plasma PAI-1 may be an important risk factor for atherosclerotic vascular disease and are associated with premature myocardial infarction. The role of the endogenous plasminogen activation system in limiting thrombus formation following atherosclerotic plaque disruption is unknown. This study found that genetic deficiency for PAI-1, the primary physiologic regulator of tissue-type plasminogen activator (tPA), prolonged the time to occlusive thrombosis following photochemical injury to carotid atherosclerotic plaque in apolipoprotein E-deficient (apoE−/−) mice. However, anatomic analysis revealed a striking difference in the extent of atherosclerosis at the carotid artery bifurcation between apoE−/− mice and mice doubly deficient for apoE and PAI-1 (PAI-1−/−/apoE−/−). Consistent with a previous report, PAI-1+/+/apoE−/−and PAI-1−/−/apoE−/− mice developed similar atherosclerosis in the aortic arch. The marked protection from atherosclerosis progression at the carotid bifurcation conferred by PAI-1 deficiency suggests a critical role for PAI-1 in the pathogenesis of atherosclerosis at sites of turbulent flow, potentially through the inhibition of fibrin clearance. Consistent with this hypothesis, intense fibrinogen/fibrin staining was observed in atherosclerotic lesions at the carotid bifurcation compared to the aortic arch. These observations identify significant differences in the pathogenesis of atherosclerosis at varying sites in the vascular tree and suggest a previously unappreciated role for the plasminogen activation system in atherosclerosis progression at sites of turbulent flow.
    Type of Medium: Online Resource
    ISSN: 1528-0020 , 0006-4971
    URL: Article
    DOI: 10.1182/blood.V96.13.4212.h8004212_4212_4215
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2000
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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