Iron Deficiency in HbSC Disease Is Associated with Less Sickle Cell Disease-Related Complications – a Rationale for Repetitive Phlebotomy As Disease Modifying Therapy

Background: Hemoglobin SC (HbSC) is the second most common genotype of sickle cell disease (SCD). Individuals with HbSC also experience severe SCD-related complications such as VOE, acute chest syndrome (ACS) and cerebral infarcts, similarly to HbSS patients. However, due to a lower degree of hemolysis, HbSC patients tend to have higher hemoglobin (Hb) and hematocrit (Ht) levels compared to HbSS patients. Higher Ht levels are associated with higher blood viscosity, which is associated with an increased incidence of retinopathy. Currently, there is no targeted therapy for HbSC disease. Retrospective studies have reported that repetitive phlebotomy can decrease blood viscosity, potentially leading to a reduction in occurrence of VOE in HbSC. Additionally, repetitive phlebotomy causes iron deficiency which results in a lower mean corpuscular hemoglobin concentration (MCHC). Whether iron deficiency improves red blood cell (RBC) characteristics such as sickling, dehydration or adhesion in HbSC is unknown.

Aims: To explore whether iron deficiency (preexistent or due to phlebotomy) is associated with blood viscosity, RBC hydration, sickling, and acute SCD-related complications in HbSC disease.

Methods: Adults and children with HbSC disease who visited outpatient clinics of the Sickle Cell Outcome Research (SCORE) consortium centers in The Netherlands were eligible to participate. Patients who had a recent blood transfusion (<3 months), phlebotomy (<3 months) and/or hydroxyurea were excluded. In addition, in a pilot study 3 HbSC individuals were studied who started repetitive phlebotomy every 2 weeks until a hemoglobin level of 10 g/dL was reached. Routine laboratory parameters including dense RBCs (Advia Analyzer) were measured. Blood viscosity was measured using a clone-plate viscometer (Brookfield). RBC hydration (Ohyper) and point of sickling (PoS) were assessed by ektacytometry using the Laser-Optical Rotational Red Cell Analyzer (Lorrca, RR Mechatronics). Logistic regression analysis was performed to explore associations of ferritin with >1 type of acute SCD-related complications (VOE, ACS, cerebral infarction).

Results: Forty-seven individuals with HbSC (median age 33y, range 6-66y) were included of whom 16 had concomitant α-thalassemia (-α/αα), 26 no α-thalassemia and in 5 α-thalassemia status was unknown. Ferritin positively correlated with reticulocyte % (r= 0.46, p=0.001), blood viscosity (r=0.34, p=0.044), Ohyper (r=0.35, p=0.022) and C-reactive protein (CRP, r=0.47, p=0.001, Spearman correlation). These results indicate that lower ferritin values are associated with lower levels of reticulocytes, lower blood viscosity, increased RBC dehydration and lower levels of inflammation. For every 100 ug/L increase in ferritin, the likelihood of experiencing >1 type of acute complication increased (odds ratio [OR] 2.72 (p=0.006); adjusted for age and α-thalassemia OR was 2.46 (p=0.019). Iron deficient HbSC individuals (ferritin<20 ug/L, n=6) had significantly lower reticulocyte counts (p=0.011 and p=0.008), CRP (p=0.019 and p=0.001), and increased RBC dehydration (lower Ohyper, p=0.046 and p=0.011) compared with patients with normal (20-240 ug/L, n=35) or high ferritin (>240 ug/L, n=6, Kruskal-Wallis test). Furthermore, SCD complication rate was significantly lower in iron deficient patients (median 1.0) compared to patients with high ferritin (median 3.0, p=0.011). Median follow-up of the 3 patients with phlebotomy induced iron deficiency was 9 months with a median number of 7 phlebotomies. Two patients experienced no VOE after initiation, although one of those patients developed progression of proliferative retinopathy, the third patient had a reduction in VOE of 67%. Phlebotomy decreased Hb, blood viscosity, MCV, MCHC, and ferritin, and improved PoS, % dense RBCs, and reticulocyte count (all p<0.05, paired t-test) in all patients.

Summary/Conclusion: Our findings demonstrate that iron deficiency in HbSC disease is associated with lower reticulocyte count, lower blood viscosity and lower levels of inflammation. More importantly, a less severe clinical phenotype was observed in iron deficient individuals with HbSC disease. In a pilot study, phlebotomy improved laboratory parameters and most clinical complications. These results warrant further prospective studies of phlebotomy as a low risk and low-cost therapy to reduce disease burden for HbSC.