Activated Protein C Resistance in Ischemic Stroke Not Due to Factor V Arginine
            <sup>506</sup>
            →Glutamine Mutation

Fisher, Mark; Fernández, José A.; Ameriso, Sebastián F.; Xie, Dangci; Gruber, András; Paganini‐Hill, Annlia; Griffin, John H.

doi:10.1161/01.str.27.7.1163

Cited by 77 publications

(44 citation statements)

References 34 publications

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“…2 Plasma from patients with ischemic stroke also exhibits reduced anticoagulant response to exogenously added APC that is not attributable to the factor V Leiden mutation. 35,36 These findings, along with recent controversy regarding thrombolytic therapy, highlight a need for further studies investigating potential cerebral protective effects of endogenous or therapeutically administered APC in acute ischemic stroke. 37 Moreover, research is needed to determine whether native antithrombotic mechanisms in the cerebral microcirculation are related to clinical outcomes or may be pharmacologically augmented by vitamin therapy to lower homocysteine, a modifiable hematologic risk factor linked to TM-PC system integrity.…”

Section: Discussionmentioning

confidence: 99%

Brain-Specific Protein C Activation During Carotid Artery Occlusion in Humans

Macko

Killewich

Fernández

et al. 1999

Stroke

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Background and Purpose-Activation of plasma protein C (PC) zymogen by thrombin-thrombomodulin at the endothelial surface is an important endogenous antithrombotic mechanism. It is unknown whether activated protein C (APC) is generated in vivo in the cerebrovasculature, because there is only limited thrombomodulin expression in human brain vascular endothelium. Therefore, we tested the hypothesis that carotid occlusion produces brain-specific PC activation. Methods-Blood samples were simultaneously collected from the ipsilateral internal jugular vein and radial artery before and during carotid cross-clamping and on "de-occlusion" in 8 awake patients undergoing routine carotid endarterectomy. Plasma PC zymogen and circulating APC levels were measured using enzyme immunocapture assay and expressed as percent of pooled plasma controls. Results-Internal jugular vein APC levels increased 28% exclusively during carotid occlusion and then decreased 32% with de-occlusion (Fϭ8.

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Section: Discussionmentioning

confidence: 99%

Brain-Specific Protein C Activation During Carotid Artery Occlusion in Humans

Macko

Killewich

Fernández

et al. 1999

Stroke

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“…6 Resistance to APC that is independent of factor V Leiden may be associated with increased risk of stroke. 7,8 In a previous study, we observed impaired endotheliumdependent vasodilatation and decreased protein C activation in aortas from monkeys with moderate hyperhomocyst(e)inemia [plasma homocyst(e)ine* Ϸ10 mol/L]. 9 These observations suggested that endothelial dysfunction, with impaired regulation of thrombin by thrombomodulin, may contribute to an increased risk of atherosclerotic and thrombotic vascular disease in hyperhomocyst(e)inemia.…”

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confidence: 89%

Impaired Anticoagulant Response to Infusion of Thrombin in Atherosclerotic Monkeys Associated With Acquired Defects in the Protein C System

Lentz

Fernández

Griffin

et al. 1999

ATVB

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Abstract-To examine the effects of atherosclerosis on the protein C anticoagulant pathway in vivo, we measured anticoagulant responses to intravenous administration of human ␣-thrombin or activated protein C (APC) in cynomolgus monkeys. Two groups of monkeys were fed either a control diet (nϭ18) or an atherogenic diet (nϭ12) that produces both hypercholesterolemia and moderate hyperhomocyst(e)inemia. A third group (nϭ8) was fed an atherogenic diet for 15 months, and then fed the atherogenic diet supplemented with B vitamins for 6 months to correct the hyperhomocyst(e)inemia. The plasma homocyst(e)ine level was higher in monkeys fed the atherogenic diet (9.6Ϯ1.0 mol/L) than in monkeys fed the control diet (3.7Ϯ0.2 mol/L) or the atherogenic diet with B vitamins (3.6Ϯ0.2 mol/L) (PϽ0.001). Infusion of thrombin produced a much greater prolongation of the activated partial thromboplastin time in monkeys fed the control diet (52Ϯ10 seconds) than in monkeys fed the atherogenic diet either with (24Ϯ4 seconds) or without (27Ϯ5 seconds) supplemental B vitamins (PϽ0.02). Thrombin-dependent generation of circulating APC was higher in control (294Ϯ17 U/mL) than in atherosclerotic (240Ϯ14 U/mL) monkeys (PϽ0.05), although levels of fibrinogen, plasminogen, D-dimer, and thrombin-antithrombin complexes were similar in each group. Injection of human APC produced a similar prolongation of the activated partial thromboplastin time in control (31Ϯ3 seconds) and atherosclerotic (29Ϯ2 seconds) monkeys. These findings provide evidence for impaired anticoagulation, due partly to decreased formation of APC, in atherosclerosis. Key Words: atherosclerosis Ⅲ cholesterol Ⅲ homocysteine Ⅲ protein C Ⅲ thrombomodulin T hrombin, a major regulator of hemostasis, has both procoagulant and anticoagulant properties. 1 Procoagulant effects of thrombin include proteolytic activation of factors V, VIII, and XI; cleavage of fibrinogen to form a fibrin clot; and stimulation of platelet aggregation. A major anticoagulant effect of thrombin involves activation of protein C, a vitamin K-dependent plasma anticoagulant. Thrombin's procoagulant and anticoagulant activities are regulated by thrombomodulin, a cofactor that is expressed on the luminal surface of vascular endothelium. 2 When bound to thrombomodulin, thrombin's ability to catalyze procoagulant reactions is inhibited, but its ability to activate protein C is enhanced Ͼ1000-fold. 3 The protein C anticoagulant pathway is impaired in patients with inherited deficiencies of protein C or protein S and also in patients with a mutation in factor V (factor V Leiden) that renders it resistant to activated protein C (APC). 4,5 The physiological importance of the protein C anticoagulant pathway is underscored by the observation that resistance to APC is found in 20% to 50% of patients with venous thromboembolism. 6 Resistance to APC that is independent of factor V Leiden may be associated with increased risk of stroke. 7,8 In a previous study, we observed impaired endotheliumdependent vasodilatation and decreas...

