Pediatric Thalassemia Follow-up

Updated: Aug 23, 2017
  • Author: Hassan M Yaish, MD; Chief Editor: Max J Coppes, MD, PhD, MBA  more...
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Further Outpatient Care

Blood transfusions are usually given at scheduled outpatient visits. Patients must be scheduled for regular laboratory studies to monitor iron deposition status and hepatic, cardiac, and renal functions. Patients receiving deferoxamine (DFO) require annual visits to assess for visual and hearing disturbances. Echocardiography and ECG are used to monitor cardiac function.


Further Inpatient Care

Uncomplicated cases of thalassemia major are usually managed in an outpatient setting. Inpatient care is usually reserved for infectious complications, surgical procedures, or for the rare patient treated with hematopoietic stem cell transplantation (HSCT).


Inpatient & Outpatient Medications

See Medication above.



Screening and prevention includes the following: [22]

  • In persons with β thalassemia trait, confirming the diagnosis is usually easy. In such situations, genetic counseling is necessary, and, if both parents are carriers, a detailed discussion with the couple should include all possible outcomes. These include the 1 in 4 chance of having a severely affected or completely healthy child and a 1 in 2 chance of having a child with heterozygous thalassemia.

  • For α thalassemia carriers, confirmation is not that simple. Hemoglobin (Hb) electrophoresis is usually not informative. For this reason, more sophisticated studies are warranted if confirmation is critical. Genetic counseling should be provided for patients with β thalassemia if a sibling or a family member is known to be affected.

  • Prenatal DNA testing has been available for several years. The decision to perform prenatal diagnosis in parents known to be at risk for having a child with thalassemia is complex and is usually influenced by several factors, such as religion, culture, education, and the number of children in the family. Genetic counseling by professionals that addresses the details of both the genetic risks and the testing risks involved is expected to help the parents make an informed and intelligent decision concerning the procedure. Unfortunately, such tests are not available in certain areas of the world where they are needed most. Extensive screening programs and prenatal diagnosis has resulted in a significant decline in the incidence of β thalassemia in some of the high-risk Mediterranean countries.

  • It is fortunate that several new methods for neonatal screening have recently evolved to replace the complex DNA sequencing, restriction enzyme polymerase chain reaction (RE-PCR), or the amplification refractory mutation system (ARMS). Such new methods include pyrosequencing, described as, "a more sensitive and rapid approach to fetal genotyping." It was used for 12 nondeletional common α- and β-globin gene mutations in the United Kingdom. This method was found to be 100% in concordance with the fetal diagnosis results obtained by ARMS-PCR or DNA sequencing. The test is a good choice for rapid and cost-effective prenatal diagnosis of thalassemia and sickle cell disease. [23]

  • In another study from Cyprus, a next-generation sequencing (NGS) of single-nucleotide polymorphism (SNPs) was introduced as a noninvasive prenatal diagnostic method. A modified version of NGS called "targeted sequencing" based on detection of paternally inherited fetal alleles in maternal plasma was used. Four SNPs located in the β-globin locus with a high degree of heterozygosity in the Cypriot population were selected as a target. The presence or absence of the paternal mutant allele was correctly determined in 27 of 34 samples analyzed, showing that NGS is effective in detecting paternally inherited alleles in the maternal plasma. [24]

  • Successful prevention programs in different parts of the world have resulted in an impressive decline in the number of patients with severe forms of thalassemia. Ferrara, Cyprus, Sardinia, Greece, and the United Kingdom were among the first to report a significant decline in the birth rate of children with thalassemia major. The Cypriot screening program continues to prove a great success, despite the false claim that it is a new form of eugenics. [25] Many other regions with more limited resources are following their steps with remarkable success.

  • In addition to the effective prenatal diagnosis adopted in the countries mentioned, other measures such as premarital screening programs, genetic counseling, and restrictions on issuing marriage certificates and licenses also proved to be effective. Because many of the countries where thalassemia prevails are poor and cannot afford sophisticated preventive programs, more practical approaches are clearly needed.

