Research by Children’s Hospital Oakland Research Institute (CHORI) scientists links imbalances in lipoprotein metabolism with vaso–occlusive events in patients with sickle cell disease (SCD). CHORI researchers, Eric Soupene, PhD, Sandra K. Larkin and CHORI Senior Scientist Frans A Kuypers, PhD, identified high density lipoprotein (HDL) metabolites in SCD plasma that promote inflammation and may reduce the effectiveness of current therapies.

The study, “Depletion of HDL3 high density lipoprotein and altered functionality of HDL2 in blood from sickle cell patients,” was published in the journal Experimental Biology and Medicine.

The red blood cells in patients with SCD contain a mutated hemoglobin, the protein that carries oxygen throughout the body. SCD patients also have abnormalities in cholesterol metabolites (plasma cholesterol and lipoproteins) and other plasma components such as acute phase reactants, inflammatory mediators, cell free hemoglobin, and heme. In SCD, the red blood cells (RBCs) become inflexible and stick to the walls of blood vessels, which prevent the delivery of oxygen to cells and tissues. These vaso–occlusive events are further exacerbated by abnormalities in plasma components. The standard treatment for vaso–occlusive events is replacement of the sickle RBCs with normal RBCs. However, RBC exchange therapy does not normalize alterations in plasma components. Thus, the majority of the plasma present after RBC exchange therapy will form a pro–inflammatory environment that can reduce the effectiveness of the treatment.

Previous studies have demonstrated that the pro–inflammatory environment of the blood in patients with SCD reduces the activity of high density lipoprotein (HDL), the so called ‘good’ cholesterol particle. In the current study, Dr. Soupene and colleagues characterized HDL metabolites in SCD plasma and their effect on endothelial cell function. SCD plasma exhibited alterations in the size distribution, but not the total level, of HDL particles.

SCD plasma was depleted of the pre–beta particle, which is essential for reverse cholesterol transport. This observation may partially explain the altered plasma cholesterol content observed in SCD patients. HDL isolated from SCD plasma upregulated PTX3, a protein that is predictive for the length of inflammatory episodes in SCD, in endothelial cells.

The addition of the heme–scavenger hemopexin (Hx) blocked PTX3 upregulation by SCD plasma. Collectively, these findings link lipoprotein alterations to SCD pathology, and suggest that replacement of plasma and RBCs, whole blood transfusion, may be a more effective treatment for vaso–occlusive events. According to Dr. Soupene, “RBC exchange therapy, a well–accepted transfusion treatment of SCD patients, may have to be re–evaluated. Replacing only the red blood cells underestimates the importance alterations in the plasma compartment.”