eMedicine Specialties > Pediatrics: General Medicine > Hematology

Thalassemia Intermedia

Hassan M Yaish, MD, Professor of Pediatrics, University of Utah School of Medicine; Director of Hematology Services, Medical Director, Mountain States Hemophilia and Thrombophilia Treatment Center; Pediatric Hematologist/Oncologist, Department of Pediatrics, Primary Children's Medical Center

Updated: Sep 29, 2009

Introduction

Background

Thalassemia intermedia is a term used to define a group of patients with β thalassemia in whom the clinical severity of the disease is somewhere between the mild symptoms of the β thalassemia trait and the severe manifestations of β thalassemia major. The diagnosis is a clinical one that is based on the patient maintaining a satisfactory hemoglobin (Hb) level of at least 6-7 g/dL at the time of diagnosis without the need for regular blood transfusions.

This initial definition of thalassemia intermedia, which was based on clinical observation alone, retained its validity even after some of the specific mutations associated with thalassemia intermedia were recognized because severity of the clinical course remains unpredictable even in known genotypes. For this reason, some patients with a β thalassemia intermedia genotype are treated as if they have thalassemia major because they present with severe manifestations; similarly, others with a thalassemia intermedia genotype are considered to have thalassemia minor because of the mild or even asymptomatic nature of their condition. This variability is most likely related to the presence or absence of modifying genes. It has been surprisingly seen among siblings with the same genotype.

Because of the significant overlap in clinical severity among the 3 types of β thalassemia and despite the fact that several genotypes are associated with the β thalassemia intermedia picture, the diagnosis continues to be a clinical one, regardless of the genotype involved. Moreover, in an individual patient, the diagnosis may change from thalassemia intermedia to thalassemia major once the patient begins to have more severe symptoms and to require regular blood transfusions.

Peripheral blood film in thalassemia intermedia.

Pathophysiology

Because, in general, all symptoms and manifestations of thalassemia are caused by an imbalance in globin chain synthesis, the milder symptoms of thalassemia intermedia in any one patient may be attributable to the following:

• The particular inherited globin chain mutations (ie, milder homozygous or combined heterozygous mutations affecting the β globin promoter) may produce these milder symptoms.
• Co-inheritance of a genetic determinant that decreases the imbalance between α and β chain production (eg, α thalassemia trait) can occur. A Chinese newborn with β thalassemia major co-inherited Hb H disease and, as a result, had a β thalassemia intermedia phenotype.¹
• γ chain production may be increased, resulting in an elevated level of Hb F, as in the case of β/δ deletion mutations that, when associated with a β thalassemia gene mutation, produce a combined heterozygous condition that can result in thalassemia intermedia. For example, a family was reported with homozygosity for a rare β (0) thalassemia; the children developed thalassemia intermedia phenotype and not the expected severe form of thalassemia major. When the mutations were studied, they were linked to the (G) γ -globin (xmnI) and (A) γ -globin promotor, resulting in production of Hb F.²
• Most patients with Hb E/β thalassemia (interaction of Hb E and β thalassemia) exhibit the clinical course of thalassemia intermedia. The incidence of this condition is increasing in the United States because of the large population of new immigrants to the United States from Southeast Asia.
• In contrast, some of the complex genetic interactions may instead result in a more severe phenotype than expected.³

The symptoms of thalassemia intermedia reflect ineffective erythropoiesis, which leads to anemia, medullary expansion, and extramedullary hematopoiesis. Iron overload is a potential complication of thalassemia, even in patients who do not require RBC transfusions. It results from excessive absorption of dietary iron, mediated by the downregulation of hepcidin, which is a hepatic hormone that acts as a major regulator of systemic iron homeostasis. Hepcidin inhibits iron absorption from the diet and inhibits the recycling of iron by the macrophages. It is increased by iron loading and is inhibited by erythropoietic activity.

In patients with thalassemia intermedia who are receiving regular blood transfusions, the erythropoietic activity is exaggerated. This usually results in inhibition of hepcidin, which causes increased absorption of iron from the diet and depletion of iron macrophages. Iron overload is supposed to increase the hepcidin level, thus, suppressing the absorption of iron. However, this does not occur in patients with thalassemia because, in β thalassemia, a serum factor produced by the bone marrow, known as growth differentiation factor 15 (GDF 15), may override the potential effect of iron overload on the expression of the hepcidin gene (HAMP), thus removing the protection of hepcidin against iron absorption. This provides an explanation for the failure to arrest the excessive iron absorption in such patients.⁴

In contrast, hepcidin levels are usually elevated in patients with thalassemia major who are receiving regular blood transfusions because of reduced erythropoietic activities and increased iron overload. As a result of hepcidin's effect on iron recycling by macrophages, ferritin levels are usually high in patients with β thalassemia major receiving blood transfusions compared with those with thalassemia intermedia who are not receiving transfusions despite similar liver iron concentrations in both conditions.⁵

Hepcidin measurements could possibly be used in the future as diagnostic tool for iron overload in patients with thalassemia, and hepcidin may even be used as a therapeutic agent for some iron overload conditions.⁶

Frequency

United States

Because of the recent immigration waves from Eastern Europe and Southeast Asia, more patients with thalassemia are expected to be encountered in the United States.

International

This condition appears to be much more common in the Mediterranean basin, northern Africa, the Indian subcontinent, and Eastern Europe than in other areas of the world. One reason for the higher incidence of thalassemia intermedia in developing countries is that medical resources for aggressive management of symptomatic thalassemia are unavailable. Most affected individuals in these regions remain untreated.

Many likely die from complications of the disease; other individuals, who have milder courses and, by definition, are considered to have thalassemia intermedia because they are able to maintain an Hb level of more than 6-7 g/dL, survive with chronic disease. If these individuals lived in a developed country, they would be diagnosed with thalassemia major and would be treated. For this reason, similar to the situation in the United States, no accurate figures for the worldwide incidence of β thalassemia intermedia are currently available.

Mortality/Morbidity

Morbidity is fairly common in thalassemia intermedia because many patients are not transfused regularly despite their marginal Hb level. The obligatory increase in erythropoiesis results in bone deformities, osteoporosis, fractures, growth retardation, tumorlike masses with possible spinal cord compression, neurologic complications, as well as thrombotic events. Additional morbidity comes from iron overload, which eventually occurs even in patients who do not receive blood transfusions. The ferritin level is usually lower in thalassemia intermedia compared with the level encountered in thalassemia major, despite the similar iron overload degree.

Mortality rates are usually high in developing countries because of complications such as organ failure, severe anemia and its sequelae, infections, and (unchelated) iron overload. Heart disease is the leading cause of mortality associated with this condition. It results from the high output state caused by chronic tissue hypoxia as well as the vascular involvement that leads to pulmonary vascular resistance.

