Erythropoiesis is not equally suppressed in transfused males and females with β-thalassemia major: are there clinical implications?

Blood transfusion in β-thalassemia major aims to suppress ineffective erythropoiesis, limit morbidity from chronic anemia, and minimize bone changes from marrow expansion and extra-medullary hemopoiesis (EMH). In the 1970s, blood transfusion was shown to suppress erythropoiesis. It is uncertain how much blood should be transfused to each patient for optimal long-term health and to minimize complications. At present, all patients are transfused equally with no consideration given to gender. There are limited data exploring differences between males and females. This study demonstrates important differences in pre-transfusion indices of erythropoiesis, descriptors of blood transfusion and the frequency of para-spinal EMH when patients are transfused according to current recommendations. These findings strongly support the notion that erythropoiesis is not being equally suppressed in males compared to females and hence that males are being undertransfused with current practices. Extra-medullary hemopoiesis is the presence of hemopoietic tissue outside of the bone marrow, which occurs as a compensatory process in the setting of ineffective erythropoiesis. Spinal cord compression is an uncommon but serious complication of para-spinal EMH. There is a clear male predominance (M:F ratio ≥4:1) that has been documented without drawing attention to gender differences or the possible need for males to be treated more intensively to avoid this complication. We aimed to determine by using readily available laboratory tests whether there were differences in erythropoietic activity between male and female adult β-thalassemia major patients receiving a regular transfusion regimen in accordance with current international recommendations. All 126 adults (≥18 years) with β-thalassemia major at our center were eligible. All patients had been receiving an individualized and regular transfusion regimen and iron chelation therapy in accordance with current recommendations. Patients’ height and weight were recorded to estimate blood volume using Nadler’s formula. Blood samples were collected on the day of, and prior to, routine transfusion when it was expected that erythropoietic activity would be maximal. Blood samples were tested for hemoglobin (Hb), nucleated red blood cell (NRBC) and absolute and relative reticulocyte counts with a Beckman Coulter LH750 hematology analyzer. Blood films were examined for manual NRBC and reticulocyte counts with a light microscope. Serum ferritin and erythropoietin (EPO) levels were determined by immunoassay (Beckman Coulter DXi 800). We perform regular MRI at 1.5 Tesla (Siemens Avanto) to assess cardiac function and to monitor hepatic and cardiac iron loading using the T2* technique. Additional chest and abdomen imaging was assessed for the presence of para-spinal EMH. This study was approved by the Monash Health Ethics Committee. Informed consent was obtained from each patient to draw blood during routine clinical care. Data were analyzed using SAS software v.9.3 (SAS Institute, Cary, NC, USA). Comparisons between groups were performed using Mann-Whitney Utest for non-normally distributed continuous variables, Student t-test for normally distributed continuous variables, and c or Fisher’s exact test as appropriate for categorical variables. Two-sided P=0.05 was considered statistically significant. One hundred and sixteen patients (51 males and 65 females) provided pre-transfusion blood samples (Table 1). The 10 patients not included were either not available or declined testing. Males and females were of similar ages and were receiving blood over a similar inter-transfusion interval. Males were heavier, taller and had a higher esti-