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Transfusional iron overload can result from the treatment of any condition that requires the repeated transfusion of red blood cells. Disorders of defective erythropoiesis, such as thalassemia, SCD and MDS are the most common diseases in which chronic transfusion may be required.
- Aplastic anemia
- Diamond-Blackfan anemia (red blood cell aplasia)
- Dyserythropoietic anemias
- Fanconi anemia (hypoplastic anemia)
Thalassemia is an inherited condition that occurs as a result of mutational changes in erythrocyte globin chains. Initially it was identified as a disease of the Mediterranean area, however, it is now recognized as being present in most ethnic groups and geographic locations, although prevalence varies between different regions (gene frequency estimates of 3-10% [1]).
The two main forms of the disease, α-thalassemia and β-thalassemia, result from mutations in genes encoding the respective globin chains (α-globin: genes HBA1 and HBA2; β-globin: gene HBB on chromosome [1]). Both forms are inherited as recessive alleles. Individuals with α-thalassemia have reduced production of α-globin chains, which leads to a relative excess of β-globin chains and, in turn, to the formation of unstable tetramers that have abnormal oxygen dissociation curves. In β-thalassemia, for which more than 200 gene mutations have been identified [2], a reduction in β-globin production occurs, which leads to a relative excess of α-globin chains. These chains do not, however, form tetramers. Instead, they bind to erythrocyte membranes causing membrane damage and, at higher concentrations, have the tendency to form toxic aggregates. The severity and required treatment regimen of both diseases depends upon the type of mutation and whether the carrier is heterozygous or homozygous to the disease.
Based on genotype, β-thalassemia can be divided into two main groups. β-thalassemia major (also known as Cooley's anemia) occurs when an individual has a homozygous genotype to the disease [1]. This is the most severe form and, if untreated, normally results in mortality before the age of 20 [3]. β-thalassemia minor occurs when only one of the mutant alleles is present, thus, the individual is heterozygous to the disease. The effects of this type are relatively mild in comparison, with symptoms including mild anemia and microcytosis. Individuals with this form of the disease are often asymptomatic, although they may experience weakness and fatigue. There is also an intermediate form of the disease, β-thalassemia intermedia, in which individuals may have a normal life but with a need for occasional transfusions (e.g. during illness, pregnancy).
Untransfused children with homozygous β-thalassemia usually exhibit one or more of the complications of defective erythropoiesis (reduced function and quality of life, increased risk of congestive heart failure, myocardial infarction, or dementia).
The goal of transfusion therapy, which remains the most effective treatment method, is to ameliorate these complications and improve patients' quality of life. A limited proportion of patients with thalassemia may be cured by bone-marrow transplantation from human leukocyte antigen (HLA)-identical donors [4]. A future direction is likely to involve gene therapy into stem cells, which can then be transplanted and subsequently differentiate into autologous erythrocytes [5].
Sickle cell disease (SCD) is an inherited condition in which red blood cells become abnormally shaped when deoxygenated due to the polymerization of hemoglobin S. Hemoglobin S is a mutant form of the protein, caused by a single point mutation in the gene that encodes the β-globin chain [6]. As a recessive allele, clinical symptoms are only shown with a homozygous genotype. Heterozygous individuals are asymptomatic and merely carriers.
Hemoglobin S is composed of two wild-type α-globin subunits and two mutant β-globin subunits (each possessing a valine instead of a glutamic acid at position 6). Hemoglobin S readily polymerizes in its deoxidized state rendering it very rigid and vulnerable to hemolysis [7].
SCD was first identified in individuals of West African descent, and 10-30% of people in Equatorial Africa carry at least one hemoglobin S gene [8].
Geographical distribution of the sickle gene in Africa and the Arab-India region [9]. © 2001 Blackwell Publishing, reprinted with permission
The greater the proportion of hemoglobin S in the blood the greater the risk of complications, including chronic anemia due to reduced erythrocyte lifespan, vaso occlusion, perfusion deficits and infection. The most significant cause of pathology is vaso-oclusive crisis, which occurs when sickle cell erythrocytes become obstructed in capillaries. While many individuals with SCD do not experience symptoms or complications until adulthood, those whose condition progresses to sickle cell anemia will certainly experience debilitating symptoms such as pain, acute chest syndrome, strokes, or other cardiovascular accidents.
Image provided courtesy of Professor Swee-Lay Thein, King's College Hospital, King's College London, London; Hb=hemoglobin
Hemoglobin S confers a survival advantage against cerebral malaria [6], a condition that was once confined to tropical regions (in particular sub-Saharan Africa) in which malarial infections were endemic. Today, the sickle cell trait is geographically more widely distributed, affecting millions worldwide, although prevalence is still higher amongst people of African, Mediterranean, East Indian, Caribbean and Central/South American descent [7]. In the USA, approximately two million Americans, or one in 12 African Americans, carry the sickle cell allele. The disease occurs in approximately one of every 500 African-American births, and one of every 1000-1400 Hispanic-American births [8].
Traditionally, regular blood transfusions have not been a common approach to the treatment of SCD. However, recent evidence highlighting the benefits of transfusion therapy has led to an increase in its use in SCD [10]. Blood transfusion increases hemoglobin content, thus increasing the oxygen-carrying capacity of blood and reducing the proportion of sickle cells in the circulation (the aim being a reduction in hemoglobin S down to <30% of total hemoglobin). Transfusion therapy provides numerous benefits to sickle cell sufferers, in particular, a significant reduction in the risk of stroke has been observed following treatment (92% according to the Stroke Prevention in Sickle Cell Anemia [STOP] study [11]). In addition, when treatment was discontinued, a high rate of reversion to abnormal blood-flow velocities was observed, thereby increasing the risk of stroke [12]. Historically, intermittent transfusions have been used as and when symptoms arise, although based on data from the STOP trials an increasing number of patients now receive chronic transfusion therapy as a key part of their management program.
Chemotherapeutic treatment with hydroxyurea, which reactivates fetal hemoglobin production thereby replacing the harmful hemoglobin S, has been shown to reduce the severity and number of 'attacks' and to increase survival [13]. It reactivates fetal hemoglobin production; replacing the harmful hemoglobin S. Investigations into its use are currently ongoing as long-term treatment may be harmful, although its benefits may outweigh this [14].
Bone-marrow transplantation remains the only curative approach to SCD, although the procedure is still in its infancy and is currently being refined. The primary limitation of this approach is the availability of suitable HLA-matched donors. However, new developments such as gene therapy involving stem cells may eventually facilitate the establishment of autologous bone marrow tissue.
Other treatment methods related to SCD involve targeting specific symptoms. For example, the extreme pain associated with this condition often requires treatment with opioid analgesics, whereas infections may require antibiotic treatment.
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