production. a-thalassemia syndromes vary from complete absence (hydrops fetalis) to only slightly reduced (a-thalassemia silent carrier) a-globin production. In the a-thalassemia syndromes, an excess of B- and y-globin chains are produced. These excess chains form Bart hemoglobin (y, ) in fetal life and HbH (8, ) after birth. These abnormal tetramers are nonfunctional hemoglobins with very high oxygen affinity. They do not transport oxygen and result in extravascular hemolysis. A fetus with the most severe form of a-thalassemia (hydrops fetalis ) develops in utero anemia and the pregnancy usually results in fetal loss because HbF production requires sufficient amounts of a-globin, In contrast, infants with B-thalassemia major become symptomatic only after birth when HbA predominates and insufficient B-globin production manifests in clinical symptoms. Homozygous B-Thalassemia (Thalassemia Major, Cooley Anemia) Clinical Manifestations If not treated, children with homozygous f° -thalassemia usually become symptomatic from progressive anemia, with profound weakness and cardiac decompensation during the 2nd 6 mo of life. Depending on the mutation and degree of HbF production, regular transfusions are necessary beginning in the 2nd mo to 2nd yr of life, but rarely later. The decision to transfuse is multifactorial but is not determined solely by the degree of anemia. The presence of signs of ineffective erythropoiesis, such as growth failure, bone deformities secondary to marrow expansion, and hepatosplenomegaly, are important variables in determining transfusion initiation. The classic presentation of children with severe disease includes thalassemic facies (maxilla hyperplasia, flat nasal bridge, frontal bossing), pathologic bone fractures, marked hepatosplenomegaly, and cachexia and is primarily seen in countries without access to chronic transfusion therapy. Occasionally, patients with moderate anemia develop these features because of severe compensatory, ineffective erythropoiesis. In nontransfused patients with severe ineffective erythropoiesis, marked splenomegaly can develop with hypersplenism and abdominal symptoms. The features of ineffective erythropoiesis include expanded medullary spaces (withmassive expansion of the marrow of the face and skull), extramedullary hematopoiesis, and higher metabolic needs (Fig. 489.7 ). The chronic anemia and increased erythroid drive produce an increase in iron absorption from the gastrointestinal tract and secondary hemosiderosis-induced organ injury. FIG, 489.7 Ineffective erythropoiesis in 3 yr old patient who has B-thalassemia major and has not received a transfusion. A, Massive widening of the diploic spaces of the ‘skull as seen on MRI. B, Radiographic appearance of the trabeculae as seen on plain radiograph. C, Obliteration of the maxillary sinuses with hematopoietic issue as seen ‘on CT scan, Chronic transfusion therapy dramatically improves the quality of life and reduces the complications of severe thalassemia. Transfusion-induced hemosiderosis becomes the major clinical complication of transfusion-dependent thalassemia. Each mL of packed red cells contains approximately 1 mg of iron. Physiologically, there is no mechanism to eliminate excess body iron. Iron is initially deposited in the liver and is followed by deposition in the endocrine organs and the heart. This leads to a high rate of hypothyroidism, hypogonadotrophic gonadism, growth hormone deficiency, hypoparathyroidism, and diabetes mellitus. Iron deposition in the heart causes heart failure and arrhythmias, and heart disease is the leading cause of death in inadequately chelated patients. Eventually, most patients not receiving adequate iron chelation therapy die from cardiac failure or cardiac arrhythmias secondary to hemosiderosis. Hemosiderosis-induced morbidity can be prevented by adequate iron chelation therapy. Laboratory Findings In the United States, some children with B-thalassemia major will be identified on newborn screening as a result of the detection of only HbF on hemoglobin electrophoresis. However, infants with B* mutations might be missed on newborn screen if small amounts of hemoglobin A are present. A hemoglobin FE pattern can be consistent with hemoglobin E B° -thalassemia, or the more benign hemoglobin EE disease, and needs to be followed up. The lack of standardized neonatal diagnosis of thalassemia disorders requires close follow-up of newborns with unclear thalassemia mutations and babies from high-risk ethnic groups. Infants with serious B-thalassemia disorders have a progressive anemia after the newborn period. Microcytosis, hypochromia, and targeting characterize the RBCs. Nucleated RBCs, marked anisopoikilocytosis, and a relative reticulocytopenia are typically seen (see Fig. 489.5E ). The Hb level falls progressively often to <6 g/dL. unless transfusions are given. The reticulocyte count is commonly <8% and is inappropriately low compared to the degree of anemia caused by ineffective erythropoiesis. The unconjugated serum bilirubin level is usually elevated, but other chemistries may be initially normal. Even if the child does not receive transfusions, iron eventually accumulates with elevated serum ferritin and transferrin saturation. Evidence of bone marrow hyperplasia can be seen on radiographs (see Fig. 489.7 ). Early definitive diagnosis is recommended. Newborn screening techniques such as hemoglobin electrophoresis is not definitive. DNA diagnosis of the B- thalassemia mutations, along with testing for common genetic modifiers of theclinical phenotype, is recommended. Co-inheritance of 1 or more a-thalassemia deletions is common, and it decreases the severity of the B-thalassemia disease as it improves the a:B chain imbalance. Some patients’ mutations cannot be diagnosed by standard electrophoresis or