The thalassemias are a group of hereditary anemias characterized by a reduced rate of synthesis of hemoglobin polypeptide chains alpha or beta. This decreased synthesis leads, in turn, to reduced hemoglobin and a hypochromic microcytic anemia. α-Thalassemia is due to a gene deletion that reduces synthesis of alpha hemoglobin chains. Homozygous α-thalassemia leads to hydrops fetalis, which usually results in intrauterine or perinatal death. β-Thalassemia is caused by a point mutation rather than a deletion. In the absence of beta chains, the excess of alpha chains leads to instability in the RBC and hemolysis. The bone marrow becomes hyperplastic, which may lead to bone deformities and fractures in severe cases.
Management includes transfusion and iron chelation to minimize iron overload. Advances in transfusion and institution of regular chelation therapy with better-tolerated iron-chelating agents—as well as earlier recognition and treatment of iron-induced organ injury—have markedly improved survival rates. Allogeneic hematopoietic stem cell transplantation (HCT) is the only cure available for thalassemia. At present, there are no randomized trials comparing HCT with medical therapy, and refinements in treatment have improved both modalities. Prognostic factors associated with a good outcome for HCT are young age of patient, availability of an HLA-identical sibling donor without thalassemia, and matched sibling bone marrow—or umbilical cord blood–derived transplant stem cells. The prognosis for HCT is also correlated with the severity and duration of iron overload. Thus, the importance of iron chelation performed on a regular basis cannot be overemphasized. The likelihood of cure in optimal patients exceeds 90%, with a 4% risk of transplant-related mortality. Splenectomy is an option for some patients with hypersplenism and splenic complications such as splenic infarction or splenic vein thrombosis and may reduce the need for transfusions. The effect of splenectomy, however, may be transient, and its benefits must be weighed against the risk of infection after the procedure.
Jagannath VA, Fedorowicz Z, Al Hajeri A, Sharma A. Hematopoietic stem cell transplantation for people with β-thalassemia major. Cochrane Database Syst Rev. 2016;11:CD008708.
Sickle cell disease
Sickle cell disease (SCD), or sickle cell anemia, is an autosomal recessive disorder caused by an amino acid substitution on the beta chain, which produces an abnormal form of hemoglobin (hemoglobin S) that leads, in turn, to chronic hemolytic anemia. Hemoglobin S, which appears several months after birth, damages the RBC membrane, resulting in malformed sickle-shaped cells. Couples at risk of having a child with SCD can be tested for sickle cell trait, and genetic counseling should be made available to them. SCD is on the list for disorders that newborns are screened for at time of birth. One out of 400 black persons born in the United States, 1 out of 250 black persons born in the West Indies, and 1 out of 4000 born in France have SCD. Chronic hemolytic anemia can result in jaundice, gallstones, poorly healing ulcers over the lower tibia, and splenomegaly (which disappears after a few years because of repeated splenic infarction).
In addition to causing hemolytic anemia, SCD has systemic, multiorgan manifestations. It is characterized by acute, painful episodes caused by the sickling of the RBCs (vaso-occlusive crisis); these episodes can be precipitated by infection, dehydration, and/or hypoxia. Vascular occlusion can lead to necrosis of bone and to infection. Hematuria can be caused by infarction of the renal papillae. Sickle cell retinopathy can lead to vision loss in severe cases.
With improved supportive care, an affected person now has an average life expectancy into the 50s or 60s. Diagnosis is made with a screening test for sickle cell hemoglobin and confirmed by hemoglobin electrophoresis. SCD requires lifelong routine medical care, which includes regular updating of vaccinations; annual ophthalmologic examinations; and screening for hypertension, proteinuria, and pulmonary hypertension. Patients should be given folic acid supplements and, if infections arise, specific antibiotic treatment. Routine oxygen is no longer used in uncomplicated crises and without pulmonary symptoms. Hydroxyurea, the only disease-modifying drug in SCD, has resulted in decreased mortality. Crizanlizumab, a novel, investigational monoclonal antibody against P-selectin adhesion molecule, has been shown to reduce episodes of painful vaso-occlusive crisis. Clinical trials are currently under way.
Hematopoietic cell transplantation from an HLA-identical sibling is a potentially curative option in the treatment of sickle cell disease. When and for whom HCT should be pursued is controversial. Current data from the Center for International Blood and Bone Marrow Transplant Research and from European Blood and Marrow Transplant registries show an overall survival of 91% and 95%, respectively, after HCT, as well as improved quality of life. However, the possible consequences of HCT must also be considered, including the risk of mortality, debilitating chronic graft-vs-host disease, and infertility. If an HLA-matched sibling donor is available, HCT is recommended for individuals under 17 years of age with severe symptoms of sickle cell disease that are unresponsive to transfusions and hydroxyurea.
Excerpted from BCSC 2020-2021 series: Section 1 - Update on General Medicine. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.