Abnormalities of cholesterol-phospholipid composition in platelets and low-density lipoproteins of human hyperbetalipoproteinemia.

Platelets from most patients with type IIa hyperlipoproteinemia (IIa) aggregate in the presence of lower concentrations of epinephrine and adenosine diphosphate (ADP) than are necessary to aggregate normal platelets. We have observed a comparable functional alteration in human platelets made cholesterol-rich in vitro by incubation in a milieu artificially rich in free cholesterol relative to phospholipid. We therefore examined platelet aggregation and lipid composition of platelets and of plasma low-density lipoprotein (LDL) in 19 individuals with IIa (including three homozygotes), seven normolipidemic individuals with symptomatic, angiographically-documented coronary atherosclerosis (atherosclerosis group), and 23 asymptomatic, normolipidemic subjects (control group). More than 99 percent of platelet cholesterol was unesterified. There was a 7 percent increase in the cholesterol content of whole platelets per mole of platelet phospholipid (C/PL) in IIa as compared to normal controls. This resulted from a 22 percent increase in the C/PL of IIa platelet membranes with no change in the C/PL of the soluble or granule fraction. The C/PL of IIa platelets was 6 percent greater than that of platelets from patients with atherosclerosis. As compared to those of normal controls, IIa platelets aggregated in response to a ninefold lower concentration of epinephrine (p less than 0.001) and a twofold lower concentration of ADP (p less than 0.02). The response of atherosclerosis platelets to these agents was comparable to that of controls. In all groups, there was a negative correlation between the log concentration of epinephrine required to produce complete platelet aggregation and the platelet C/PL (r = -0.06; p less than 0.002). The composition of LDL isolated from the plasma of patients with IIa was characterized by a 39 percent increase in the amount of free cholesterol relative to protein and a 35 percent increase in C/PL, as compared with control LDL. These values were increased 23 and 19 percent, respecitvely, when IIa was compared with the atherosclerosis group. In all groups the C/PL of LDL correlated well with the C/PL of platelets (r = =0.61; p less than 0.001). However, a simple cause-and-effect relationship did not appear to exist since (1) erythrocyte membrane C/PL was not affected and (2) normal platelets or erythrocytes underwent no change in C/PL during 18 hours' incubation in IIa plasma. These studies demonstrate that LDL and platelets in IIa contain an increased amount of free cholesterol relative to its principal solubilizer, phospholipid. In platelets this correlates with an increased sensitivity to aggregating agents. Moreover, the similarity between the functional abnormality in IIa platelets and that previously observed in normal platelets made cholesterol-rich in vitro suggests that the lipid composition of platelet membranes may have a direct effect on the function of platelets in man.