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

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.