In recent years, several publications have addressed the issue of hypercoagulability and pulmonary hypertension in patients with thalassemia intermedia, especially those who underwent splenectomy.⁷ This trend is continuing, with a large number of reports describing several clinical presentations, all of which point to an underlying thrombotic event as a cause of the clinical complications.

Pulmonary emboli,⁸ cerebrovascular accidents,⁹ pulmonary hypertension,¹⁰ Moyamoya disease,¹¹ and silent cerebral infarction¹² are among such reports. The etiology of the hypercoagulability state is multifactorial,¹³ involving endothelial dysfunction, lack of bioavailability of nitrous oxide (NO),⁸ increased platelet aggregation, and RBCs membrane phospholipid contribution.¹⁴ However, the major role of splenectomy in thalassemia intermedia should not be underestimated. The hypercoagulability state that is somewhat striking in thalassemia intermedia is not limited to this condition; it is also reported in sickle cell disease.¹⁵

A multicenter study to assess the incidence of thrombotic events in patients with thalassemia found that 4% of patients with thalassemia intermedia develop thrombotic events compared with only 0.9% with thalassemia major.¹⁶

Race

As with all thalassemia syndromes, the condition is encountered in people of all races. However, thalassemia intermedia is more common among certain racial groups in the United States, such as persons of Mediterranean, Asian, or African descent.

Sex

Thalassemia intermedia occurs with equal frequency in males and females. Menstruating females are, on average, somewhat more anemic and marginally less likely to develop iron overload.

Age

Unlike thalassemia major, which usually becomes evident during the first year of life, the onset of thalassemia intermedia is typically somewhat later because of its milder clinical picture. In some cases, the diagnosis is made by chance when a hematologic abnormality is found incidentally.

Clinical

History

The history in thalassemia intermedia usually depends on the patient's age at diagnosis and the severity of the condition at onset.

• Patients with mild cases show no significant symptoms and may go undiagnosed.
• In moderately severe cases, patients or their family members may observe slight pallor, slight yellowish discoloration of the sclerae, or enlarged abdomen. Low hemoglobin (Hb) levels or an enlarged spleen upon routine physical examination may represent the first indication of the disease.
• In more severe forms, the patient may seek medical advice because of malaise, pallor, easy fatigability, or bone deformities or fractures.
• In extremely rare circumstances, a patient with anemia and an enlarged abdomen may develop a serious unexpected symptom, such as paralysis.
  • This usually reflects transverse myelopathy that results from compression of the spinal cord by a tumorlike mass of extramedullary hematopoietic tissue.
  • In such patients, detailed workup reveals the correct diagnosis.
• The patient might seek medical advice because of a family history of thalassemia or the knowledge that both parents are carriers of a thalassemic condition.

Physical

The physical examination findings vary according to severity and stage of the disease.

• Pallor is almost always present to some degree.
• Abnormal facies with prominent facial bones and dental malocclusions are observed in patients with severe disease who are untreated. Growth retardation, failure to thrive, fractures, and bone deformities are also commonly found in this group of patients.
• An enlarged spleen is a common finding.
• Younger patients who are seen early may show only minimal findings upon examination, such as pallor or splenomegaly.

Causes

• The condition is inherited and may result from a wide variety of genotypes. Certain homozygous β thalassemia alleles, such as β+ thalassemia in some African Americans or homozygous β0 alleles (δ-β/δ-β) in some patients of Arabic descent, have produced thalassemia intermedia.
• Several forms of combined heterozygous thalassemia can also result in a clinical course consistent with thalassemia intermedia. Two examples are β0/(δ-β)0 thalassemia, described in Greeks, Italians, and Asians, and the β+/(δ-β)0 variant, which is clinically similar to the first condition but can be differentiated by the presence of some Hb A.
• Heterozygosity for Hb Lepore, a thalassemic hemoglobinopathy, when associated with either β+ or β0 thalassemia can also produce thalassemia intermedia. As previously noted, the interaction of β thalassemia with Hb E disease produces thalassemia intermedia in many patients.
• More than 150 different mutations in the β thalassemia genes are currently known. For more detailed information, see Thalassemia.

Differential Diagnoses

Acrodermatitis Enteropathica

Other Problems to Be Considered

Acute leukemias
Hemolytic anemias (autoimmune, metabolic)
Hemophagocytosis
Hypersplenism
Iron-deficiency anemia
Beta thalassemia major
Thalassemia traits
Thrombocytopenia, associated with splenomegaly in various clinical entities
Anemia, hypochromic and microcytic

Workup

Laboratory Studies

• Severe forms of thalassemia intermedia must be differentiated from β thalassemia major; this is mainly a clinical differentiation based on close monitoring to determine whether the patient's Hb level can be maintained at 6-7 g/dL without blood transfusions. The severe anemia, if associated with thrombocytopenia, hypersplenism, and the immature leukocytes often observed on peripheral blood films, raises the question of acute leukemia or metastatic lymphoma. Milder cases, on the other hand, must be differentiated from thalassemia trait or even anemias related to iron deficiency or chronic inflammation. Unlike the intermedia forms, β thalassemia trait rarely produces an Hb level less than 9 g/dL. Iron deficiency anemia is characterized by a normal Hb electrophoresis pattern and abnormal iron study results.
• The following tests are usually adequate to suggest a diagnosis of thalassemia major or intermedia:
  • CBC count and differential reveal anemia with marked hypochromasia and microcytosis. An Hb level below 7-8 g/dL indicates a severe case; whether the thalassemia is major or intermedia can be determined only after adequate monitoring.
  • Hb electrophoresis shows an abnormal pattern. An elevated Hb A₂ fraction of as much as 7% indicates β thalassemia, typically β thalassemia trait or certain forms of thalassemia intermedia. However, absence of Hb A₂ does not exclude the diagnosis of β thalassemia; in fact, an Hb A₂ of 0% frequently arises from a homozygous deletion of both the β and the δ chain genes because δ chains are needed to produce Hb A₂. In the intermedia type overall, Hb F ranges from 20-100%, Hb A from 0-80%, and A₂ up to 7% of total.
  • Peripheral blood film examination usually reveals marked hypochromasia and microcytosis, polychromasia, target cells, and significant variation in the size of the RBCs (see Media file 1).
    
    

    

    Peripheral blood film in thalassemia intermedia.

