Platelet function in hyperlipoproteinemia and effects of lipid-lowering treatment

Coronary atherosclerosis and thrombus formation on fissuring atherosclerotic plaques are key events in the development of coronary artery disease. Hyperlipoproteinemia induces atherosclerosis but may also exert direct prothrombotic effects via platelet activation. The present thesis has concerned the effect of acute and chronic elevations of blood lipids on platelet function in vitro and in vivo. Moreover, the impact of lipid-lowering interventions and mental stress on platelet function in vivo was also studied.

Incubation of isolated autologous low density lipoprotein (LDL) with whole blood showed that an acute elevation of plasma LDL levels enhances platelet aggregability in a concentration dependent manner, as measured by filtragometry in vitro.

Studies in patients with isolated hypercholesterolemia (phenotype IIa) and combined hyperlipidemia (type IIb), revealed that a chronic elevation of plasma lipoprotein levels are associated with certain aspects of platelet hyperactivity in vivo. Platelet hyperactivity, indicated by enhanced urinary excretion of 11-dehydro-TxB2 and platelet release of B-thromboglobulin, was most evident in patients with combined hyperlipidemia. However, measurements by filtragometry ex vivo, showed reduced platelet aggregability in hyperlipidemic patients at rest but not during mental stress. The mechanisms behind the increased thromboxane generation and platelet release, and the differences between type IIa and type IIb patients are unclear. No correlations were found between plasma lipoprotein concentrations and platelet function markers, suggesting indirect effects of plasma lipoproteins in vivo. As positive relationships were found between thromboxane excretion and plasma fibrinogen levels or leukocyte counts, it is hypothesized that mediators of inflammation may be involved.

The theory of indirect effects of plasma lipids on platelet function were supported by data obtained during lipid-lowering interventions. Treatment with gemfibrozil, pravastatin, simvastatin and selective LDL-apheresis was not found to improve platelet function in vivo, despite marked reductions of plasma lipoprotein levels. In fact, gemfibrozil and pravastatin had unexpected platelet stimulatory properties, as evidenced by enhanced platelet aggregability and increased excretion of 11-dehydro-thromboxane B2 (only gemfibrozil).

Acute mental stress enhanced platelet secretion of B-thromboglobulin, whereas platelet aggregability was unaltered in middle-age men with combined hyperlipidemia and in healthy controls. The response to mental stress was unrelated to blood lipid levels.

In conclusion, hyperlipoproteinemia is associated with certain aspects of platelet activation, and particularly so in patients with combined hyperlipidemia. Reduction of plasma lipoprotein levels does not improve platelet function in vivo. On the contrary, some lipid-lowering agents may even have platelet activating effects. The association of platelet function to mediators of inflammation, and the contrasting effects of different lipid-lowering agents on platelet function should be subject of future studies.