Patients with sickle cell disease have abnormalities of plasma lipoproteins that likely contribute to the disease’s characteristic vasculopathy and would not be addressed by simple red blood cell transfusion, suggesting that it may be time to rethink treatment strategy, according to a new study.
Previous research has shown that sickle cell disease (SCD) is associated with perturbations of cholesterol metabolism, according to the investigators, who were led by Eric Soupene, PhD, of the Children’s Hospital Oakland (Calif.) Research Institute. In particular, altered interactions of HDL particles appear to play a role.
For the study, the investigators analyzed 31 plasma samples obtained from patients with SCD during routine clinic visits and, in a subset, during vaso-occlusive crises, and 12 plasma samples obtained from healthy individuals serving as controls.
Main results showed that the patients with SCD had reduced levels of HDL3 particles (which play roles in macrophage handling of cholesterol and endothelial protection) and altered functionality of HDL2 particles, possibly as a compensatory mechanism (Exp Biol Med [Maywood]. 2017 Jan 1:1535370217706966. doi: 10.1177/1535370217706966). These changes were more pronounced during vaso-occlusive episodes.
In addition, endothelial cells exposed to lipoproteins from patients exhibited enhanced formation of inflammatory mediators, and this response could be blocked by treatment with hemopexin, a naturally occurring protein that scavenges heme.
“These findings indicate a significant imbalance of lipoprotein function,” the investigators write. “Our study adds to the growing evidence that the dysfunctional red blood cell ... in SCD affects the plasma environment, which contributes significantly in the vasculopathy that defines the disease.”
“The use of [red blood cell] concentrates in transfusion therapy of SCD patients underestimates the importance of the dysfunctional plasma compartment, and transfusion of whole blood or plasma may be warranted,” they propose. Furthermore, “[hemopexin] may provide an additional option to reduce inflammatory pathways by lowering the burden of cell-free heme.”
Study details
In the study, the investigators carried out a series of laboratory experiments comparing the quantity and function of lipoproteins between patients with SCD and healthy individuals. Patients receiving transfusion recently or on a long-term basis were not eligible, but patients receiving hydroxyurea were.
Results of gel electrophoresis showed that, compared with healthy individuals, patients with SCD not having a vaso-occlusive episode had a mean ratio of HDL2 to HDL3 that was 1.4 times higher (P less than .006), according to the published data. Moreover, the ratio for patients rose further on the 1st day of a vaso-occlusive episode (P = .005), so that the difference became even more pronounced.
Incubation of red blood cells with plasma from healthy individuals did not alter the HDL2 to HDL3 ratio, whereas incubation with plasma from patients with SCD increased this ratio.
When a fluorescent assay was used to assess oxidation, HDL2 from patients with SCD had altered function, whereby it had greater antioxidant capacity than HDL2 from healthy individuals. In fact, its antioxidant capacity was now very similar to that of HDL3.
Endothelial cells showed a greater increase in expression of long pentraxin 3, an acute phase protein produced in response to inflammatory stimuli, when exposed to HDL2 from patients with SCD as compared with HDL2 from healthy individuals (P less than .05). Hemopexin, the heme scavenger, nearly abolished this increase for SCD patients (P = .003) but had little effect for healthy individuals.
“This links hemolysis to lipoprotein-mediated inflammation in SCD, and hemopexin treatment could be considered,” the investigators maintain.
Dr. Soupene disclosed that he had no relevant conflicts of interest.