    
    
• Iron studies should be performed, either as baseline in anticipation of iron overload in the future or for diagnosis and management of this condition when suspected.
  • Ferritin level is an adequate tool for screening but is not the perfect test for a precise evaluation of the progress of iron overload and the development of tissue damage as a complication. It is a noninvasive test that is easy to obtain and is of value in the early stages of iron overload process; however, it becomes inaccurate when iron accumulates heavily, it lacks sensitivity and specificity, and it correlates poorly with hepatic iron concentration. It is also known to be a positive plasma reactant, which rises in association with inflammation.
  • Serum transferrin saturation may provide some information about the patient's iron status; however, it lacks sensitivity. Twenty-four–hour deferoxamine-induced urinary iron excretion is a beneficial test in deciding when chelation therapy should be started (presence of adequate iron available for chelation); it is not a practical test to evaluate iron overload, however. Urine aliquots are not usually collected correctly, the ratio of stool-to-urine iron varies, and furthermore, correlates poorly with hepatic iron deposits. 
  • Either bone marrow grading of iron stores or monitoring the numbers of nucleated red blood cells in the peripheral blood may reflect the stage of iron overload. Patients with thalassemia intermedia tend to develop iron overload somewhat later than those with thalassemia major regardless of whether they are on a transfusion schedule.
  • Once the patient is started on blood transfusions, the onset of iron overload should be expected earlier than in patients who are not receiving transfusion, and closer follow-up is required.
• Tests to identify endocrine disturbances such as diabetes mellitus or thyroid, adrenal, or other gland dysfunction are also required.
• Liver function tests are needed at diagnosis and during follow-up, especially in patients who are receiving blood transfusions. 

Imaging Studies

• Chest radiography should be obtained to evaluate the size of the heart.
• A skeletal survey should be conducted to evaluate the status of the bones and to monitor bone changes that are due to the chronic hyperactivity of the marrow.
• CT scanning or even MRI of the liver to evaluate iron deposition has been helpful in monitoring patients on transfusion regimens and chelation therapy. Variable correlation results were reported for both. However, R2*-MRI appears to be very informative, with strong correlation with hepatic iron content (HIC) and weak but significant association with ferritin level. It is an excellent noninvasive method to assess iron overload and response to chelation therapy.¹⁷ Cardiac magnetic resonance (CMR) is used to measure cardiac T2 in patients with thalassemia. Unlike liver MRI, which correlates well with iron concentration in the liver measured by liver biopsy and with serum ferritin level, CMR does not correlate well with ferritin, liver iron level, or even echocardiographic imaging results. This suggests that surrogate measurement of cardiac iron is misleading.¹⁸
• Echocardiography should be performed to evaluate the function of the heart.

Other Tests

• With iron overload, ECG is necessary to monitor for cardiac conduction defects (eg, atrioventricular block).
• Genetic counseling and DNA studies using DNA probes from known thalassemia intermedia genotypes are very useful in prenatal diagnosis and identification of new cases in selected patients at risk.
• Study of the genotype yields no advantage and is not warranted to differentiate between thalassemia major and intermedia when, for example, a previously stable Hb level in a patient assumed to have thalassemia intermedia suddenly drops and the patient becomes transfusion dependent.
• Genotype testing is beneficial when deciding whether to terminate a pregnancy when the fetus is affected. A thalassemia intermedia genotype probably indicates a milder disease, and parents may decide to continue the pregnancy.

Procedures

• Examination of liver tissues obtained by ultrasonographically guided biopsy is an optimal way to evaluate body iron burden and the status of the liver itself (eg, fibrosis, inflammation). Cardiac biopsy is not sensitive because the distribution of iron in the heart is not homogeneous. A noninvasive method that correlates precisely with biopsy-determined hepatic iron levels is the susceptometry superconducting quantum interference device (SQUID).
• Once chelation therapy is deemed necessary, evaluation of liver tissue damage from iron deposition is required. Some have suggested that liver histologic studies for iron status be obtained every 2 years.

Histologic Findings

• Erythroid hyperplasia is the major finding in the bone marrow. In addition, excessive iron deposition is observed in later stages in both marrow and liver. Osteopenia and osteoporosis are also observed in untreated individuals with relatively low Hb levels.
• Quantitative assessment of liver iron deposition can be used as a guideline for starting chelation; an iron concentration of 1.5 mg/g of liver (dry weight) has been suggested as an appropriate threshold.

Treatment

Medical Care

The treatment of most cases of thalassemia intermedia involves close monitoring and observation.

• Patients with satisfactory hemoglobin (Hb) levels are frequently monitored.
• These patients usually require blood transfusions only on certain occasions such as the presence of intercurrent infections, hypersplenism, or other illnesses.
• If patients can no longer maintain an Hb level of more than 6 g/dL, they are either started on a regimen of regular blood transfusions or a different option, such as splenectomy, should be tried. Patients with evidence of hypersplenism have a good chance to have their need for blood transfusion reduced or totally eliminated; this might last for months or years. Others may try to administer one of the drugs that may induce stress erythropoiesis and raise Hb levels. Hydroxyurea has been frequently used for this purpose. In separate studies on a large number of patients, a response rate exceeding 75% was reported after long-term therapy.¹⁹ However, this high rate of response was not confirmed by other studies until a study on a small number of patients with β thalassemia major and intermedia treated with hydroxyurea demonstrated a response rate of more than 82%.²⁰
  • The initial regimen includes transfusion of 10-15 mL of packed red blood cells (PRBC) every 4-5 weeks to keep the Hb level over 10 g/dL.
  • Blood transfusions should be leukocyte poor to avoid sensitization because such patients have the potential of becoming transfusion dependent in the future.
  • Patients should be checked and typed for minor blood groups to avoid further difficulties in providing appropriate blood for them in the future.
  • Identification of a small group of dedicated donors minimizes the risk of viral exposure and alloimmunization.
• Iron status must be carefully monitored, and patients with iron overload should be treated with an aggressive chelation regimen as soon as indicated.
  • A popular chelation regimen includes administration of deferoxamine 5 days per week as a subcutaneous infusion over 8-12 hours. This regimen revolutionized the treatment of β thalassemia major in patients regularly receiving PRBC transfusions and resulted in longer survival and near-normal quality of life. An oral iron chelator, deferasirox (Exjade), has been in use in the United States for some time now. This agent has a long half-life and, for this reason, is orally administered once daily. Several studies have confirmed the long-term efficacy and safety of this agent. It is now much more popular and, due to the ease and convenience of administration and better compliance, is probably replacing deferoxamine.²¹
  • A similar dose is often administered at the time of blood transfusions to help bind the transfused iron (from hemolyzed RBCs).
• Nutritional deficiencies should be addressed and treated.
  • A folic acid supplement should be administered.
  • Vitamin C supplementation has been effective in enhancing the efficiency of chelating iron from tissues.
• Patients who have undergone a splenectomy should be placed on prophylactic antibiotics and be treated empirically for any signs of infection or fever while awaiting the results of blood cultures.
• Appropriate vaccinations, including the polyvalent polysaccharide pneumococcal, the Haemophilus influenzae type b, and the quadrivalent meningococcal vaccines, should be administered to patients 1-2 weeks before splenectomy.
• Patients with severe β thalassemia intermedia are prone to infection with Yersinia enterocolitica, similar to individuals with the severe forms of thalassemia major. For this reason, patients who develop fever without clear cause should receive appropriate treatment even if culture results are negative.
• Young children should have their growth and development closely monitored; any deviation from normal should alert the physician to further investigate the need for blood transfusions.
• Failure to thrive, exercise intolerance, bone deformities and fractures are all potential complications; the health care provider should always look for ways to prevent these complications or at least identify and treat them early with regular blood transfusions, which are frequently effective in reversing or preventing their progress.
• In patients with severe thalassemia intermedia who require aggressive therapy to sustain life, bone marrow transplant, similar to that performed in patients with thalassemia major, is a reasonable alternative to transfusion and chelation if a matched sibling donor is available.
• Many studies have shown that patients with thalassemia intermedia who are not on regular blood transfusion because of their milder symptoms nevertheless develop major complications related to their chronic anemia and ineffective erythropoiesis (IE). Considering the cost-benefit balance of regular treatment in patients with thalassemia major, most patients with thalassemia intermedia would apparently benefit from similar therapy to prevent the complications, rather than waiting to deal with such complications when they occur.

