Resistance of Platelets in Hypercholesterolemia to Inhibition by Activated Coagulation Factor X

Abstract

Platelet hyperactivity may be involved in the pathogenesis of both thrombogenesis and hypercholesterolemia. The cholesterol-enriched states may contribute to accelerated development of atherosclerosis. The effect of high cholesterol on platelet activation and on inhibition by coagulation factor Xa, was studied in vitro . Incubation of normal platelets ( n = 20 ) with cholesterol-rich dispersion resulted in a small increase of platelet aggregation (PA) and thromboxane A 2 ( TXA 2 ) synthesis when compared with platelets incubated with cholesterol-normal dispersion. In hypercholesterolemic patients ( n = 20 ), ADP-induced PA and TXA 2 synthesis showed only small increases over normal controls. Addition of factor Xa (1 unit/mL) prevented the ADP-induced PA and markedly inhibited TXA 2 synthesis in normal platelets ( 1.3 ± 0.2 and 8.7 ± 2.0 pmol TXA 2 / 10 8 platelets, with and without factor Xa, resp.). However, factor Xa failed to significantly suppress TXA 2 synthesis in cholesterol-incubated normal platelets ( 9.5 ± 1.4 and 11.8 ± 1.3 pmol TXA 2 / 10 8 platelets, with and without factor Xa; resp., P = NS ) as well as in platelets from patients with hypercholesterolemia ( 8.6 ± 4.0 and 10.9 ± 4.9 pmol TXA 2 / 10 8 platelets, with and without factor Xa; resp., P = NS ). Exposure of platelets to high cholesterol concentrations, in vitro and in vivo , marginally increased PA and TXA 2 synthesis but resulted in loss of responsiveness to factor Xa, which could significantly contribute to platelet activation in hypercholesterolemic states.