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“…Protein C and protein S are physiological antithrombotic factors, and a severe deficiency of protein S or protein C is associated with life-threatening thrombosis, while heterozygous deficiencies are associated with a mild risk of venous thrombosis (18,19). The abnormality known as APC resistance, which is due to a subnormal anticoagulant response of a patient's plasma to APC, causes a mild hypercoagulable state and is a risk factor for venous thrombosis (18,19) and ischemic stroke (20,21). The factor V (FV) polymorphism of Arg506Gln that most often causes hereditary APC resistance in venous thrombosis patients is not associated with increased risk for CAD or ischemic stroke (20,22).…”

Section: Introductionmentioning

confidence: 99%

“…The abnormality known as APC resistance, which is due to a subnormal anticoagulant response of a patient's plasma to APC, causes a mild hypercoagulable state and is a risk factor for venous thrombosis (18,19) and ischemic stroke (20,21). The factor V (FV) polymorphism of Arg506Gln that most often causes hereditary APC resistance in venous thrombosis patients is not associated with increased risk for CAD or ischemic stroke (20,22). Abnormalities of thrombomodulin, the cell-surface cofactor for generation of APC by thrombin, may be associated with increased risks for myocardial infarction (23).…”

Section: Introductionmentioning

confidence: 99%

High-density lipoprotein enhancement of anticoagulant activities of plasma protein S and activated protein C

Griffin¹,

Kojima²,

Banka³

et al. 1999

J. Clin. Invest.

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Low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels are associated, respectively, with either increased risk or apparent protective effects for atherothrombosis. The ability of purified LDL and HDL to downregulate thrombin formation, a contributor to atherothrombotic processes, was assessed. Purified HDL, but not LDL, significantly enhanced inactivation of coagulation factor Va by activated protein C (APC) and protein S, and HDL stimulated protein S-dependent proteolytic inactivation of Va by APC, apparently due to cleavage at Arg306 in Va. In normal plasma, added HDL enhanced APC/protein S anticoagulant activity in modified prothrombin-time clotting assays. When the anticoagulant potency of HDL was compared with phospholipid (PL) vesicles of well-defined composition using this assay, HDL appeared qualitatively different from PL vesicles because HDL showed only good anticoagulant activity, whereas PL vesicles were rather procoagulant. When 20 normal plasmas were tested using this clotting assay, apoA-I levels correlated with anticoagulant response to APC/protein S (r = 0.47, P = 0.035), but not with activated partial thromboplastin time-based APC resistance ratios. Because HDL enhances the anticoagulant protein C pathway in vitro, we speculate that HDL may help downregulate thrombin generation in vivo and that this anticoagulant action is one of HDL's beneficial activities.

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Activated Protein C Resistance in Ischemic Stroke Not Due to Factor V Arginine ⁵⁰⁶ →Glutamine Mutation

Abstract: In Hispanic patients with ischemic stroke, the incidence (approximately 10%) of APC resistance is not caused by the factor V Arg506-->Gln mutation. APC resistance not caused by this factor V mutation may be a risk factor for ischemic stroke in this population.

Cited by 77 publications

References 34 publications

Brain-Specific Protein C Activation During Carotid Artery Occlusion in Humans

Brain-Specific Protein C Activation During Carotid Artery Occlusion in Humans

Impaired Anticoagulant Response to Infusion of Thrombin in Atherosclerotic Monkeys Associated With Acquired Defects in the Protein C System

High-density lipoprotein enhancement of anticoagulant activities of plasma protein S and activated protein C

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Activated Protein C Resistance in Ischemic Stroke Not Due to Factor V Arginine 506 →Glutamine Mutation

Abstract: In Hispanic patients with ischemic stroke, the incidence (approximately 10%) of APC resistance is not caused by the factor V Arg506-->Gln mutation. APC resistance not caused by this factor V mutation may be a risk factor for ischemic stroke in this population.

Cited by 77 publications

References 34 publications

Brain-Specific Protein C Activation During Carotid Artery Occlusion in Humans

Brain-Specific Protein C Activation During Carotid Artery Occlusion in Humans

Impaired Anticoagulant Response to Infusion of Thrombin in Atherosclerotic Monkeys Associated With Acquired Defects in the Protein C System

High-density lipoprotein enhancement of anticoagulant activities of plasma protein S and activated protein C

Contact Info

Product

Resources

About

Activated Protein C Resistance in Ischemic Stroke Not Due to Factor V Arginine ⁵⁰⁶ →Glutamine Mutation