Surgical Care

• Splenectomy is frequently recommended for patients who are no longer able to maintain an adequate Hb level. It is usually performed to restore the Hb steady state in patients who are not receiving blood transfusions and frequently succeeds in averting the need for regular transfusions.
• Observations and case reports have shown that splenectomy in such patients may cause serious venous thrombotic events, ranging from deep vein thrombosis to pulmonary thrombotic lesions complicated by pulmonary hypertension.^22,23,7,24 Several reports of serious thrombotic events such as transient ischemic attacks associated with hemiparesis and intracranial manifestations of Moyamoya syndrome were reported postsplenectomy in patients with thalassemia intermedia.²⁴ For this reason, one should delay or reconsider such a procedure whenever possible. This is supported by the fact that many children who underwent splenectomy to avoid becoming transfusion dependent experienced only a transient effect, and most later required regular transfusions.
• Placement of a central vascular access catheter in patients with severe disease is very helpful for blood transfusions, and laboratory work, especially when accessing a patient's peripheral veins becomes very difficult.
• In the rare patient with large tumorlike masses that compress vital organs, surgical resection rather than radiation therapy is usually preferred.
• Liver biopsy is indicated in the patient receiving chelation therapy for hemosiderosis to evaluate the degree of liver involvement and iron overload.

Consultations

• Patients in whom thalassemia is suspected should be seen and evaluated by a hematologist.
• Consultation with a cardiologist is indicated to evaluate cardiac function and monitor potential complications due to the anemia, transfusion, or iron overload.
• Consultation with an endocrinologist is also indicated for evaluation of possible involvement of various endocrine glands, which could result in diabetes mellitus, thyroid disorder, or growth retardation.
• Patients should be seen by a gastroenterologist for diagnosis and management of liver complications.

Diet

• A well-balanced diet with adequate folic acid supply is a necessity. Foods with high iron content should be avoided, particularly meat because heme iron is especially well absorbed. Vitamin C assists absorption of dietary iron; patients should avoid co-ingesting vitamin C and iron-rich foods.
• Alternatively, drinking tea with iron-rich foods helps chelate some of the iron before it is absorbed in the bowels.

Activity

• Many patients with thalassemia intermedia should be able to tolerate most daily activities. However, once the anemia worsens, exercise intolerance develops and may represent a warning sign indicating the need for initiation of blood transfusions.
• Massive splenomegaly has been observed in severe cases and is a cause for limiting the patient's activity for fear of injury to the abdomen causing rupture of the spleen.
• Regular transfusions decrease the size of the spleen in most instances, allowing splenectomy to be avoided whenever possible.

Medication

No specific medications are available for the treatment of thalassemia intermedia. Most patients with severe disease are prone to developing megaloblastic anemia due to folate deficiency for several reasons, including poor absorption, low dietary intake, and, most importantly, the extreme demand of the very active bone marrow for folic acid. For this reason, most patients benefit from a low dose of folate.

Many patients with thalassemia intermedia ultimately require regular blood transfusions, usually about every 3-5 weeks. Similar to patients with thalassemia major, patients with thalassemia intermedia who receive regular transfusions are usually premedicated with an antipyretic, such as acetaminophen, and an antihistamine, such as diphenhydramine, 30 minutes before transfusion to prevent both febrile and allergic reactions.

Patients with iron overload should be treated with chelation therapy (orally or parenterally). The drugs of choice at the present time are the oral agent deferasirox and deferoxamine administered subcutaneously by infusion pump 5 times per week. It can be administered while the patient sleeps. Low-dose vitamin C with each infusion of deferoxamine is beneficial in enhancing iron chelation. Combination therapy with more than one agent has proved to be effective in certain situations.

Patients with iron overload who develop fever of unknown origin may have Y enterocolitica infection. Treatment with gentamicin and oral trimethoprim-sulfamethoxazole should be initiated if no other cause for the fever is identified.

Hepatitis C virus (HCV) infection is the most common cause of hepatitis in patients with thalassemia. Because of the high risk of liver failure or even hepatocellular carcinoma in a liver already damaged by iron toxicity and frequent blood transfusions, HCV infection should be aggressively treated in these patients. Interferon alfa therapy has been effective in many children with HCV infection.

Other agents that may be of value in patients with thalassemia intermedia include vitamin E, which may prevent some of the toxic effects of the free radicals and other iron-related toxicity. Penicillin or one of its derivatives should be prophylactically administered for patients who have undergone a splenectomy. Some have also recommended a daily low dose of aspirin as prophylactic treatment in patients with thalassemia intermedia who underwent a splenectomy to prevent thrombotic events.

Antipyretics, analgesic

These agents can help prevent febrile reactions in patients who are frequently transfused and thus may develop sensitization to blood products.

Acetaminophen (Feverall, Tylenol, Tempra)

Antipyretic effect through action on hypothalamic heat-regulating center. Although equal to aspirin in action, preferred because it has fewer adverse effects.

Dosing

Adult

325-650 mg PO 30 min before transfusion

Pediatric

10-15 mg/kg/dose PO 30 min before transfusion

Interactions

Rifampin can reduce analgesic effects of acetaminophen; coadministration with barbiturates, carbamazepine, hydantoins, and isoniazid may increase hepatotoxicity

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Hepatotoxicity possible in people with chronic alcoholism following various dose levels; severe or recurrent pain or high or continued fever may indicate a serious illness; APAP is contained in many OTC products, and combined use with these products may result in cumulative APAP doses exceeding recommended maximum dose

Antihistamines

These agents prevent or ameliorate allergic reactions associated with transfusion of blood products.