  • Screening of children, pregnant women, and individuals visiting public health facilities is effective in identifying individuals at risk who require further testing. A simple CBC count, with emphasis on the RBC counts and indices, including the mean corpuscular volume (MCV), mean corpuscular Hb (MCH), and RBC distribution width (RDW), is the main component of such screening processes. Persons suspected to be positive for thalassemia are checked for elevated levels of Hb A2, Hb F, or both for confirmation. In some situations, this simple method is not adequate, and further testing, including analyses of globin chain synthesis, must be performed to reach a final diagnosis.

Prenatal diagnosis includes the following:

  • Globin chain synthesis, which was once used in postnatal diagnosis, was also used on fetal cells obtained by fetoscopy to screen the fetus. This test reveals imbalanced production of certain globin chains that are diagnostic of thalassemia.

  • Since polymerase chain reaction (PCR) techniques have become available, several new methods are now in use to identify affected babies or carrier individuals accurately and quickly. The DNA material is obtained by chorionic villus sampling (CVS), and mutations that change restriction enzyme cutting sites can be identified.

  • Because many of the mutations that cause α and β thalassemia have become known in recent years, identifying such mutations on the amplified β-globin gene region is now possible with specific labeled oligonucleotide probes. Some of the new techniques can give accurate results in less than 3 hours.

  • Several publications have shown that prenatal diagnosis of thalassemia and hemoglobinopathies could be achieved by simple methods in routine setting. Capillary electrophoresis on fetal cells has proved to be reliable. [26] The same method has also been reported to have an advantage over other methods of Hb E evaluation because it could separate the peaks of Hb A2 from that of Hb E in patients with Hb E mutations. [27] In a study from Yi et al, PCR/ligase detection reaction (LDR) capillary electrophoresis assay for the detection of β thalassemia fetal mutation in maternal plasma was shown to be a noninvasive and highly sensitive procedure with good potential. [28]



Complications include the following:

  • Iron overload

    • Traditionally, ferritin level assessment has been the most commonly used test for indirect evaluation of body iron stores, even though it reflects only 1% of the total iron storage pool. The test is not perfect or accurate, as various conditions complicate the interpretation of its values. For this reason, reliance on serum ferritin assessment alone can lead to an inaccurate assessment of body iron stores in patients with iron overload who have been transfused heavily and who have levels in excess of the upper limit for the physiologic ferritin synthesis (400 mcg/L). At high levels, the test loses its clinical relevance since ferritin can be released from damaged cells in certain pathologic conditions.

    • Furthermore, certain drugs and clinical conditions such as ascorbate deficiency, fever, acute and chronic infections, and hemolysis may influence the ferritin level, producing misleading values. Despite its deficiencies, and for lack of a better practical, noninvasive test, ferritin assessment continues to be the most commonly used tool to diagnose and to monitor iron overload.

    • MRI or CT scanning is used to assess liver iron levels as a measure of total body iron load.

    • Liver biopsy may be performed to assess liver iron concentration, which is considered the most sensitive method to assess body iron burden. Again, this procedure is an invasive one and not without complications. Furthermore, because iron distribution in the thalassemic liver is uneven and could be affected by fibrosis, one can expect conflicting and inaccurate results in some patients. Grading of stainable iron or measuring parenchymal iron by atomic absorption spectroscopy has been helpful in measuring tissue iron levels, with good correlation to calculated body iron burden.

  • Cardiac complications

    • Most deaths in patients with thalassemia are due to cardiac involvement.

    • These complications range from constrictive pericarditis to heart failure and arrhythmias.

    • Transfusional hemosiderosis has been classified into 3 stages based on the number of blood units given. The higher the number of packed red blood cell (PRBC) units given, the more advanced the stage. Advanced stage is associated with more severe clinical symptoms and more abnormal findings on cardiac function studies.

    • Cardiac hemosiderosis does not occur without significant accumulation of iron in other tissues.

    • Chelation therapy has shown promising results in patients with cardiac symptoms due to iron overload.

    • Ventricular myocardium is the first site of cardiac iron deposition, while the conduction system is usually the last to be affected. The value of endomyocardial biopsy, which has been used to evaluate iron deposits in the heart, has been questioned. Iron has been reported as absent from the right ventricular subendocardium in some patients with cardiac iron overload.

    • Echocardiography, radionuclide cineangiography, and 24-hour ECG are to be used to monitor these patients.

