Summary
Individuals with familial hyperbetalipoproteinemia are at increased risk of premature
atherosclerosis and thrombosis. Although there is controversy whether platelet survival
is shortened or normal in this disease, several in vitro tests of platelet function are abnormal including a decreased threshold concentration
for stimulation of aggregation by ADP, epinephrine and collagen and increased release
of nucleotides to the same agents. These functional changes are accompanied by an
increase of cholesterol to phospholipid ratio in the platelet membrane and in low
density lipoprotein in individuals with type Ha hyperlipoproteinemia. Clofibrate and
halofenate reverse some of the abnormalities in vitro and the former drug, when administered for 6 weeks to patients with type II a hyperlipoproteinemia
decreases platelet sensitivity to ADP and epinephrine. The platelet hypersensitivity
to aggregating agents can be reproduced in vitro by increasing the cholesterol to phospholipid rather in normal platelets. These artificially
hypersensitive platelets can be returned to normal by halofenate in vitro. Incorporation of cholesterol into platelet membranes increases the basal level of
the membrane associated enzyme adenylate cyclase. However, the enzyme no longer responds
to stimulation by prostaglandin E1 and this is associated with relative resistance of the platelet to inhibition by
this pharmacologic agent. These functional alterations produced by cholesterol enrichment
of platelet membranes occur is parallel with an increase in platelet membrane microviscosity
suggesting that the more rigid membrane can alter the behavior of membrane associated
enzymes and receptors. A correlation appears to exist between the ability of certain
drugs to induce phase separation in model membranes and the potency in inhibitory
platelet aggregation.
