Leukocytopenia is defined as low count of circulating WBCs. This can be caused by low neutrophils count, low lymphocytes count, other WBCs components or combined. Neutropenia can be primary idiopathic or secondary to many conditions including viral infections, hematological diseases, thyroid disorders, drug related or autoimmune diseases. (6) Lymphopenia has a broad variety of causes, most importantly are viral infections, hematological disorders and corticosteroids therapy, (7, 8)
Iron deficiency has been proposed to be infrequently associated with neutropenia and lymphopenia when other causes are ruled out. (9–11)
Although parenteral iron replacement has a relatively high safety profile, previous case reports suggested a link between iron therapy and impaired production of cell lineages like thrombocytes and leukocytes. The burden of leukopenia/neutropenia/lymphopenia as a consequent of iron therapy has not been well addressed in the literature. One review of 11 case reports and a case series described that thrombocytopenia can be induced by iron replacement (ferrous sulphate).(12)
Brito-Babapulle et al reported a case of fatal bone marrow suppression linked to ferric carboxymaltose therapy in a patient with IDA. This case started as amegacaryocytic thrombocytopenia and erythroid cell aplasia which was followed by a drop in neutrophils count. Other causes were well excluded death occurred before a donor for bone marrow transplant was found. (13) Another case report described the occurrence of neutropenia in a man after oral iron therapy that was transient and improved 1 month after stopping the iron tablets. (14) In our study the incidence of leukopenia, neutropenia and lymphopenia were with parental iron therapy was 1.9, 0.95, 0.76 percent, respectively in a large cohort of females treated with intravenous iron for IDA.
Iron is required for the oxidative response of neutrophils to allow the production of reactive oxygen species (ROS). However, neutrophil function may be severely altered in conditions of iron overload, as observed in chronically transfused patients. Therefore, a tight regulation of neutrophil iron homeostasis seems to be critical for avoiding iron toxicity.
In animal models, it was found that iron-dependent increase of hepatic hepcidin resulted in neutrophil intracellular iron trapping and consecutive defects in oxidative burst activity. Moreover, systemic iron overload has been correlated with a surprising neutrophil priming and resulted in a more powerful oxidative burst. (15)
Excessive iron may impair haematopoiesis, although the mechanisms of this deleterious effect is not entirely known.
In vitro tests show that commonly available intravenous iron formulations have differing capacities to saturate transferrin directly: Iron gluconate > iron sucrose > iron dextran. Intravenous iron treatment produces oxidative stress, as demonstrated by increases in plasma levels of lipid peroxidation products (malondialdehyde), at a point that is much earlier than the time to peak concentration of catalytically active iron, suggesting a direct effect of iron sucrose on oxidative stress. (16)
In animal models, iron overload was found to have a negative impact on the hematopoietic system through the accumulation of the reactive oxygen species (ROS) and its effect on adhesion molecules and cytokine production. It was suggested that ferrous ammonium sulfate can mediate cell apoptosis and cause growth arrest in immature cells.(17) One study found that ferrous ammonium sulphate (FeAS), induced growth arrest and apoptosis in immature hematopoietic cells, which was mediated via reactive oxygen species (ROS) activation of p38MAPK and JNK pathways. (17)
It has been postulated that i.v. iron might promote infection but there are conflicting studies in the literature. The risk of infection is thought partly to be because of some i.v. irons having a potentially immune activating effect. Iron sucrose can induce phenotypical and functional monocytic alterations and have a higher potential to modulate monocyte differentiation to macrophages and mature dendritic cells than more stable preparations. (18, 19)
In our cohort, with normal renal function, there was no significant association with infections, with only 2 infections reported in 1567 females who received i.v. iron therapy.
A few small trials in CKD populations suggest an increased infection risk with i.v. iron. Agarwal et al. undertook a single-centre RCT that randomly assigned no dialysis-dependent CKD (NDD-CKD) patients with IDA to either oral iron (69 patients) or i.v. iron sucrose (67 patients). As a secondary outcome measure, they found an increase in serious adverse events (SAEs) because of infections in patients receiving i.v. iron, with infections in the oral iron group occurring 27 times in 11 patients, whereas in the i.v. iron group, they occurred 37 times in 19 patients; the adjusted RR ratio was 2.12 (1.24–3.64), P < 0.006) (20, 21)
A systematic review and meta-analysis of RCT investigated the safety and efficacy of i.v. iron therapy. They obtained data from Medline, Embase, and the Cochrane Central Register of Controlled Trials from 1966 to June 2013. In total, 72 trials with 10 605 patients were included. Intravenous iron was found to be associated with a significant increase in RR of infection of 1.33 (95% CI: 1.10–1.64) compared with oral or no iron supplementation. (22)
However, these findings were subject to bias as infection was not a predefined endpoint in many of the trials and patients had renal disorders. They could also not detect a dose–response association between iron and risk of infection.(23)
Other studies have shown contrasting results regarding risk of infections associated with i.v. iron. In another meta-analysis that included 103 RCT, Avni et al. concluded that there was no increased risk of infections with the use of i.v. iron. (24)
More prospective studies are needed to address the possibility of increased infection risk in patients receiving i.v. iron therapy.