  • Hepatic complications

    • Patients who have received regular blood transfusions for some time develop liver enlargement due to swelling of the phagocytic and parenchymal cells from the deposition of hemosiderin.

    • Liver enzyme levels are not typically elevated unless hemosiderin deposition is associated with hepatitis.

    • Chelation therapy may prevent or delay progressive liver disease, which may end in cirrhosis.

    • A report on chelation use and iron burden in North American and British thalassemia patients has shown that advances in organ-specific imaging and the availability of oral deferasirox have improved clinical care and outcome in this patient population. [29]

    • In this study, [29] 327 patients with transfusion-dependent thalassemia with age at entry (mean 22.1± 2.5 y) were followed from 2002-2011, with a mean follow up of 8 years (range 4.4-9 y). Deferasirox was the main agent used, followed by deferoxamine, and to a lesser degree, combination therapy. The use of both hepatic and cardiac MRI increased by 5-fold (P< .001) during the study period, leading to an 80% increase in the number of subjects undergoing liver iron concentration (LIC) measurements.

    • The overall results of the measurements show improvement from (median 10.7-5.1 mg/g/dry weight, but nonsignificant improvement in cardiac T2* (median 23.55-34.50 ms). The percentage of patients with markers of inadequate chelation were ferritin less than 2500 ng/mL, LIC greater than 15 mg/g/dry weight, and T2* shorter than 10 ms and also declined from 33% to 26%. [29]

    • A study by Vichinsky et al indicated that deferasirox therapy can be safe and effective long-term in young children treated for hemosiderosis. The report involved pediatric patients aged 2 years to less than 6 years, many of whom had β thalassemia, with the investigators finding that the median serum ferritin level dropped from 1702 ng/mL at baseline to 1127 ng/mL in those patients who completed 5 years of treatment. [30]

  • Long-term therapy complications

    • Because of improved medical care, patients with thalassemia are surviving their disease longer and reaching old age. With this longer survival comes new issues related to complications that need to be addressed.

    • Hepatitis C virus (HCV) has emerged as the paramount risk in patients who have been receiving blood transfusions all their lives. HCV screening was initiated in 1990. Since then, according to the Registry of the TCRN, the incidence rate of HCV has dropped significantly. The current prevalence of HCV in patients with thalassemia older than 25 years is 70%, as opposed to only 5% in those with thalassemia aged 15 years or younger.

    • Unfortunately, a high incidence rate of HCV continues in developing countries, leading to an increased incidence of fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), especially in the presence of a second risk factor such as iron overload. For this reason, many centers advocate screening patients with HCV every 6 months by obtaining a fetoprotein (AFP) and an ultrasound of the liver. According to the TCRN, approximately 33% of patients with thalassemia major who are also HCV positive develop a spontaneous clearance of the HCV.

    • Two-thirds of patients with β thalassemia major have multiple calcified bilirubin stones by age 15 years.

  • Hematologic complications

    • Thrombosis was encountered in relatively significant numbers of patients with thalassemia. In a study of 83 patients with thalassemia intermedia, a 26% incidence rate of venous thromboembolic events (VTEs) was encountered, whereas only 2% of 65 patients with thalassemia major developed VTE.

    • One study determined that most of the patients with thalassemia intermedia who developed VTE had been splenectomized. Based on this fact, several centers recommend some type of prophylactic therapy to prevent thrombosis in such patients. Short-term antithrombotic therapy, both perioperatively and in the presence of thrombotic risk factors, is recommended. Patients who have undergone splenectomy and have a platelet count in excess of 600,000/µL receive low-dose daily aspirin

    • Pulmonary hypertension as a result of small pulmonary thrombi represents a significant indication of the increased risk for clotting in such patients. This complication is emerging as major cause of morbidity and mortality in patients with chronic hemolytic anemia. The incidence in such population was estimated at 10%. [31]

    • According to one study, endothelial dysfunction due to lack of bioavailability of NO is one of the main reasons for developing such complications. [32] Free plasma Hb resulting from hemolysis directly consumes NO, and the presence of arginase in the hemolysate depletes arginine, which is the substrate for NO synthetase, thus preventing generation of such product. The presence of excessive oxygen radicals in patients with chronic hemolytic anemia who are on regular packed RBC (PRBC) transfusions adds to the problem by causing rapid consumption of NO. Studies have showed that treatment with hydroxyurea may improve or prevent this complication. [19, 33]

