Management of iron overload in hemoglobinopathies.

Hemoglobinopathies, thalassemia and sickle cell disease are among the most frequent monogenic diseases in the world. Transfusion has improved dramatically their prognosis, but provokes iron overload, which induces multiple organ damages. Iron overload is related to accumulation of iron released from hemolysis and transfused red cell, but also, in thalassemic patients, secondary to ineffective erythropoiesis, which increases intestinal iron absorption via decreased hepcidin production. Transfusion-related cardiac iron overload remains a main cause of death in thalassemia in well-resourced countries, and is responsible for severe hepatic damages in sickle cell disease. Regular monitoring by Magnetic Resonance Imaging (MRI) using myocardial T2* (ms) and Liver Iron Content (LIC) (mg of iron/g dry weight) are now standards of care in chronically transfused patients. Serum ferritin level measurements and record of the total number of transfused erythrocyte concentrates are also helpful tools. Three iron chelators are currently available, deferoxamine, which must be injected subcutaneously or intravenously, and two oral chelators, deferiprone and deferasirox. We will review the main characteristics of these drugs and their indications.

[Diagnosis of hypochromic microcytic anemia in children]. / Exploration d'une anémie microcytaire chez l'enfant.

Iron deficiency is the most frequent cause of hypochromic microcytic anemia in children, but other causes, some of them requiring specific management, may be involved. Checking the iron-status is absolutely mandatory. When iron-status parameters are low, inadequate intake, malabsorption, blood loss, and abnormal iron utilization must be tested. In absence of iron deficiency, α- and ß-globin and heme biosynthetic gene status must be checked. Assessing the iron stock level is difficult, because there is an overlap between the values observed in iron-replete and iron-deprived patients, so that at least 2 iron-status parameters must be below normal for diagnosing iron deficiency. Furthermore, inflammation may also mimic some characteristics of iron deficiency. Diagnosing iron deficiency leads to prescribing iron supplementation with follow-up at the end and 3 months after cessation of treatment. When iron stores are not replete at the end of treatment, compliance and dosage must be reevaluated and occult bleeding sought. The latter is also required when the iron store decreases 3 months after cessation of iron replacement.

[Management of children with sickle cell anemia: a collaborative work]. / Prise en charge des enfants drépanocytaires: un travail d'équipe.

Treatment of children with sickle cell disease has been impressively improved during recent years. Neonatal screening is now generalized to all continental France. Coupled with parents' education and a comprehensive care program, it allows a reduction of pneumococcal infections, and of the mortality related to splenic sequenstration, the occurrence of cerebrovascular accidents being also reduced by the use of transcranial Doppler ultrasonography. However, to be effective these measures require a close collaboration not only between parents and the medical team but frequently also between the medical team and social workers, as many affected children living in France are born from first generation African migrants, for whom it may be difficult to understand and/or to apply the care program.

[Transfusion in patients with hemoglobinopathies]. / Transfusion des patients atteints d'hémoglobinopathies.

A-Thalassemia involves a production deficiency concerning the synthesis of alpha-globin chains, and beta-thalassemia involves the beta-globin chains. Only a few patients in France are affected by the major form of thalassemia (certain types of homozygotic beta-thalassemia). Also, the systematic screening of 'at-risk' couples and prenatal diagnosis has helped to considerably reduce the incidence of new cases. The decision to perform regular blood transfusions is made when Hb levels fall below values that are compatible with normal activity. Hb levels above 10 g/dL permit normal educational, recreational and professional activity. This level is generally maintained via a 15 mL/kg erythrocyte concentrate supplement every three weeks, or 20 mL/kg every four weeks. However, the appearance of antierythrocytic autoantibodies is possible, and this may also result in an increase in blood transfusion requirements. In intermediate thalassemia patients, residual Hb levels are maintained at between 7 and 10 g/dL, and transfusion of erythrocyte concentrates is only made in the case of aggravation of chronic anemia or when there are signs of intolerance to chronic anemia. In France, there is relatively large population of patients with sickle cell disease. Blood transfusion is a major element in the treatment of these patients. Simple transfusion is performed in cases of a lack of iron or folates, increased hemolysis, splenic sequestration or parvovirus 19 infection. The target hematocrit should mostly remain at the patient's baseline value. Exchange transfusions are not performed on a regular basis, but only in cases of stroke or other severe vaso-occlusive events, or when a patient has to be prepared for surgery. A minority of subjects are involved in chronic blood transfusion, which is used mostly to prevent cerebrovascular accidents but also in cases of cardiac, renal, or respiratory insufficiency. There is an increased prevalence of antierythrocytic alloimmunization in sickle cell patients, most probably because of the discrepancies in red cell antigens between mainly Caucasian blood donors and Afro-Caribbean recipients.