Diphenhydramine hydrochloride (Benadryl, Benylin)

Elicits anticholinergic and sedative effects.

Dosing

Adult

25-50 mg PO q6-8h prn; not to exceed 400 mg/d
10-50 mg IV/IM q6-8h prn; not to exceed 400 mg/d

Pediatric

Neonates and premature infants: Do not administer
Infants and children: 1 mg/kg/dose PO/IV q6h or 5 mg/kg/d PO/IV divided q6h

Interactions

Potentiates effect of CNS depressants; because of alcohol content, do not administer syr dosage form to patient taking medications that can cause disulfiramlike reactions

Contraindications

Documented hypersensitivity; MAOIs

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May exacerbate angle closure glaucoma, hyperthyroidism, peptic ulcer, and urinary tract obstruction

Chelating agents

Chelating agents are an integral part of successful treatment of thalassemia. They remove excess iron deposits that are the main cause of long-term morbidity and mortality in this condition.

Deferoxamine mesylate (Desferal)

Chelates iron from ferritin and hemosiderin but not from transferrin, cytochrome, or Hb. Helps prevent damage to liver and bone marrow from iron deposition.

Dosing

Adult

1000 mg IV may be administered at a rate not to exceed 15 mg/kg/h; follow by a dose of 500 mg q4h for 2 doses; may administer additional IV infusion slowly over 24 h; not to exceed 6000 mg/d

Pediatric

20-40 mg/kg/d SC by infusion pump over 8-12 h 5 d/wk
With blood transfusions: 1-2 g IV slow infusion; not to exceed infusion rate of 15 mg/kg/h

Interactions

Can cause loss of consciousness when administered with prochlorperazine

Contraindications

Documented hypersensitivity; patients that do not have acute iron poisoning; severe renal disease and anuria (dose reduction after the loading dose should be considered in these circumstances)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Tachycardia, hypotension, and shock may occur in patients receiving long-term therapy and could add to the cardiovascular collapse due to iron toxicity; GI adverse effects of the drug include abdominal discomfort, nausea, vomiting, and diarrhea, which may add to the symptoms of acute iron toxicity; flushing and fever are reported; increased susceptibility to Y enterocolitica infection

Deferasirox (Exjade)

Tab for oral susp. Oral iron chelation agent demonstrated to reduce liver iron concentration in adults and children who receive repeated RBC transfusions. Binds iron with high affinity in a 2:1 ratio. Approved to treat chronic iron overload due to multiple blood transfusions. Treatment initiation recommended with evidence of chronic iron overload (ie, transfusion of about 100 mL/kg packed RBCs [about 20 U for 40-kg person] and serum ferritin level consistently >1000 mcg/L).

Dosing

Adult

Initial: 20 mg/kg/d PO on empty stomach 30 min ac; as initial dose calculate dose to nearest whole tab
Maintenance: Adjust dose by 5- to 10-mg/kg/d increments q3-6mo according to serum ferritin level trends; not to exceed 30 mg/kg/d
Note: Dissolve tab completely in water, orange juice, or apple juice, then immediately drink susp; resuspend any remaining residue in small volume of liquid and swallow

Pediatric

<2 years: Not established
>2 years: Administer as in adults

Interactions

Data limited; do not take with aluminum-containing antacids

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Common adverse effects include diarrhea, nausea, abdominal pain, headache, pyrexia, cough, and rash; may increase serum creatinine and hepatic enzyme levels; decrease dose with persistent elevation of serum creatinine level; may cause auditory and visual disturbances; slight decreases in serum copper and zinc levels may occur; dissolve tab completely in water, orange juice, or apple juice and drink resulting susp immediately (do not swallow tab whole, do not chew or crush); measure serum ferritin levels monthly and adjust dose every 3-6 mo based on serum ferritin trends

Antimicrobial agents

These agents are known to be effective against organisms that may cause infection in patients with iron overload who are also receiving deferoxamine therapy. Y enterocolitica infections are rare in healthy patients because the organism requires siderophores, which are present in patients with thalassemia but not in healthy patients. The appropriate therapy is a combination of trimethoprim-sulfamethoxazole and gentamicin. Patients who require splenectomy must receive prophylactic antibiotics to prevent fulminating sepsis, especially patients younger than 5 years.

Trimethoprim-sulfamethoxazole (Bactrim, Septra, Cotrim)

By blocking tetrahydrofolic acid, selectively inhibits synthesis of nucleic acids and proteins by bacteria.

Dosing

Adult

160 mg (trimethoprim)/800 mg (sulfamethoxazole) PO q12h (ie, one double-strength [DS] tab PO q12h)

Pediatric

<2 months: Do not administer
>2 months: 8-10 mg/kg/d (based on trimethoprim component) PO/IV divided q12h

Interactions

May increase PT when used with warfarin (perform coagulation tests and adjust dose accordingly); coadministration with dapsone may increase blood levels of both drugs; coadministration of diuretics increases incidence of thrombocytopenia purpura in elderly patients; phenytoin levels may increase with coadministration; may potentiate effects of methotrexate in bone marrow depression; hypoglycemic response to sulfonylureas may increase with coadministration; may increase levels of zidovudine

Contraindications

Documented hypersensitivity; megaloblastic anemia due to folate deficiency; age <2 mo

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Do not use near term in pregnancy because of risk of kernicterus; discontinue at first appearance of skin rash or sign of adverse reaction; obtain CBC counts frequently; discontinue therapy if significant hematologic changes occur; goiter, diuresis, and hypoglycemia may occur with sulfonamides; prolonged IV infusions or high doses may cause bone marrow depression (if signs occur, administer 5-15 mg/d leucovorin); caution in folate deficiency (eg, people with long-term alcoholism, elderly people, those receiving anticonvulsant therapy, those with malabsorption syndrome); hemolysis may occur in individuals with G-6-PD deficiency; patients with AIDS may not tolerate or respond to therapy; caution in renal or hepatic impairment (perform urinalyses and renal function tests during therapy); administer fluids to prevent crystalluria and stone formation

Gentamicin

An aminoglycoside. Effective against gram-negative aerobic microorganisms.

