Flow cytometry analyses reveal association between Lu/BCAM adhesion molecule and osteonecrosis in sickle cell disease

To the Editor

To identify relevant biomarkers of sickle cell disease (SCD), we determined by flow cytometry the expression of 10 adhesion membrane proteins present in reticulocytes and of eight adhesion membrane proteins present in red blood cells (RBCs; CD36 and CD49d are expressed in reticulocytes but not expressed in mature RBCs).

The study was conducted with a cohort of 68 homozygous SCD adult patients (SS or S beta-thal), untreated by hydroxycarbamide, and at basal steady state defined as a visit >1 month after an acute clinical event and >3 months after blood transfusion. Patients were categorized according to the absence versus presence of one out of eight clinical complications: renal dysfunction (defined as proteinuria ≥0.3 g/L or estimated glomerular filtration rates <80 mL/min) (chronic); leg ulcer (chronic); priapism (acute); pulmonary arterial hypertension (PAHT) confirmed by right heart catheterization (chronic); cerebral vasculopathy confirmed by magnetic resonance imaging (chronic); history of acute chest syndrome (ACS; acute); retinopathy (chronic); aseptic osteonecrosis confirmed by radiography or magnetic resonance imaging (chronic). Some patients exhibiting more than one complication belonged to several groups. Comparisons were made between symptomatic versus asymptomatic patients included in glomerulopathy group (13 vs. 55), in leg ulcer group (9 vs. 59), in priapism group (14 vs. 24 (men only)), in PAHT group (5 vs. 63), in cerebral vasculopathy group (6 vs. 62), in ACS group (29 vs. 39), in retinopathy group (26 vs. 42), and in aseptic osteonecrosis of hip and/or shoulder group (18 vs. 50).

When considering both the percentage of positive cells and the mean fluorescence intensity on both reticulocytes and mature RBCs, only CD239 (Lu/BCAM), the unique erythroid laminin α-5 receptor 1, 2 was found associated with a clinical complication. CD239 expression was significantly higher in reticulocytes and mature RBCs from patients with osteonecrosis than in those from patients exhibiting other complications (Table 1). Similarly, a higher percentage of CD239 positive reticulocytes and RBCs were observed in patients with osteonecrosis. It is noteworthy that the ligand of CD239, α-5 laminin, is abundant in bone marrow 4, where osteonecrosis takes place. CD239 is involved in abnormal adhesion of RBCs from SCD patients to components of the vascular wall and may participate to the occurrence of vaso occlusive crisis (VOC) 5.

The pathogenesis of osteonecrosis in SCD remains largely unknown, although a recent study demonstrated an association between osteonecrosis and increased RBC deformability 6. As analyses were performed in patients at steady state, i.e., at a distance from an hospitalization due to VOC, we suggest that CD239 might represent a predictive rather than a diagnosis marker of a vascular osteonecrosis. Although further longitudinal studies will be necessary to confirm this hypothesis, our results suggest that CD239 may play a role in this SCD complication, opening a new avenue of research.