[Autologous transfusion: when best should not be the enemy of good enough...]. / Transfusion autologue: quand le mieux ne doit pas être l'ennemi du bien....

Autologous blood transfusion has been shown to decrease allogeneic transfusion in patients undergoing elective procedures, in adults as well as in children. However, its indication must be carefully discussed for each patient, since, on the one hand, viral risks associated with allogeneic blood are greatly reduced, while on the other hand, adverse events may occur in some patients with poor physical condition. An assessment of the ratio 'benefit-risk' has to be made for each patient.

Autologous blood donation for elective surgery in children weighing 8-25 kg.

To determine whether autologous blood donation can be used safely and efficiently in children weighing 8-25 kg, we studied children whose perioperative blood losses were expected to exceed 25% of total blood volume. Blood donations were performed in pediatric units, under the direction of an anesthesiologist and a blood bank physician experienced in paediatric care. Twenty-four children, median age 6 years (1-13), were included. They underwent surgery mainly for digestive or urological disorders, and for orthopedic defects. Forty blood collections were performed of the 46 prescribed. Phlebotomies could not be performed in 1 child because of the mother's apprehension, and in 5 cases because of venous access problems. All phlebotomies were hemodynamically well tolerated. Hemodilution was also performed in 17 children, and cell saver used in 2. Allogeneic blood transfusion was avoided in 21/24 children.

[Growth and endocrine function in major thalassemia]. / Croissance et fonction endocrine dans la thalassémie majeure.

BACKGROUND: The risk of secondary endocrine dysfunction in patients with thalassemia major remains high, despite improvements in the care of hematologic problems. POPULATION AND METHODS: 31 patients (15 males, 16 females) with thalassemia major were studied. 28 of them had been regularly given blood transfusions since the age of 3.7 +/- 3.6 years. Iron chelation therapy had started before the age of 10 years in 9 patients, after this age in 15 patients; it was not performed or the time not specified in the 7 others. The mean dosage of deferoxamine was 20 +/- 6 mg/kg/day (9.6-34 mg/kg/day). Endocrine functions were evaluated at a mean age of 11.8 +/- 4.9 years and were monitored for 6.1 +/- 4.6 years (0 to 19 years). The hormones assay were: growth hormone (GH), thyroid, adrenal cortex, parathyroid and gonadal functions. RESULTS: The GH peak after stimulation was normal, but plasma somatomedin CIGFI was low and did not increase at puberty. 6 patients had peripheral hypothyroidism. Plasma cortisol was normal in the 16 patients examined, but plasma dehydroepiandrosterone sulfate was low in 24; this might be partly responsible for the delayed development of pubic hair. 2 patients aged 20 and 27 years was suffered from diabetes mellitus. Hypoparathyroidism occurred in 7 patients and 12 of the 24 patients with impuberism had a gonadotropin deficiency. The mean final height was -1.3 +/- 1.0 SD in boys (n = 7, mean age: 20 +/- 1 yr) and -1.3 +/- 0.9 SD in girls (n = 7; mean age: 19 +/- 1 yr), whether puberty was spontaneous or induced. CONCLUSIONS: The most frequent endocrine complications in these patients are delayed puberty because of gonadotropin deficiency, hypoparathyroidism and peripheral hypothyroidism. Substitution therapy, using sex steroids at an appropriate age, can induce the pubertal growth spurt.

[Treatment of post-transfusion iron overload by deferoxamine]. / Traitement de la surcharge en fer post-transfusionnelle par la déféroxamine.

Iron chelation therapy must be associated with the regular blood transfusions required for thalassaemia and other chronic anemias. We report here a study concerning 4 groups of patients, aged 6 to 28, regularly transfused at Necker Enfants-Malades hospital: a) 20 with thalassaemia major; b) 6 with thalassaemia intermedia; c) 2 with sickle cell disease and d) 2 with Blackfan-Diamond syndrome. The transfusion regimen consisting of monthly or quarterly transfusions varied as a function of the groups. Desferal was used in all patients. The dosage and the route of administration (IV, IM, SC) were adapted to the amount of iron transfused and to the nature of the disease. The serum ferritin level was considered as the indicator of the iron overload. Comparisons were established between the quantities of iron transfused, ferritin levels, and parameters such as dosage, route of administration and compliance to Desferal. During the period of study 3 patients died from cardiac failure due to transfusional hemosiderosis. Endocrine complications (diabetes 2 cases, hypocalcemia 3 cases, hypothyroidism 1 case and delayed puberty 7 cases) were observed. This high incidence of complications induced by post-transfusional iron overload has recently prompted us to improve the quality of chelation therapy through the use of the services of a specialized center where patients as well as their families can be trained more adequately in home care and self-treatment.