Platelet function in hyperbetalipoproteinemia.
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 IIa hyperlipoproteinemia. Clofibrate and halofenate reverse some of the abnormalities in vitro and the former drug, when administered for 6 weeks to patients with type IIa 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.
D000244:Adenosine Diphosphate; D000262:Adenylyl Cyclases / Q000378:metabolism; D001792:Blood Platelets / Q000473:pathology*; D002994:Clofibrate / Q000494:pharmacology; D006218:Halofenate / Q000494:pharmacology; D006801:Humans; D006949:Hyperlipidemias / Q000097:blood* / Q000235:genetics*; D010974:Platelet Aggregation / Q000187:drug effects
D000244:Adenosine Diphosphate; D000262:Adenylyl Cyclases; D002994:Clofibrate; D006218:Halofenate