We evaluated platelet function in patients with
familial hypertriglyceridemia (FHTG). Compared with healthy gender-matched controls, platelets from patients showed lower aggregation (P < .01) and
thromboxane formation (P < .01) in response to
collagen.
Very-low-density lipoprotein (VLDL) particles obtained from the patients inhibited
collagen-induced aggregation, whereas VLDL particles from controls had opposite effects. The VLDL-induced effect was regulated by its
apolipoprotein E (
apoE) content. Indeed,
apoE-VLDL-rich fractions caused antiaggregative effects, whereas
apoE-VLDL-poor fractions produced a strong proaggregative response. Since we have recently demonstrated that VLDL particles may regulate the activity of platelet
low-density lipoprotein (
LDL) receptor by a phenomenon of downregulation and desensitization, in this study, we have investigated the effect of prolonged exposure to circulating VLDL levels on the activity of platelet
LDL receptor by a double-blind controlled study with
gemfibrozil (600 mg twice daily) in 18 subjects with FHTG. Platelets from patients exhibited fewer platelet
LDL receptors and 125I-LDL binding was saturable at a lower
protein concentration. After 6 months,
gemfibrozil therapy versus placebo had a marked
lipid-lowering effect, significantly decreased
triglycerides (61%),
VLDL cholesterol (72%),
apoB (28%), and
apoE (55%), and increased
high-density lipoprotein (44%) and
apoA-I (18%). Furthermore,
gemfibrozil affected the
apoprotein composition of VLDL: total
protein increased by 28%, the molar ratio of
apoE to
apoB decreased 64%, and
apoE content decreased 55%. However, no differences in
phospholipid,
triglyceride, or total
cholesterol were detected. Moreover, platelet function was markedly altered by
gemfibrozil therapy.
Collagen-induced aggregation and
thromboxane formation were significantly enhanced (P < .01). The initial antiaggregative pattern of VLDL particles was changed to a significant proaggregative effect (P < .01), and the number of
LDL binding sites was markedly upregulated (P < .001). Both receptor upregulation and the change in the aggregative effect of VLDL particles were associated with the reduction of
apoE content in VLDL particles (P < .05). The overall results indicate that in the regulation of platelet reactivity in hypertriglyceridemic patients,
apoE content of VLDL particles and their interaction with the platelet
LDL receptor are involved.