Dosing

Adult

1-1.5 mg/kg IV q8h with normal renal function

Pediatric

6-7.5 mg/kg/d IV divided q8h

Interactions

Coadministration with other aminoglycosides, cephalosporins, penicillins, and amphotericin B may increase nephrotoxicity; aminoglycosides enhance effects of neuromuscular blocking agents, thus prolonged respiratory depression may occur; coadministration with loop diuretics may increase auditory toxicity of aminoglycosides; possible irreversible hearing loss of varying degrees may occur (monitor regularly)

Contraindications

Documented hypersensitivity; non–dialysis-dependent renal insufficiency

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Narrow therapeutic index (not intended for long-term therapy); caution in renal failure (patient not on dialysis), myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission; adjust dose in renal impairment

Penicillin V (Veetids)

DOC for prophylaxis in patients with thalassemia who have undergone a splenectomy (erythromycin used in patients allergic to penicillin); active against most microorganisms considered to be major pathogens in splenectomized patients (ie, streptococcal, pneumococcal, and some staphylococcal microorganisms) but not penicillinase-producing species. Prophylaxis provided for >3 y after splenectomy.

Dosing

Adult

250-500 mg PO bid

Pediatric

<5 years: 125 mg/dose PO bid
>5 years: 250 mg/dose PO bid
Streptococcal infections: Administer above doses for >10 d
Prophylaxis: Treat for >3 y after splenectomy

Interactions

Probenecid may increase effectiveness by decreasing clearance; tetracyclines are bacteriostatic, causing a decrease in the effectiveness of penicillins when administered concurrently

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Patients with asthma may have hypersensitivity; PO route usually not adequate for treatment of severe infections; treat for minimum of 10 d for streptococcal infections

Vitamins

These agents are compounds that are present in small amounts in food and are essential for normal metabolism, cell function, and healthy tissues.

Ascorbic acid (Cecon, Cevalin, Vita-C)

Vitamin C has been shown to enhance the function of deferoxamine by keeping iron in a form that can be chelated. When administered with deferoxamine, allows more iron to be removed.

Dosing

Adult

100-200 mg/d PO during deferoxamine therapy

Pediatric

3 mg/kg/d PO with SC deferoxamine infusion

Interactions

Decreases effects of warfarin and fluphenazine; increases aspirin levels

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Use in patients with severe iron overload may induce a short-term deterioration with acute cardiac toxicity

Folic acid (Folvite)

Required for DNA synthesis; therefore, patients with all conditions associated with rapid cellular turnover, such as hyperactive marrow in thalassemia, have greatly increased demand. Because use of folic acid in hemolytic anemias is extreme, deficiency states are fairly common in most of these patients. Patients who do not receive folic acid supplementation may develop megaloblastic anemia, increasing the severity of the original disease process.

Dosing

Adult

1 mg PO qd

Pediatric

Administer as in adults

Interactions

Increase in seizure frequency and a decrease in subtherapeutic levels of phenytoin reported when used concurrently

Contraindications

Documented hypersensitivity; pernicious anemia; aplastic anemia

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Pregnancy category C if dose exceeds RDA; benzyl alcohol may be contained in some products as a preservative (associated with a fatal gasping syndrome in premature infants); resistance to treatment may occur in patients with alcoholism and deficiencies of other vitamins

Antioxidants

Vitamin E has been shown to help in decreasing iron-mediated toxic effects on cells by preventing or decreasing membrane-lipid peroxidation.

Vitamin E (Vita-Plus E Softgels, Vitec, Aquasol E)

MOA has been known for many years. In newborn or premature infants, in particular, deficiency has resulted in peculiar red blood cell morphology, leading to hemolysis; these changes are reversed by vitamin E. Peroxidation of membrane lipids by various oxidants, including iron-mediated oxygen radicals, is the main cause of this hemolysis and can be prevented by antioxidants such as vitamin E.

Dosing

Adult

50-2000 IU/d PO

Pediatric

1 IU/kg/d PO

Interactions

Mineral oil decreases absorption of vitamin E; vitamin E delays absorption of iron and increases effects of anticoagulants

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Pregnancy category C if dose exceeds RDA; vitamin E may induce vitamin K deficiency; necrotizing enterocolitis may occur when large doses of vitamin E are administered

Corticosteroids

These agents can help prevent local and systemic reactions to exogenous agents.

Hydrocortisone (Solu-Cortef, Cortef)

An anti-inflammatory adrenocortical steroid. Helps prevent local reaction to SC perfusion of deferoxamine. Both sodium succinate (Solu-Cortef) and sodium phosphate (Cortef) forms are used for IV infusions, but sodium acetate form (Hydrocortone) is not.

Dosing

Adult

Pediatric

Newborns: Do not administer
Infants and children: 5-10 mg added to deferoxamine solution before infusion

Interactions

Corticosteroid clearance may decrease with estrogens; may increase digitalis toxicity secondary to hypokalemia

Contraindications

Documented hypersensitivity; systemic fungal infection; tuberculosis; peptic ulcer; newborn infant (because of benzyl alcohol content)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Many adverse effects are known, but minimal doses used in this setting reduce this concern; however, because deferoxamine therapy is long term and must be administered almost daily, serious consideration is required for any condition that might be a contraindication; abrupt withdrawal may cause acute adrenal insufficiency; caution in hyperthyroidism, liver cirrhosis, ulcerative colitis, hypertension, and osteoporosis

Vaccines

Patients who have undergone a splenectomy are prone to developing infections with any of 3 common encapsulated organisms (ie, Pneumococcus species, H influenzae, and Meningococcus species). Patients who are to undergo splenectomy now receive immunizations against these organisms 1-2 weeks before the procedure. This practice allows the spleen to participate in production of antibodies before being removed.

Pneumococcal vaccine/PS23 (Pneumovax-23, Pnu-Imune 23)

The older polyvalent/polysaccharide vaccine contains the 23 most prevalent serotypes responsible for about 70% of all invasive infectious diseases, but it cannot be administered to children <2 y. A new generation of this vaccine, called conjugate vaccine, now available, has only 7 serotypes, but it can be administered to infants as young as 2 mo. This is a very important achievement because splenectomized infants are more prone to develop pneumococcal infections than any other group of patients. Conjugate form is administered in a series of 2-3 doses at ages 2, 4, and 6 mo.

Dosing

Adult

Pediatric

<2 years: Do not administer polyvalent vaccine
>2 years: 0.5 mL IM as primary vaccination
Splenectomy: 0.5 mL IM 1-2 wk before surgery
Booster dose (ie, 0.5 mL IM) usually administered 3-5 y after first dose

Interactions

May be administered with other vaccines recommended before splenectomy in different syringes and at different sites; immunosuppressive agents (eg, large amounts of corticosteroids, antimetabolites, alkylating agents, cytotoxic agents) may reduce effectiveness; therapy with immunoglobulin preparations is likely to block the active immunity induced with pneumococcal vaccination, withhold for 3 mo after discontinuation of immunoglobulin therapy

Contraindications

Documented hypersensitivity; children <2 y (polyvalent vaccine)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May cause moderately severe or severe illness with or without fever, arthralgias, urticaria, or Guillain-Barré syndrome (rarely)

Haemophilus influenzae b conjugate vaccine (ActHIB, HibTITER, PedvaxHIB

Recommended 2 wk before splenectomy. Patients who have already received their primary vaccination early in life and also received booster at 12 mo or later are usually protected, even though they may benefit from an additional dose before procedure. Conjugate form administered in a series of 2-3 doses at ages 2, 4, and 6 mo.