    • Silent cerebral infarction (SCI) was diagnosed by MRI in 24% of patients with β-thalassemia/Hb E disease in a study conducted in Thailand. [34] A Cambodian child who also has β-thalassemia/Hb E disease has also been described. [35]

    • Increasing reports addressing the issue of thrombotic tendency in patients with thalassemia have revealed that such tendency is indeed seen in all types of chronic hemolytic anemia and is not limited to thalassemia intermedia as suggested earlier. Numerous factors for the thrombotic complications in this patient population were reported by many authors. A study conducted on patients with thalassemia has shown that the patients' platelets, as well as their RBCs when mixed individually with normal RBCs or normal platelets, have resulted in increased platelets adhesions; this was not noticed when control cells were used in both instances. [36] This finding may suggest that both platelets and RBCs in thalassemia could induce increased platelets adhesion which may predispose to thrombotic events.

    • Based on these reports and several others which confirm the presence of hypercoagulable state in patients with chronic hemolysis such as thalassemia and sickle cell disease, one should seriously reconsider the role of splenectomy in such conditions to avoid further risk for thrombotic events in this population of patients. [37]

  • Endocrine complications

    • People with thalassemia major frequently exhibit features of diabetes mellitus; 50% or more exhibit clinical or subclinical diabetes. This is believed to be due to defective pancreatic production of insulin, but insulin resistance also has been implicated.

    • Glucose intolerance encountered in these patients usually correlates with the numbers of transfusions received and the patient's age and genetic background.

    • A study compared the incidence of endocrinopathy in patients with thalassemia with the incidence in patients with sickle cell disease and a similar iron overload due to transfusion. [38] The study also compared patients with sickle cell disease who received transfusion with those who did not receive transfusion. The study showed that patients with thalassemia are far more prone to develop various endocrinopathies than patients with sickle cell disease. Furthermore, the incidence did not differ between patients with sickle cell disease who received transfusion and those who did not. However, the duration of transfusion was found to be a significant predictor. Thus, the underlying disease may modulate iron-related endocrine injury.

    • Osteoporosis is a severe complication of thalassemia and is thought to be related to a Wnt signaling inhibitor produced by the osteocytes, termed sclerostin, which inhibits osteoblast function. A study to evaluated circulating sclerostin in patients with thalassemia and osteoporosis who were also part of phase 2 randomized study for the effect of zoledronic acid versus placebo. Results were compared with those of healthy controls without osteoporosis and a group of women with postmenopausal osteoporosis (all patients were mostly adults). At baseline, thalassemia patients with osteoporosis had elevated circulating levels of sclerostin compared with healthy controls without osteoporosis and reduced levels of sclerostin compared with postmenopausal women with osteoporosis. Circulating sclerostin levels correlated with bone mineral density in lumbar spine, distal radius, and femoral neck. Zoledronic acid did not alter the sclerostin level after 12 months of therapy. [39]

    • In a recent publication, 26 adult women with thalassemia major were evaluated for iron-induced compromised fertility. The low gonadotropin secretion known to occur in this population to cause reduced ovarian antral follicle counts and ovarian volume was confirmed. A new player related to compromised fertility in this population was identified, however. Anti-müllerian hormone (AMH), a sensitive marker for ovarian reserve, independent of gonadotropin effect, was found to be mostly in the normal range. AMH was found to closely correlate with nontransferrin-bound iron (NTBI), indicating a role of labile iron in the pathogenesis of decreased reproductive capacity, possibly occurring in line to cardiac iron overload, which usually presents with amenorrhea and increased NTBI levels. As a result, one may conclude that AMH is an important biomarker for assessment of reproductivity in thalassemia major women, showing that fertility is preserved in the majority of women younger than 30-35 years. AMH, as wellas NTBI, are both potential markers for future studies and close monitoring to preserve fertility in this population of patients. [40]

    • Growth retardation is frequently severe in patients with thalassemia (30%). This retardation is caused, in part, by the diversion of caloric resources for erythropoiesis, as well as by the chronic anemia because hypertransfusion usually restores normal growth. Unless chelation therapy is initiated early in life, patients rarely grow normally. Excessive chelation with DFO may also cause growth retardation

