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 studiedin vitro. Incubation of normal platelets (n=20) with cholesterol-rich dispersion resulted in a small increase of platelet aggregation (PA) and thromboxaneA2(TXA2) synthesis when compared with platelets incubated with cholesterol-normal dispersion. In hypercholesterolemic patients (n=20), ADP-induced PA andTXA2synthesis showed only small increases over normal controls. Addition of factor Xa (1 unit/mL) prevented the ADP-induced PA and markedly inhibitedTXA2synthesis in normal platelets (1.3±0.2and8.7±2.0pmolTXA2/108platelets, with and without factor Xa, resp.). However, factor Xa failed to significantly suppressTXA2synthesis in cholesterol-incubated normal platelets (9.5±1.4and11.8±1.3pmolTXA2/108platelets, with and without factor Xa; resp.,P=NS) as well as in platelets from patients with hypercholesterolemia (8.6±4.0and10.9±4.9pmolTXA2/108platelets, with and without factor Xa; resp.,P=NS). Exposure of platelets to high cholesterol concentrations,in vitroandin vivo, marginally increased PA andTXA2synthesis but resulted in loss of responsiveness to factor Xa, which could significantly contribute to platelet activation in hypercholesterolemic states.