Blood Lipid Abnormalities in Sickle Cell Disease Are Pancellular and Clinically Important.

Abstract

In a previous study, we observed that high expression of the adhesion molecules L-selectin and αMβ2 integrin on leukocyte membranes is associated with severe sickle cell disease (Eur J Haem. 2002; 69: 135– 144). The lipid composition of cell membranes affects adhesion molecule expression, cell integrity and function (Calder P Lipids. 2003; 38: 343–352). Omega-3 fatty acids (FA) such as docosahexaenoic (DHA) and eicosapentaenoic (EPA) are vital for the structure and function of cell membranes. Sickling perturbs the normal asymmetry of erythrocyte membrane lipids. Choline phosphoglycerides (CPG) move from the outer to inner leaflet. Ethanolamine (EPG) and serine (SPG) phosphoglycerides shift from the inner to the outer layer. Exposure of the highly reactive SPG to plasma promotes clotting, rbc adhesion to vascular endothelium, wbcs and platelets; vaso-occlusion, and ischaemic organ damage. Loss of lipid asymmetry impairs the structure of rbc membranes, causes abnormal ion flux and exacerbates haemolysis. Although rbc and plasma lipid abnormalities are recognised, there is little data on occurrence and clinical relevance of leukocyte or platelet FA anomalies in SCD. The aim of this study is to find out if the FA constitution of blood cell membranes modulates the clinical features of SCD. The FA composition of blood cells and plasma was analysed in 68 HbSS and 9 HbSC patients in steady-state (40M, 37F, age 11–52 yr, mean 26 yr); and 58 healthy, age, sex and race matched HbAA controls from the same environment. We excluded cigarette smokers, anyone who had blood transfusion or pregnancy in the previous 4 months, and SCD patients with co-morbidities or HbF ≥ 10%. Steady-state Hb level in HbSS patients showed highly significant positive correlation with the proportions of DHA in erythrocyte membrane CPG (p<0.001, r = 0.42); and of EPA in membrane EPG (p<0.01, r = 0.57). There was very significant reduction of red cell and plasma EPA of HbSS patients compared to HbSC and HbAA individuals (p<0.001). Similarly, DHA and EPA were significantly reduced in leukocytes and platelets of HbSS patients relative to controls (p<0.005). Compared to HbSS patients who had no complications of SCD (n=9), those with complications (n=19) had markedly reduced DHA and total omega-3 fatty acids in erythrocytes (p<0.005), and platelets (p<0.05). Since EPA and DHA are essential structural and functional components of cell membranes, and precursors of potent anti-inflammatory eicosanoids and cytokines, decrease in their proportions exacerbates haemolysis, inflammation, vaso-occlusion and organ damage in SCD. Tomer et al (Thromb. Hemost. 85; 966–974) and our group observed reduction in the number of sickle cell crisis during pilot clinical trials of EPA and DHA. The current study and pilot trials suggest that omega-3 FA therapy has considerable potential in SCD. As natural constituents of fish oil omega-3 FA are eaten safely world-wide, and are affordable in developing countries where majority of SCD patients live. Unlike hydroxyurea, they are not cytotoxic, teratogenic or immunosuppressive. Unlike regular blood transfusions, there is no risk of HIV or other infections. Omega-3 FA are beneficial in cardiovascular and multi-organ chronic inflammatory conditions. There are sufficient grounds for a large clinical trial of EPA and DHA in the multi-system disorder that is SCD.