    • Some clinicians recommend growth hormone testing in all children with thalassemia who are short so that those with growth hormone deficiency (GHD) can receive recombinant human growth hormone treatment. This treatment proved in this study to be effective in increasing the growth rate in all patients with thalassemia, particularly the ones with GHD. [21] The efficacy of growth hormone therapy in this population of patients was questioned in a study from Italy; the study concluded that long-term treatment with recombinant growth hormone (rGH) does not improve final height. [41]

    • The direct cause of growth retardation in these patients is thought to be an impaired growth hormone production or deficiency in production of somatomedin by the hemosiderotic liver. This has been questioned by a report that suggested GHD does not correlate with the efficacy of transfusional or chelation therapy. [42] Other factors are thought to be involved

    • Involvement of the adrenal glands or the thyroid gland may also contribute to growth failure.

  • Fertility and pregnancy complications

    • The survival of patients with thalassemia major has improved significantly. Since the introduction of effective transfusion and chelation regimens. Patients are now reaching their adulthood, and the questions regarding fertility becomes relevant. Adult patients with thalassemia major have low fertility; this was thought to be related to endocrine toxicity as a consequence to iron overload.

    • One study reported 12 patients with thalassemia major with a mean age of 24.8 years and a long history of transfusion and chelation with deferoxamine who underwent fertility evaluation tests, including semen parameters, endocrine functions, and serum zinc level. [43]

      • Fifty percent of the patients were found to have normal sperm counts, motility, and morphology; the other 6 patients had oligospermia (< 20 x 106/mL) and asthenospermia (motility < 40%).

      • Basal serum gonadotrophins (luteinizing hormone, follicle-stimulating hormone), total and free testosterone, and serum zinc levels did not differ from those found in healthy matched controls.

      • Patients with abnormal semen parameters were noticed to have low ferritin level, whereas those with high ferritin had normal sperms parameters.

      • This is an interesting observation that is not fully understood; however, it raises the question whether the abnormal sperm parameters are related to a negative effect of intensive chelation therapy.

    • Females are frequently oligomenorrheic or amenorrheic. Pregnancy complications are also seen frequently and are likely due to endocrinologic and cardiac complications. Case reports demonstrated, however, that successful pregnancy and delivery of healthy babies is possible in women with thalassemia major. Gonadal dysfunction that results in arrested or delayed puberty is reported in females with thalassemia major receiving transfusion and chelation therapy. [44] A small uterus was noted in all women with delayed or arrested puberty. The size may improve with hormonal replacement therapy (HRT).

    • Adequate transfusion to keep Hb at normal or near normal level at all times, effective chelation and early intervention with hormonal therapy may prevent permanent damage and help to preserve fertility.

  • Transfusion complications: The most common complications of blood transfusions are discussed in Treatment.

  • Chelation therapy complications: These complications and the specific adverse effects of DFO are discussed in Treatment.

  • Viral hepatitis: Viral hepatitis has been reported in nontransfused patients with iron overload, suggesting that iron overload predisposes patients to viral hepatitis, as was stated above.



The prognosis depends on the type and severity of thalassemia. As stated above, the clinical course of thalassemia varies greatly from mild or even asymptomatic to severe and life threatening.


Patient Education

Patients and their parents and caregivers should be made aware of the nature of their disease, the fact that it is inherited, and the need to comply with the treatments as scheduled to avoid serious complications. They should be informed that the treatment does not prevent serious complications from developing and to be aware of what to expect.

Several publications are available for patients and primary care physicians. Many support services are available, such as those offered by the Cooley Anemia Foundation, Inc., and other groups. Contact 718-321-CURE or email

Many of the measures used in prevention are based on educating the population and providing resources for advice and guidance. Because of the large numbers of Asian immigrants to the western United States and the high rate of thalassemia carriers among such populations, several effective programs have been initiated, especially in the state of California. Cord blood screening now includes a screen for Hb H disease in addition to the other thalassemias and hemoglobinopathies. Extensive efforts by public health and other organizations are underway to gain the trust of new immigrants and to educate them regarding the seriousness of the problem. All such measures are a first step toward more advanced educational programs for screening in order to decrease the birth rate of affected children.