Iron deficiency in HbSC disease is associated with less sickle cell disease-related complications – a rationale for repetitive phlebotomy as disease modifying therapy
Hemoglobin SC (HbSC) is the second most common genotype of sickle cell disease (SCD) and causes severe SCD-related complications such as vaso-occlusive episodes (VOE), acute chest syndrome (ACS) and cerebral infarcts. HbSC patients have higher hematocrit and blood viscosity levels with an increased incidence of retinopathy compared to HbSS patients. Currently, there is no targeted therapy for patients with HbSC. Repetitive phlebotomy can decrease blood viscosity and induce iron deficiency, potentially leading to a reduction in occurrence of VOE in HbSC. The effect of iron deficiency on RBC characteristics and acute complications in HbSC is yet unknown.
Adults and children with HbSC from Dutch outpatient clinics in the Sickle Cell Outcome Research (SCORE) consortium were eligible, excluding those with blood transfusion (<3 months) or on hydroxyurea. Four HbSC patients underwent biweekly phlebotomy until hemoglobin reached 10g/dL. Laboratory parameters including RBC characteristics (Advia) and viscosity (Brookfield) were measured. RBC hydration (Ohyper) and point of sickling (PoS) were assessed by ektacytometry using the Lorrca (RR Mechatronics). Logistic regression analysis was performed to explore associations of ferritin with >1 type of acute SCD-related complications (VOE, ACS and cerebral infarction).
Forty-seven individuals with HbSC (median age 31y, range 6-66) were included of whom 16 had concomitant α-thalassemia (-α/αα, 28 had no α-thalassemia and in 4 α-thalassemia status was unknown. Ferritin was positively correlated with reticulocyte % (r=0.42, p=0.004), blood viscosity (r=0.35, p=0.037), RBC hydration (Ohyper, r=0.32, p=0.038) and CRP (r=0.45, p=0.002, Spearman correlation). For every 100ug/L increase in ferritin, the likelihood of experiencing >1 type of acute complication increased (OR 2.72, p=0.006); adjusted for age and α-thalassemia the OR was 2.46 (p=0.019). Iron deficient HbSC individuals (ferritin <20ug/L, n=6) had significantly lower reticulocyte and CRP levels, and increased RBC dehydration compared to 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 0.75) compared to patients with high ferritin (median 3.3, p=0.011). 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. After initiation of phlebotomy, the patients experienced no or less VOEs. One patient developed progression of proliferative retinopathy.
Our findings demonstrate that iron deficiency in HbSC disease is associated with a lower reticulocyte count, decreased viscosity and reduced inflammation. More importantly, a less severe clinical phenotype was observed in iron deficient individuals with HbSC disease. Phlebotomy improved laboratory parameters and most clinical complications. There results warrant further prospective studies of phlebotomy to reduce disease burden for HbSC.