Platelet function in hyperlipoproteinemia and effects of lipid-lowering treatment

Coronary atherosclerosis and thrombus formation on fissuring atherosclerotic plaques are keyevents in the development of coronary artrey disease. Hyperlipoproteinemia inducesatherosclerosis but may also exert direct prothrombotic effects via platelet activation. Thepresent thesis has concerned the effect of acute and chronic elevations of blood lipids on plateletfunction in vitro and in vivo. Moreover, the impact of lipid-lowering interventions and mentalstress on platelet function in vivo was also studied. Incubation of isolated autologous low density lipoprotein (LDL) with whole blood showedthat an acute elevation of plasma LDL levels enhances platelet aggregability in a concentrationdependent manner, as measured by filtragometry in vitro. Studies in patients with isolated hypercholesterolemia (phenotype IIa) and combinedhyperlipidemia (type IIb), revealed that a chronic elevation of plasma lipoprotein levels areassociated with certain aspects of platelet hyperactivity in vivo. Platelet hyperactivity, indicatedby enhanced urinary excretion of 11-dehydro-TxB2 and platelet release of B-thromboglobulin,was most evident in patients with combined hyperlipidemia. However, measurements byfiltragometry ex vivo, showed reduced platelet aggregability in hyperlipidemic patients at restbut not during mental stress. The mechanisms behind the increased thromboxane generationand platelet release, and the differences between type IIa and type IIb patients are unclear. Nocorrelations were found between plasma lipoprotein concentrations and platelet functionmarkers, suggesting indirect effects of plasma lipoproteins in vivo. As positive relationshipswere 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 dataobtained 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 hadunexpected platelet stimulatory properties, as evidenced by enhanced platelet aggregability andincreased excretion of 11-dehydro-thromboxane B2 (only gemfibrozil). Acute mental stress enhanced platelet secretion of B-thromboglobulin, whereas plateletaggregability was unaltered in middle-age men with combined hyperlipidemia and in healthycontrols. 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 lipoproteinlevels does not improve platelet function in vivo. On the contrary, some lipid-lowering agentsmay even have platelet activating effects. The association of platelet function to mediators ofinflammation, and the contrasting effects of different lipid-lowering agents on platelet functionshould be subject of future studies.ISBN 91-628-2101-