Fresh Frozen Plasma Plus Iron Therapy in Congenital Hypotransferrinemia in the Second Decade: A Dynamic Approach to Maintaining Hematological Stability

To the Editor,

Congenital hypotransferrinemia (CH) is a rare disorder characterized by deficiencies in transferrin and consequently hepcidin in serum [1,2]. The former leads to anemia due to lack of transferrin-mediated iron delivery to erythroid cells, whereas the latter results in severe iron overload in all non-hematopoietic tissues. Fresh frozen plasma transfusions, as a natural source of transferrin, lead to hemoglobin (Hb) synthesis by increasing the iron supply to the marrow with a consequent increase in hepcidin production. Plasma is known to have no effect on iron overload [3].

In 2018, we reported the observational follow-up of a child affected by CH who had been successfully treated with monthly plasma transfusions fortified with oral iron since 2007 [4]. Our first-decade results showed both correction and stable control of Hb. Ferritin levels were also stabilized. However, at the start of the second decade, Hb and ferritin began to decline and the therapy was revised. We herein present the 44-month follow-up results with updated therapy of the original case for the conscious management of other cases.

By the second decade, with no change in patient compliance, a decrease in Hb and ferritin began, probably due to a growth-related increase of erythroid iron demand or a reciprocal interaction between the actors in iron metabolism (Figure 1). The two major factors affecting these levels in this therapy are transferrin (here, plasma transfusion) and iron (here, additional iron). Since monthly plasma transfusions were thought to provide sufficient transferrin for erythropoiesis and reducing the interval between transfusions would negatively affect quality of life, the change was made to the iron therapy. As the iron dose was at the upper limit (10 mg/kg/day elemental iron), its duration was extended from 7 to 10 days: for maximum iron-transferrin interaction time, iron was started 1 day prior to fresh frozen plasma transfusion and continued for 2 days beyond the 1-week administration (though fresh frozen plasma transferrin persists in the serum for 1 week considering its molecular half-life of 8-10 days [5]). Hb and ferritin were measured monthly. Serum iron was checked before and transferrin before and after transfusions. The physical and social development of the patient was also followed.

Figure 1

Hemoglobin and ferritin in the first and second decades.

The 44-month follow-up revealed the following: a) the fall in Hb was controlled (Figure 1); b) the fall in ferritin was not completely controlled (Figure 1); c) growth and development remained stable (Figures 2A and (2B) and the patient’s social skills were compatible with those of her peers while she successfully continued her education; d) no side effects were observed with either fresh frozen plasma or iron therapy. Average transferrin before and after transfusion was 39.3 mg/dL and 118 mg/dL, respectively. Average serum iron before transfusion was within normal limits (23.1 mg/dL).

Figure 2

Growth and development remained stable (A, height; B, weight).

This combination provides a sufficient and stable Hb level for normal growth and development. Despite mild fluctuations, the Hb level was maintained above 12 g/dL and no anemia or need for increased amounts of plasma transfused or frequency of transfusions developed, unlike in a previous case under plasma therapy alone [6]. In this case with relatively long-term follow-up, Hb decreased to a level of about 7.0 g/dL in 5 years and the frequency of transfusions was increased to every week for 2 months along with the amount of fresh frozen plasma transfused to maintain normal erythropoiesis until Hb normalized.

With plasma transfusions, iron storage declines. Additional iron can delay the development of ferritin decline but it cannot permanently prevent it. The explanation for this might be as follows: hepcidin is the key regulator of iron metabolism [7,8]. Although additional iron may increase hepcidin at first, the effect of active erythropoiesis augmented by additional iron due to erythroferrone (ERFE) produced by erythroblasts is much stronger and reduces the hepcidin, facilitating prolonged ferritin stability [9]. After a constant return to normal sufficient erythropoiesis (in our patient, after the first decade), since ERFE is not required in this resting erythropoiesis phase and its hepcidin suppression disappears, an increase in hepcidin develops, leading to a reduction of iron, including toxic non-transferrin-bound iron [10], and a decline in iron storage (Figure 1).

Sufficient and stable levels of Hb can provide and support normal growth and development. The absence of iron overload in vital organs may also contribute to this physiological process.

Stable levels of erythropoietic indicators (e.g., Hb and reticulocytes) suggest that monthly fresh frozen plasma transfusion is sufficient for normal erythropoiesis. This report is the first to present fresh frozen plasma transferrin values in the pre- and post-transfusion periods, confirming this suggestion.

In conclusion, our experience of almost 14 years reveals that fresh frozen plasma plus iron therapy may be advantageous over standard fresh frozen plasma transfusion. With this therapy, the stable Hb control seen in this case in the first decade was re-achieved in the second decade. Despite a decline in iron storage, no anemia developed and there was no need to increase transfusion frequency. Optimal growth and development were achieved with minimal need for hospital services. Due to the reciprocal interactions between the actors of iron metabolism, a dynamic approach is necessary in the long-term treatment of CH to maintain hematological stability.