Prolonged Activation of Prothrombin on the Vascular Wall After Arterial Injury

Ghigliotti, G; Waissbluth, Alvaro R.; Speidel, Christopher M.; Abendschein, Dana R.; Eisenberg, Paul R.

doi:10.1161/01.atv.18.2.250

Cited by 33 publications

(31 citation statements)

References 63 publications

(63 reference statements)

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“…20 Measurements of thrombin activity bound to the wall of balloon-injured rabbit arteries reveals that local thrombin generation peaks within the first 24 to 48 hours after acute injury but may persist at low levels for more than 7 days. 16,17,21 Similar measurements in vein grafts have not previously been reported. In the present study, the extent of local thrombin generation in vein grafts was found to be of the same magnitude as in injured arteries but with a later peak and of longer duration.…”

Section: Local Thrombin Generation In Vein Graftssupporting

confidence: 83%

“…16,17 Freshly excised vessels were washed with HBSS and placed in the template as described above. Because of the technical inability of placing rabbit jugular vein segments into the template reliably without exposing their adventitial surface to the substrate, rabbit inferior vena cavae (IVC) were used as venous controls.…”

Section: In Situ Protein C and Thrombin Activity Assaysmentioning

confidence: 99%

“…This degree of bound thrombin activity is similar to that observed after acute balloon injury of rabbit aortas. 16 …”

Section: Loss Of Tm Expression Is Associated With Decreased Graft Thrmentioning

confidence: 99%

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Early Loss of Thrombomodulin Expression Impairs Vein Graft Thromboresistance

Kim

Walinsky

Kolodgie

et al. 2002

Circulation Research

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Abstract-Thrombosis is the major cause of early vein graft failure. Our aim was to determine whether alterations in the expression of the anticoagulant proteins, thrombomodulin (TM) and the endothelial cell protein C receptor (EPCR), impair endothelial thromboresistance that may contribute to vein graft failure. Immunohistochemical staining of autologous rabbit vein graft sections revealed that the expression of TM, but not EPCR, was reduced significantly early after graft implantation. Western blot analysis revealed that TM expression was reduced by Ͼ95% during the first 2 weeks after implantation, with gradual but incomplete recovery by 42 days. This resulted in up to a 95% reduction in the capacity of the grafts to activate protein C and was associated with an increase in bound thrombin activity, which peaked on day 7 at 28.7Ϯ3.8 mU/cm 2 and remained elevated for more than 14 days. Restoration of TM expression using adenovirus vector-mediated gene transfer significantly enhanced the capacity of grafts to activate protein C and reduced bound thrombin activity on day 7 to levels comparable to that of normal veins (5.7Ϯ0.4 versus 5.2Ϯ1.1 mU/cm 2 , respectively, Pϭ0.74). Surprisingly, neointima formation was not affected by this inhibition of local thrombin activity. These data suggest that the early loss of TM expression significantly impairs vein graft thromboresistance and results in enhanced local thrombin generation. Although enhanced local thrombin generation may predispose to early vein graft failure due to thrombosis, it does not seem to contribute significantly to late vein graft failure due to neointimal hyperplasia.

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Section: Local Thrombin Generation In Vein Graftssupporting

confidence: 83%

Section: In Situ Protein C and Thrombin Activity Assaysmentioning

confidence: 99%

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Early Loss of Thrombomodulin Expression Impairs Vein Graft Thromboresistance

Kim

Walinsky

Kolodgie

et al. 2002

Circulation Research

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“…17 The procoagulant status of the vessel wall due to vascular injury or atherosclerosis leads to adhesion and accumulation of platelets, initiation of coagulation cascades, and enhanced thrombin generation. 18 Therefore, modulation of thrombogenesis and fibrinolysis has been a major focus in atherosclerosis research.…”

Section: Discussionmentioning

confidence: 99%

Recombinant Annexin II Modulates Impaired Fibrinolytic Activity In Vitro and in Rat Carotid Artery

