Inhibition of thrombus formation by activated recombinant protein C in a primate model of arterial thrombosis.

Gruber, András; Hanson, Stephen R.; Kelly, Andrew B.; Yan, Betty S.; Bang, Nils U.; Griffin, John H.; Harker, Laurence A.

doi:10.1161/01.cir.82.2.578

Cited by 134 publications

(90 citation statements)

References 22 publications

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“…1,11,12 Therapies that enhance PC activation reduce these markers of a prothrombotic state, and in a primate arterial and venous thrombosis model, significantly inhibit platelet and fibrin deposition, indicating that endogenous APC inhibits thrombin procoagulant activity in vivo. [12][13][14] Recent studies 15 demonstrate that neonatal death in homozygous PC-deficient mice occurs because of severe thrombosis in the brain microvasculature. In a porcine model, 16 endogenous APC is rapidly generated in the microcirculation during coronary artery occlusion and provides a direct cardioprotective benefit.…”

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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“…52,53,55 Subsequently, many laboratories provided evidence of the beneficial properties of wt-APC and APC variants across a broad spectrum of preclinical animal injury models, as briefly highlighted below.…”

Section: Apc: Translation To Preclinical Therapiesmentioning

confidence: 99%

Activated protein C: biased for translation

Griffin

Zloković

Mosnier

2015

Blood

221

320

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The homeostatic blood protease, activated protein C (APC), can function as (1) an antithrombotic on the basis of inactivation of clotting factors Va and VIIIa; (2) a cytoprotective on the basis of endothelial barrier stabilization and anti-inflammatory and antiapoptotic actions; and (3) a regenerative on the basis of stimulation of neurogenesis, angiogenesis, and wound healing. Pharmacologic therapies using recombinant human and murine APCs indicate that APC provides effective acute or chronic therapies for a strikingly diverse range of preclinical injury models. APC reduces the damage caused by the following: ischemia/reperfusion in brain, heart, and kidney; pulmonary, kidney, and gastrointestinal inflammation; sepsis; Ebola virus; diabetes; and total lethal body radiation. For these beneficial effects, APC alters cell signaling networks and gene expression profiles by activating protease-activated receptors 1 and 3. APC’s activation of these G protein–coupled receptors differs completely from thrombin’s activation mechanism due to biased signaling via either G proteins or β-arrestin-2. To reduce APC-associated bleeding risk, APC variants were engineered to lack >90% anticoagulant activity but retain normal cell signaling. Such a neuroprotective variant, 3K3A-APC (Lys191-193Ala), has advanced to clinical trials for ischemic stroke. A rich data set of preclinical knowledge provides a solid foundation for potential translation of APC variants to future novel therapies.

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“…Protein C was purified from human plasma by immunoaffinity chromatography as described. 15 Protein C was activated in vitro with human thrombin, and APC was purified by anion exchange chromatography. 16 The purified APC contained no detectable thrombin (Ͻ0.05 U of thrombin per mg of APC).…”

Section: Experimental Protocolmentioning

confidence: 99%

“…15,16,18 After determination of immunocaptured APC amidolytic activity, immobilized protein C zymogen was activated with 1.0 U/mL Protac (American Diagnostica Inc), and total protein C amidolytic activity was determined as described. 15 Standard curves were generated using plasma pooled from 19 monkeys. One unit of APC or protein C was defined as the amount present in 1.0 mL of pooled monkey plasma.…”

Section: Hemostatic Assaysmentioning

confidence: 99%

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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Inhibition of thrombus formation by activated recombinant protein C in a primate model of arterial thrombosis.

Cited by 134 publications

References 22 publications

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

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

Activated protein C: biased for translation

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

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