Dosing

Adult

Pediatric

0.5 mL IM before surgery

Interactions

Corticosteroids or cyclosporine may inhibit full immunologic response

Contraindications

Documented hypersensitivity to any component including thimerosal

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Delay immunization if febrile illness is evident; may cause erythema, swelling, or tenderness; cause-and-effect relationship with observed postvaccine Guillain-Barré syndrome has not been established

Meningococcal vaccine (Menomune A/C/Y/W-135)

Similar to polyvalent pneumococcal vaccine, this is used in children >2 y with risk (eg, complement deficiency, asplenia). Serogroup specific against groups A, C, Y, and W-135 N meningitides.

Dosing

Adult

Pediatric

<2 years: Do not administer
>2 years: 0.5 mL SC

Interactions

Administration of immunoglobulin within 1 mo or concurrent administration with immunosuppressive agents may inhibit full immunologic response; coadministration with whole-cell pertussis or whole-cell typhoid vaccines may increase endotoxin content

Contraindications

Documented hypersensitivity; age <2 y; IV/IM/ID administration

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Localized erythema at injection site; asplenic patients with lymphoid tumors who receive either chemotherapy or irradiation respond poorly; avoid during course of acute illness; routine vaccination recommended for high-risk groups (eg, deficiencies in late complement components [C3, C5-C-9], personnel with laboratory or industrial exposure to Neisseria meningitidis aerosols, travelers, residents of hyperendemic areas); for information concerning geographic areas in which vaccination is recommended, contact the Centers for Disease Control and Prevention (404-332-4559); serious adverse reactions should be reported to United States Department of Health and Human Services (1-800-822-7967)

Pneumococcal 7-valent conjugate vaccine (Prevnar)

Sterile solution of saccharides of capsular antigens of Streptococcus pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F individually conjugated to diphtheria CRM197 protein. These 7 serotypes have been responsible for >80% of invasive pneumococcal disease in children <6 y in the United States. Also accounted for 74% of penicillin-nonsusceptible S pneumoniae (PNSP) and 100% of pneumococci with high-level penicillin resistance. Customary age for first dose is 2 mo, but it can be administered to infants as young as 6 wk.

Dosing

Adult

Not established

Pediatric

3 doses of 0.5 mL IM each at 6-8 wk intervals, followed by a fourth dose of 0.5 mL at age 12-15 mo; recommended dosing interval is 6-8 wk; administer fourth dose 2 mo, or later, following the third dose

Interactions

Effects may decrease with immunosuppressive agents (eg, immunosuppressive doses of corticosteroids, antimetabolites, alkylating agents, cytotoxic agents); pneumococcal 7-valent conjugate vaccine may increase effects of anticoagulant therapy; globulin preparations may interfere with immune response to pneumococcal vaccine and reduce efficacy (do not administer within 3 mo of vaccine)

Contraindications

Documented hypersensitivity to any component or diphtheria toxoid; severe or moderate febrile illness; thrombocytopenia or coagulation disorder contraindicating IM injection (unless benefits outweigh risks of administration)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

For IM use only, do not administer IV under any circumstances; take special care to prevent injection into or near a blood vessel or nerve; caution in patients with possible history of latex sensitivity (packaging contains dry natural rubber); use of pneumococcal conjugate vaccine does not replace use of 23-valent pneumococcal polysaccharide vaccination in children aged >24 mo with sickle cell disease, asplenia, HIV infection, chronic illness, or those who are immunocompromised; caution in coagulation disorders

Erythropoiesis

Hydroxyurea was found to induce erythropoiesis and raise Hb levels.²⁰

Hydroxyurea (Hydrea)

Inhibits deoxynucleotide synthesis. S-phase specific nonDNA hypomethylation chemotherapeutic agent. Mechanism of action for thalassemia is unknown but has shown Hb F–inducing activity.

Dosing

Adult

15 mg/kg/d PO initially (initial dose ranges from 10-20 mg/kg/d); may increase by 5 mg/kg/d q12wk, not to exceed 35 mg/kg/d

Pediatric

Administer as in adults

Interactions

Coadministration with fluorouracil can increase neurotoxicity; coadministration with didanosine or stavudine may cause fatal pancreatitis and hepatotoxicity; immunization with live virus vaccine may cause severe or fatal infection in immunocompromised patient

Contraindications

Documented hypersensitivity; severe anemia or bone marrow suppression

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in renal impairment; for sickle cell, monitor blood count q2wk and adjust dose accordingly (ie, discontinue if hematologic toxicity occurs, then resume after recovery by reducing dose associated with hematologic toxicity by 2.5 mg/kg/d); hematologic toxicity is defined as neutrophils <2000/mL, platelets <80,000/mL, hemoglobin <4.5 g/dL, and reticulocytes <80,000/mL (if Hbg <9 g/dL)

Follow-up

Further Inpatient Care

• Most medical care in thalassemia intermedia is provided in an outpatient setting. Inpatient care is reserved for surgical procedures such as splenectomy or resection of large extramedullary hematopoietic tumor-like masses compressing vital organs, infectious complications, or in rare severe cases that are treated by a bone marrow transplant.

Further Outpatient Care

• Frequent outpatient visits are needed in the early stages to monitor hematologic parameters, activity, exercise tolerance, growth, and development of bone changes.
• Once the patient requires regular transfusions, monthly outpatient visits for blood transfusions and laboratory work for monitoring iron load status are usually required. Guidelines for transfusion in neonates and older children have been established.⁵
• While receiving chelation therapy, patients should have eye examinations and hearing tests as part of monitoring for the complications of therapy.

Deterrence/Prevention

• Prevention of thalassemia intermedia is based on public education, family counseling, and widespread measures, such as screening before marriage in high-risk populations, similar to those recommended for thalassemia in general.

