Medical director: Doc. Cinchini Elisabetta
Approximately 1.5% of the global population are heterozygotes (carriers) of the β-thalassemias: there is a high incidence in populations extending from the Mediterranean basin throughout the Middle East, the Indian subcontinent, Southeast Asia, Melanesia and into the Pacific Islands (Figure; in yellow the areas after immigrations).
More than 30,000 babies are born with homozygous β- thalassaemia worldwide each year and there are 100 million individuals who are asymptomatic β-thalassaemia carriers. Three clinical and haematological conditions of increasing severity are recognized: the β -thalassemia carrier state, β-thalassemia intermedia (Non Transfusion DependentThalassemia; NTDT) and β-thalassaemia major (TM).Today in developed countries, survival of patients on conventional treatment increased to 40–50 years; it is also expected in the near future to extent further to the senility (Figure).
Parallel to the significant amelioration of the main clinical features of the disease (severe anemia, bone changes, hepatosplenomegaly, and stunting of growth), adult patients suffer from complications that are mainly related to transfusions and the huge amounts of transfusional iron input that affect the heart, liver, and endocrine glands.These complications, especially those of the endocrine glands are very common among the long‑lived patients, requiring special health care andfollowed by specialists.Recent advances in the management of thalassemia syndromes have led to improved survival and better quality of life among thalassemics world wide.However, multi-transfused thalassemic patients continue to have several complications among which endocrinopathies contribute to significant morbidity (Table).
Apart from iron overload (Figure; adapted from Modell B, Mathews R. BirthDefects Orig Artic Ser. 1976; 12:13), other factors responsible for organ damage have been previously pointed out, including chronic hypoxia, due to anaemia, that may potentiate the toxicity of iron deposition in endocrine glands.
Adequate transfusion therapy will also reduce splenomegaly and hypersplenism and decrease absorption of dietary iron. The product of choice is packed red blood cells depleted of leucocytes and matched with the patient’s red antigen phenotype for at least D, C, c, E, e, and Kell. Whole blood or blood without leukodepletion is unsuitable for regular transfusions, since non-hemolytic transfusion reactions are common. When possible, large units less than two weeks of age are recommended.
The goal of transfusion is to shut off erythropoiesis as much as possible. Transfusions should generally be given at an interval of three to four weeks.Appropriate goals of transfusion therapy and optimal safety of transfused blood are the key concepts in the protocol for routine administration of red blood cells to patients with thalassemia.The major goals are:
1. Maintenance of red cell viability and function during storage, to ensure sufficient transport of oxygen
2. Use of donor erythrocytes with a normal recovery and half-life in the recipient
3. Achievement of appropriate hemoglobin level
4. Avoidance of adverse reactions, including transmission of infectious agents.
To date, there are 3 major classes of iron chelators: hexadentate (deferoxamine - DFO), in which 1 atom of iron is bound to 1 DFO molecule; bidentate (deferiprone- DFP), in which 1 atom of iron is bound to 3 DFP molecules; and tridentate (deferasirox - DFX), in which 1 atom of iron is bound to 2 DFX molecules. The goals of iron chelation therapy and the properties of different iron chelating agents are reported in the next two figures.
Effective chelation reduces or prevents iron accumulation and iron-mediated organ damage, resulting in a consistent decrease of morbidity andmortality. Combined therapy (use of two chelators on the same day), may induce negative iron balance and may reverse hypogonadism and endocrine complications in severe iron overloaded TM subjects.Long-term studies have shown that deferiprone and deferoxamine (DFO) accelerate iron chelation by rapidly reducing liver iron, serum ferritin, and myocardial siderosis.Combination chelation therapy with deferasirox and DFO has also been shown to be beneficial.
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