© 1999 American Heart Association, Inc.
Thrombosis |
Impaired Anticoagulant Response to Infusion of Thrombin in Atherosclerotic Monkeys Associated With Acquired Defects in the Protein C System
From the Veterans Affairs Medical Center (S.R.L., R.A.E., D.D.H.), and the Departments of Internal Medicine (S.R.L., D.J.P., D.D.H.) and Pharmacology (D.D.H.), University of Iowa College of Medicine, Iowa City, Iowa; The Scripps Research Institute (J.A.F., J.H.G.), La Jolla, Calif; and the Oregon Regional Primate Research Center (M.R.M.), Beaverton, Ore.
Correspondence to Steven R. Lentz, MD, PhD, Department of Internal Medicine, C303 GH, University of Iowa, Iowa City, IA 52242. E-mail steven-lentz{at}uiowa.edu
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 (n=18) or an atherogenic diet
(n=12) that produces both hypercholesterolemia
and moderate hyperhomocyst(e)inemia. A third group (n=8) 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 (9.6±1.0 µmol/L) than in
monkeys fed the control diet (3.7±0.2 µmol/L) or the
atherogenic diet with B vitamins (3.6±0.2 µmol/L)
(P<0.001). Infusion of thrombin produced a much greater
prolongation of the activated partial thromboplastin time in
monkeys fed the control diet (52±10 seconds) than in monkeys fed the
atherogenic diet either with (24±4 seconds) or without (27±5 seconds)
supplemental B vitamins (P<0.02). Thrombin-dependent
generation of circulating APC was higher in control (294±17 U/mL) than
in atherosclerotic (240±14 U/mL) monkeys (P<0.05),
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 (31±3 seconds) and
atherosclerotic (29±2 seconds) monkeys. These findings provide
evidence for impaired anticoagulation, due partly to decreased
formation of APC, in atherosclerosis. The blunted
anticoagulant response to thrombin in
hypercholesterolemic monkeys was not corrected by
supplementation with B vitamins.
Key Words: atherosclerosis • cholesterol • homocysteine • protein C • thrombomodulin
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