M. Cazzola

New tools for clinical evaluation of erythron function in man

The diagnostic approach to anaemia is based on a battery of tests that define the nature of the abnormality in erythron function (Hillman & Finch, 1985). In particular, the initial separation of anaemia into one of three major categories (hypoproliferative, maturation defect, or haemolytic anaemia) requires measurements of red cell production and destruction (Cazzola & Finch, 1987). Some of these measurements, however, involve laboratory methods that are unreliable or cumbersome in a clinical setting, so that classification of anaemia is not infrequently inaccurate. In the last years, new tools have been developed for clinical evaluation of erythron function in man. The basic components of erythropoiesis are erythroid progenitors, their stimulation by erythropoietin, and adequate supply of iron from which to make haemoglobin (Finch, 1982). Endogenous erythropoietin production can be blunted in several anaemic conditions, and determining serum erythropoietin levels has provided clinicians with a convenient means of assessing this mechanism of anaemia. On the other hand, serum erythropoietin has proved to be of value also in the differential diagnosis of erythrocytosis. Iron delivery to erythroblasts is mediated by the interaction of plasma transferrin with surface transferrin receptors (Huebers & Finch, 19 87). One of the most valuable advances in the clinical assessment of erythropoiesis has been the detection of soluble transferrin receptors in human plasma. This has proved to have important clinical implications, since the soluble receptor level has been shown to be closely related to the number of red cell precursors in the bone marrow and to provide a reliable quantitative assay of the rate of erythropoiesis. This annotation discusses the clinical significance of serum erythropoietin and circulating transferrin receptor.

A moderate transfusion regimen may reduce iron loading in beta‐ thalassemia major without producing excessive expansion of erythropoiesis

BACKGROUND: Hypertransfusion with a baseline hemoglobin of 10 to 12 g per dL is still considered by many to be the mainstay of conservative therapy for beta‐thalassemia major. However, this regimen is frequently associated with manifestations of transfusion iron overload, despite regular chelation therapy with subcutaneous desferoxamine. STUDY DESIGN AND METHODS: To verify whether a transfusion regimen with a target pretransfusion hemoglobin level between 9 and 10 g per dL can allow a significant reduction in blood consumption, while still effectively suppressing erythropoiesis, the records were reviewed of 32 beta‐ thalassemia major patients, who were maintained at a pretransfusion hemoglobin of 11.3 +/− 0.5 g per dL between 1981 and 1986. These patients were switched at the beginning of 1987 to a transfusion regimen with pretransfusion hemoglobin of 9.4 +/− 0.4 g per dL. The degree of erythroid marrow activity was evaluated in these patients and in 32 subjects with beta‐thalassemia intermedia through the simple measurement of serum transferrin receptor. RESULTS: After the adoption of the moderate transfusion regimen, transfusion requirements decreased from 137 +/− 26 to 104 +/− 23 mL per kg per year of red cells (p < 0.0001), and mean serum ferritin decreased from 2448 +/− 1515 to 1187 +/− 816 micrograms per L (p < 0.0001), with one‐half of patients achieving serum ferritin levels lower than 1000 micrograms per L. The proportion of patients having spontaneous pubertal development increased significantly (p < 0.01), as a result of less iron‐related gonadotropin insufficiency. At the lower pretransfusion hemoglobin, erythroid marrow activity did not exceed two to three times normal levels in most subjects. CONCLUSION: As compared with hypertransfusion, moderate transfusion may allow more effective prevention of iron loading, with higher likelihood of spontaneous pubertal development and without producing excessive expansion of erythropoiesis.

Relationship between transfusion regimen and suppression of erythropoiesis in β-thalassaemia major

In the management of β‐thalassaemia major, different transfusion schemes are employed with baseline haemoglobin levels ranging from 8 to over 12 g/dl. We studied the relationship between transfusion regimen and suppression of erythropoiesis in 52 patients with β‐thalassaemia major whose mean pretransfusion haemoglobin levels ranged from 8.6 to 10.9 g/dl. Multiple, regression analysis showed that serum transferrin receptor was the parameter more closely related to mean pretransfusion haemoglobin (r = ‐0.77, P < 0.001). As measured through serum transferrin receptor, erythroid activity was 1‐2 times normal for pretransfusion haemoglobin levels between 10 and 11 g/dl, 1‐4 times normal for levels from 9 to 10 g/dl, and 2‐6 times normal for levels from 8.6 to 9 g/dl. Mean pretransfusion haemoglobin was also inversely related to serum erythropoietin (r = ‐0.72, P < 0.001), whereas it showed no or a weak relationship with Hb F, reticulocyte count, or circulating nucleated red cell count. This study suggests that serum transferrin receptor is a reliable indicator of suppression of erythropoiesis in β‐thalassaemia major. On the basis of our findings, pretransfusion haemoglobin values of ≦ 9 g/dl should be adopted with caution, because these levels can be associated with an insufficient inhibition of erythroid marrow expansion. However, a transfusion programme, with a baseline haemoglobin of 9‐10 g/dl, may provide enough suppression of erythropoiesis and allow a reduction in blood consumption as compared with the classic hyper‐ or supertransfusion schemes. Since fixed haemoglobin levels may not be the best target for transfusion treatment in all thalassaemic patients, assay of serum transferrin receptor may be helpful for individualizing the transfusion regimens.

Accelerated erythroid repopulation with no stem-cell competition effect in children treated with recombinant human erythropoietin after allogeneic bone marrow transplantation.

Summary. We carried out a pilot study on the use of recombinant human erythropoietin (rHuEPO) to accelerate erythropoietic engraftment in paediatric patients undergoing allogeneic BMT. rHuEPO was administered intravenously at a dose of 75 U/kg per day for 30 d after transplant. Erythroid repopulation, evaluated sequentially through the serum transferrin receptor, was faster in 15 patients receiving rHuEPO than in 16 historical controls (P= 0·0003). This faster erythroid engraftment resulted in a reduction in the total number of red blood cell units required to reach transfusion independence (2·7 ± 1·2 v 4·2 ± 2·3, P= 0·027). No significant difference in leucocyte or platelet regeneration was observed. These findings indicate that rHuEPO administration can accelerate erythroid recovery after allogeneic BMT and reduce red cell transfusion requirements with no stem‐cell competition effect.