Ishii

Yoshida

Hiraoka

et al. 2001

Circulation Research

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Abstract-Fibrinolytic activity has been reported to be decreased in atherosclerosis. Recently, annexin II was identified as a coreceptor on endothelial cells for plasminogen and tissue plasminogen activator. In this study, we examined whether recombinant annexin II (rAN II) protein can modulate fibrinolytic activity on vascular endothelium in vitro and in vivo. Key Words: annexin II Ⅲ rat carotid artery Ⅲ thrombus V ascular endothelial cell luminal surfaces maintain a "thromboresistant status" by dynamic balancing between the coagulation and fibrinolytic systems; however, the damage to vessel walls often seen in ischemic syndromes leads to thrombus formation. The fibrinolytic characteristics of vascular endothelium are modulated by the activity of plasminogen activators that facilitate conversion of plasminogen to active plasmin, 1 and the binding of plasminogen to endothelial cells significantly enhances the catalytic efficiency of its activation by tissue plasminogen activator (t-PA). 2,3 Annexins are a superfamily of calcium-dependent phospholipid binding proteins, 4 which have a highly conserved core domain preceded by a more variable amino terminal tail domain. 5 Recently, annexin II, a member of this superfamily, has been identified on endothelial cells and found to bind t-PA and plasminogen, as well as to enhance plasmin generation. 6,7 The expression and cell surface transport of annexin II is not fully understood; however, several important features of this molecule have been reported, including calciumdependent high-affinity binding to phospholipid. 8,9 Annexin II is now considered to be one of the key fibrinolytic modulators on the surface of endothelial cells. 7Considering the hypercoagulable state of most vascular diseases, including atherosclerosis, the possibility of modulation of fibrinolytic activity by annexin II is of great interest. Recently, annexin V, another annexin family member, was shown to be effective in reducing thrombus formation in a rat carotid artery injury model by using a mechanism that may involve inhibition of platelet activity in the injured vessel. 10 In this study, we examined the potential role of annexin II in a rat carotid artery model utilizing a recombinant annexin II (rAN II) protein. Our results indicate that intravenous administration of annexin II significantly inhibits thrombus formation in vivo without affecting systemic hemostatic parameters, and may demonstrate its potential as a novel therapeutic tool for vascular diseases.

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“…This rupture initiates hemostasis in the blood vessel and leads to activation of thrombin and a thrombus to form at the site of rupture. Elevated levels of activated thrombin bound to the vessel wall have been observed up to 72 h after vascular injury (3). These elevated thrombin levels not only induce clot formation but also have been implicated in the progression of atherosclerosis by causing smooth muscle cells to bind circulating low density lipoprotein (4).…”

Section: Ardiovascular Disease Affects 1 In 3 People In the Unitedmentioning

confidence: 99%

Targeting atherosclerosis by using modular, multifunctional micelles

Peters

Kastantin

Kotamraju

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

257

252

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Subtle clotting that occurs on the luminal surface of atherosclerotic plaques presents a novel target for nanoparticle-based diagnostics and therapeutics. We have developed modular multifunctional micelles that contain a targeting element, a fluorophore, and, when desired, a drug component in the same particle. Targeting atherosclerotic plaques in ApoE-null mice fed a high-fat diet was accomplished with the pentapeptide cysteine-arginine-glutamic acid-lysine-alanine, which binds to clotted plasma proteins. The fluorescent micelles bind to the entire surface of the plaque, and notably, concentrate at the shoulders of the plaque, a location that is prone to rupture. We also show that the targeted micelles deliver an increased concentration of the anticoagulant drug hirulog to the plaque compared with untargeted micelles.cysteine-arginine-glutamic acid-lysine-alanine ͉ hirulog ͉ plaque ͉ imaging ͉ nanoparicles C ardiovascular disease affects 1 in 3 people in the United States during their lifetime, and accounts for nearly a third of the deaths that occur each year (1). Atherosclerosis is one of the leading causes of cardiovascular disease, and it results in raised plaques in the arterial wall that can occlude the vascular lumen and block blood flow through the vessel. Recently, it has become clear that not all plaques are the same. Those susceptible to rupture, fissuring, and subsequent thrombosis are most frequently the cause of acute coronary syndromes and death (2).Rupture of an atherosclerotic plaque exposes collagen and other plaque components to the bloodstream. This rupture initiates hemostasis in the blood vessel and leads to activation of thrombin and a thrombus to form at the site of rupture. Elevated levels of activated thrombin bound to the vessel wall have been observed up to 72 h after vascular injury (3). These elevated thrombin levels not only induce clot formation but also have been implicated in the progression of atherosclerosis by causing smooth muscle cells to bind circulating low density lipoprotein (4). Subtle clotting in plaques is also indicated by deposition of fibrin(ogen) both inside and on the surface of atherosclerotic plaques, which has been well documented since the 1940s (5-7).Fibrin-containing blood clots have been extensively used as a target for site-specific delivery of imaging agents and anticlotting agents to thrombi (8-10). Delivering anticoagulants into vessels where clotting is taking place has been shown to be effective at reducing the formation and expansion of clots, and it also decreases the risk of systemic side effects (11,12). Antibodies and peptides that bind to molecular markers specifically expressed on atherosclerotic plaques have shown promise for plaque imaging in vivo (13-16), but clotting on the plaque has not been used as a target. We reasoned that the fibrin deposited on plaques could serve as a target for delivering diagnostic and therapeutic compounds to plaques.We chose the clot-binding peptide cysteine-arginine-glutamic acid-lysine-alanine (CREKA) to te...

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Prolonged Activation of Prothrombin on the Vascular Wall After Arterial Injury

Cited by 33 publications

References 63 publications

Early Loss of Thrombomodulin Expression Impairs Vein Graft Thromboresistance

Early Loss of Thrombomodulin Expression Impairs Vein Graft Thromboresistance

Recombinant Annexin II Modulates Impaired Fibrinolytic Activity In Vitro and in Rat Carotid Artery

Targeting atherosclerosis by using modular, multifunctional micelles

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