common DNA probes. Referral of the samples to a tertiary laboratory is indicated, along with parental and family testing. Following the definitive diagnosis, families should undergo detailed counseling. Management and Treatment of Thalassemia Transfusion Therapy B-thalassemia major is a clinical diagnosis that requires the integration of laboratory findings and clinical features. Of patients with homozygous B° - thalassemia (the most severe mutations), 15-20% may have a clinical course that is phenotypically consistent with thalassemia intermedia. In contrast, 25% of patients with homozygous f* -thalassemia, typically a more benign genotype, may have transfusion-dependent thalassemia. Transient clinical events, such as a sudden fall in hemoglobin secondary to an episode of parvovirus requiring transfusion, do not necessarily indicate a transfusion-dependent patient. The long-term observation of the clinical characteristics, such as growth, bony changes, and hemoglobin, are necessary to determine chronic transfusion therapy. Guidelines for Transfusion Therapy. Patients who require transfusion therapy should have an extended red cell phenotype and/or genotype. Patients should receive RBCs depleted of leukocytes and matched for D, C, c, E, e, and Kell antigens at a minimum. Cytomegalovirus-safe units are indicated in stem cell transplantation candidates. Transfusions should generally be given at intervals of 3-4 wk, with the goal being to maintain a pretransfusion Hb level of 9.5-10.5 g/dL. Ongoing monitoring for transfusion-associated transmitted infections (hepatitis A, B, and C, HIV), alloimmunization, annual blood transfusion requirements, and transfusion reactions is essential. Iron Overload Monitoring Excessive iron stores from transfusion cause many of the complications of B-thalassemia major. Accurate assessment of excessive iron stores is essential to optimal therapy. Serial serum ferritin levels provide a useful screening technique in assessing iron balance trends, but results may not accurately predict quantitative iron stores. Undertreatment or overtreatment of presumed excessive iron stores can occur in managing a patient based on serum ferritin alone. Quantitative measurement of liver iron and cardiac iron by magnetic resonance imaging are standard noninvasive methods to measure tissue iron overload; estimation of pancreatic and gonadal iron is being studied. This technology, along with access to multiple chelators, enable targeted chelation therapy for patients with organ-specific hemosiderosis before the onset of overt organ failure. Integration of these imaging technologies with chelation therapy may prevent heart failure, diabetes, and other organ dysfunction. Quantitative liver iron by approved R2 or R2* MRI is the best indicator of total body iron stores and should be obtained in patients after chronic transfusion therapy has been initiated. The liver iron results will help guide the chelation regimen. Quantitative cardiac iron, determined by T2* MRI cardiac software, is usually obtained starting at 10 yr old, but should be obtained earlier in the setting of severe iron overload or if the transfusion and chelation history is not known. There may be a discrepancy between the liver iron and the heart iron because of different rates of tissue loading and unloading and the differential effects of iron chelators on organ-specific iron removal. Chelation Therapy Iron-chelation therapy should start as soon as the patient becomes significantly iron-overloaded. In general, this occurs after 1 yr of transfusion therapy and correlates with the serum ferritin >1,000 ng/mL and/or a liver iron concentration of >5,000 pg/g dry weight. Iron chelation is not currently labeled for use in children <2 yr. There are 3 available iron chelators (deferoxamine, deferasirox, and deferiprone); each varies in its route of administration, pharmacokinetics, adverse events, and efficacy. Combination chelation therapy may be required for high iron burden. The overall goal is to prevent hemosiderosis-induced tissue injury and avoid chelation toxicity. This requires close monitoring of the patients. In general, chelation toxicity increases as iron stores decrease. Deferoxamine (Desferal) is the most studied iron chelator; it has an excellent safety and efficacy profile. It requires subcutaneous or IV administration because of its poor oral bioavailability and short half-life of <30 min, necessitatingadministration as a continuous infusion over at least 8 hr daily, 5-7 days/wk. Deferoxamine is initially started at 25 mg/kg and can be increased to 60 mg/kg in heavily iron-overloaded patients. The major problem with deferoxamine is poor adherence because of the difficult, time-consuming route of administration. Adverse side effects include local skin reactions, ototoxicity, retinal changes, and bone dysplasia with truncal shortening. The oral iron chelator deferasirox (Exjade, JadeNu) is commercially available in the United States. Of patients treated with deferoxamine, 70% have switched to deferasirox because it is orally available. Deferasirox has a half-life of >16 hr and requires once-daily administration. Two forms of the drug are available, a dispersible tablet that is dissolved in water or juice and a film-coated tablet. A granule form that is sprinkled on soft food and ingested recently was FDA approved. Dosing is different for the different deferasirox formulations. For the dispersible tablet form (Exjade), the initial dose typically is 20 mg/kg/day and can be escalated to as high as 40 mg/kg/day based on the iron burden. The dosing for the film-coated tablet and granule (JadeNu) forms is 30% lower than the dispersible tablet, with a starting dose of 14 mg/kg/day, which can be escalated to a maximum of 28 mg/kg/day. The most common side effects are gastrointestinal (GI) symptoms, which may be lessened with the film-coated tablet form because it does not contain lactose and sodium laureate, which are found in the dispersible tablet and are thought to be responsible for some of the GI symptoms. The most serious side effect of deferasirox is potential kidney damage. Up to 30% of patients have transient increases in creatinine that may require temporary modifications of dosing. This toxicity may occur more commonly in the setting of dehydration. Long-term studies in thousands of patients have not demonstrated progressive renal dysfunction, but isolated cases of renal failure in patients have occurred. In addition, hepatic transaminitis may occur, with an increase to >5 times the upper limit of normal in approximately 8% of patients. All patients require monthly chemistry panels and ongoing monitoring for proteinuria. Deferiprone (Ferriprox), an oral iron chelator, is approved in the United States for use as a second-line agent. Deferiprone has a half-life of approximately 3 hr and requires dosing 3 times daily. The starting dose is 75 mg/kg/day and can be escalated to 99 mg/kg/day based on the degree of iron overload. Deferiprone, a small molecule, effectively enters cardiac tissue and may be more effective than other chelators in reducing cardiac hemosiderosis. The most serious side effect of deferiprone is transient agranulocytosis, whichoccurs in 1% of patients and usually in the Ist yr of treatment. It has been associated with rare deaths where patients were not adequately monitored. The use of deferiprone requires frequent blood count monitoring, typically weekly for at least the 1st yr of therapy. Most importantly, the drug should be held and the neutrophil count checked with all febrile illnesses. As thalassemia patients live longer, the iron chelation goals have changed. Aggressive treatment with combination chelation therapy is often used in heavily iron-overloaded patients to prevent or reverse organ dysfunction. Deferoxamine, in combination with deferiprone, is routinely used in patients with increased cardiac iron. Combination therapy of deferoxamine and deferasirox or deferasirox and deferiprone may also be efficacious in patients with severe iron overload. Hydroxyurea Hydroxyurea, a DNA antimetabolite, increases HbF production. It has been most successfully used in sickle cell disease and in some patients with B-thalassemia intermedia. Studies in B-thalassemia major are limited. In many parts of the world, hydroxyurea therapy is used in f-thalassemia intermedia patients. Even though increases in HbF levels are observed, they do not predictively correlate with increase in total Hb in these patients. In general, there appears to be a mean increase in Hb of 1 g/dL. (range: 0.1-2.5 g/dL). Hydroxyurea therapy in thalassemia intermedia is associated with a reduced risk of leg ulcers, pulmonary hypertension, and extramedullary hematopoiesis. The initial starting dose for thalassemia intermedia is 10 mg/kg and may be escalated to 20 mg/kg/day. Patients with B-thalassemia are at increased risk of developing cytopenias with hydroxyurea use, which may prevent dose escalation. Close monitoring of the CBC with differential is required. Hematopoietic Stem Cell Transplantation Hematopoietic stem cell transplantation has cured >3,000 patients who had B- thalassemia major. In low-risk HLA-matched sibling patients, there is at least a 90% survival and an 80% event-free survival. In general, myeloablative conditioning regimens have been used to prevent graft rejection and thalassemia recurrence, Most success has been in children <14 yr old without excessive iron stores and hepatomegaly who undergo sibling HLA-matched allogeneic transplantation. All children who have an HLA-matched sibling should beoffered the option of bone marrow transplantation. Alternative transplantation regimens for patients without appropriate donors are experimental and have variable success. Gene therapy approaches are under study, and early results with lentiviral vectors have been promising, particularly for patients with B* - or HbE B-thalassemia genotypes. Splenectomy Splenectomy may be required in thalassemia patients who develop hypersplenism. These patients have a falling steady-state Hb level and/or a rising transfusion requirement. However, splenectomy is less frequently used as a therapeutic option; serious adverse effects of splenectomy are increasingly recognized beyond infection risk. In thalassemia intermedia, splenectomized patients have a marked increased risk of venous thrombosis, pulmonary hypertension, leg ulcers, and silent cerebral infarction compared to nonsplenectomized patients. All patients should be fully immunized against encapsulated bacteria and receive appropriate instructions regarding fever management. Prophylactic penicillin should be administered after splenectomy to prevent sepsis, and families need to be educated on the risk of fever and sepsis. Preventive Monitoring of Thalassemia Patients Cardiac Disease Cardiac disease is the major cause of death in thalassemia. Serial echocardiograms should be monitored to evaluate cardiac function and pulmonary artery pressure. Pulmonary hypertension frequently occurs in non- transfusion dependent thalassemia patients and may be an indication for transfusion therapy. After approximately 8 yr of chronic transfusion therapy, cardiac hemosiderosis may occur; consequently, cardiac T2* MRI imaging studies are recommended. Patients with cardiac hemosiderosis and decreasing cardiac ejection fraction require intensive combination chelation therapy. Periodic electrocardiogram studies also are obtained after age 10 yr because of the risk of arrhythmia from cardiac iron overload. Endocrine Disease Endocrine function progressively declines with age secondary to hemosiderosis