Published Online
on July 22, 2002

A more recent version of this article appeared on August 13, 2002

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Submitted on February 20, 2002
Revised on May 17, 2002
Accepted on May 17, 2002

Anticoagulant Responses to Thrombin Are Enhanced During Regression of Atherosclerosis in Monkeys

Steven R. Lentz MD, PhD^*, Francis J. Miller Jr MD, Donald J. Piegors MBA, Rochelle A. Erger BS, José A. Fernández PhD, John H. Griffin PhD, and Donald D. Heistad MD

From the Veterans Affairs Medical Center (S.R.L., R.A.E., D.D.H.) and Departments of Internal Medicine (S.R.L., F.J.M., D.J.P., D.D.H.) and Pharmacology (D.D.H.), University of Iowa College of Medicine, Iowa City, Iowa, and The Scripps Research Institute (J.A.F., J.H.G.), La Jolla, Calif.

^* To whom correspondence should be addressed. E-mail: steven-lentz{at}uiowa.edu.

Background—Diet-induced atherosclerosis in monkeys produces abnormal anticoagulant responses to thrombin, including decreased generation of activated protein C (APC). We tested the hypothesis that anticoagulant responses to thrombin increase toward normal during regression of atherosclerosis.

Methods and Results—Six cynomolgus monkeys were fed a high-fat atherogenic diet for 44 months and then a low-fat regression diet for 8 months. Serum total cholesterol decreased from 417±44 to 68±6 mg/dL (mean±SEM) and LDL cholesterol decreased from 375±44 to 27±5 mg/dL after the regression diet. In response to infusion of thrombin, the activated partial thromboplastin time (APTT) increased by 11±3 seconds before the regression diet and by 41±22 seconds after the regression diet (P=0.01). The peak level of circulating plasma APC was 52±9 ng/mL before the regression diet and 88±17 ng/mL after the regression diet (P=0.01). The APC sensitivity of plasma factor V was identical before and after the regression diet. Three additional atherosclerotic monkeys that remained on the high-fat diet for 8 months demonstrated no change in APTT or activation of protein C in response to thrombin.

Conclusions—Short-term dietary regression of atherosclerosis produces enhanced anticoagulant responses to thrombin in vivo.

Key words: atherosclerosis • endothelium • coagulation • thrombin

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