Complications

• Most complications expected in thalassemia intermedia have been described in other sections. The conversion of thalassemia intermedia to a transfusion-dependent state is, by itself ,the most serious complication because that marks the transition of thalassemia intermedia to a more severe form of β thalassemia.
• As a result of the advanced care provided to patients with thalassemia, they are now surviving to an advanced age. With this longer survival comes new problems, which require a change in the approach to the care of affected patients. Three such complications have recently been described as major issues in the adults with thalassemia.
  • Hepatitis C virus (HCV) infection is a major complication of the lifelong blood transfusions in patients with the severe forms of thalassemia. This is probably less of a problem in patients with thalassemia intermedia who are not transfusion dependent. Nevertheless, HCV has also been reported in patients with thalassemia who have never had transfusions.
    • The incidence of positive HCV antibodies or RNA in patients aged 25 years or older (who were treated before the screening for HCV was initiated in 1990) was reported by the Thalassemia Clinical Research Network (TCRN) to be as high as 70% compared with only 5% in patients aged 15 years or younger.²⁵ The American Association of Blood Banks (AABB) has reported that the chance to contract HCV from blood transfusions in the United States is 1 per 1 million units transfused. Unfortunately, this is not the case in some developing countries where the rate was reported to be 63.8%.
    • HCV and iron overload are risk factors for cirrhosis and hepatocellular carcinoma (HCC); for this reason, many recommend to monitor such patients closely with liver ultrasonography and alpha fetoprotein level (AFP). About 33% of patients with HCV in North America are expected to spontaneously clear the virus; if this does not occur, aggressive treatment should be initiated. Pegylated interferon alpha (INF-alpha), in combination with Ribavirin, has been very effective in treating children with HCV infection.²⁶
  • Thrombotic events have been increasingly encountered not only in patients with thalassemia intermedia but also in those with thalassemia major and β thalassemia/Hb E disease. In one study of 85 patients with thalassemia intermedia and 65 with thalassemia major, the incidence of venous thromboembolic events was 29% and 2%, respectively. Twenty-three of the 24 patients with thalassemia intermedia and venous thromboembolic events had undergone splenectomy. For this reason, some recommend short-term antithrombotic therapy both perioperatively and when a risk factor for thrombosis exists. A low-dose daily aspirin is also recommended for all patients with thalassemia who are splenectomized and for those with thalassemia major and a platelet count of 600,000/m L after splenectomy.
  • Fertility in adult patients with thalassemia is another new issue that providers have to deal with.
• Severe thalassemia is often characterized by hypersplenism, which usually results in exaggerated anemia, thrombocytopenia, and enlarged abdomen.
• Iron overload, liver disease, and cardiac and endocrine defects are also encountered in this condition.
• Bone deformities, fractures, and neurologic complications from compression by tumorlike extramedullary hematopoietic tissue masses are more frequently observed in thalassemia intermedia than in thalassemia major because the hyperactivity of the marrow in patients with untreated thalassemia intermedia is not suppressed by repeated blood transfusions.
• Complications of blood transfusions, such as hepatitis and other transmitted organisms, are all well known.

Prognosis

• Patients with milder cases have good prognosis; however, after several years of stable disease, many patients develop the severe form and become transfusion dependent. Patients with the severe forms have the same prognosis as those with thalassemia major.
• In most cases, the transformation from the stable state to the transfusion-dependent state is usually gradual. A patient with an Hb of 7-8 g/dL for a long time may drop to 6 g/dL or less. In this case, and in the closely monitored patient, the drop is frequently attributed to a viral infection or transient cause. A single blood transfusion is usually recommended, and the patient is closely monitored. In many occasions, the patient's status continues as before, and no more blood is needed for the time.
• However, in other patients, a month or so after the transfusion, the Hb drops again and, at this time, the spleen (which has been enlarged all along) is now larger or more active; therefore, splenectomy is usually considered. Many patients respond well to the procedure and require no more blood for the time being. However, others maintain good Hb for several months or longer before developing the severe anemia again. At this time, the need for regular blood transfusions becomes clear; close monitoring for iron overload followed by chelation therapy when indicated should be undertaken. For this reason, all patients with thalassemia intermedia should be closely monitored in anticipation for developing such changes, which require immediate action.

Patient Education

• Education of the population at risk is the most effective prevention method. Measures similar to those undertaken in certain parts of Europe have been very effective in decreasing the numbers of patients with thalassemia in general (see Thalassemia, Beta).
• Even in developing countries, massive education about thalassemia has changed the outlook and provided local people a great incentive to do whatever is necessary to eliminate the condition or at least minimize its severity.

Miscellaneous

Medicolegal Pitfalls

• The diagnosis of thalassemia intermedia is purely clinical and is usually made after a period of observation to determine that the patient is able to maintain a satisfactory Hb level for a long time without the need for blood transfusions. If the physician settles for a marginal level of hemoglobin (Hb) and decides not to initiate blood transfusion therapy, the patient's Hb level may fluctuate and decrease further, potentially reaching a very low level if the patient is not closely monitored. Should this occur, permanent damage, including heart failure, bone deformity, hypersplenism, liver damage, or other complications, may occur. In otherwise similar circumstances, patients with marginally severe disease should be treated in the same way as patients with thalassemia major to avoid medicolegal actions that may leave the provider liable.
• In prenatal diagnosis of thalassemia intermedia, DNA probes of known genotypes are usually used. Because this condition varies significantly in severity (despite the misleading name), a milder form of disease may be anticipated in a baby who turns out to be affected by a more severe form of the disease. For this reason, parents should be informed in advance that testing may help rule out the possibility of severe disease (such as when a heterozygous condition is diagnosed) or may confirm severe disease when a homozygosity or heterozygosity for 2 severe mutations is confirmed. However, intermediate cases may be misleading, and the predictability is much less accurate.
• Increased absorption of iron in all forms of thalassemia results in hemosiderosis or iron overload regardless of whether the patient is receiving regular blood transfusions. Failure to monitor for or recognize this may end in significant organ damage. For this reason, close monitoring of iron status, ferritin level, and liver function tests is needed for evaluation. When in doubt about whether iron levels in the patient's tissues are sufficient to initiate chelation, a deferoxamine challenge test with measurement of urinary iron excreted is appropriate.

Multimedia

Media file 1: Peripheral blood film in thalassemia intermedia.

References

1. Li Q, Li LY, Mo QH. [A rare thalassemia intermedia case caused by co-existence of Hb H disease (--(SEA)/-alpha(4.2)) and beta-thalassemia major (beta (CD17A)>T/beta (IVS2-654C)>T): implications for prenatal diagnosis]. Nan Fang Yi Ke Da Xue Xue Bao. Jan 2008;28(1):16-9. [Medline].

2. Haghi M, Feizi AA, Harteveld CL, Pouladi N, Feizi MA. Homozygosity for a rare beta 0-thalassemia mutation [frameshift codons 25/26 (+T)] causes beta-thalassemia intermedia in an Iranian family. Hemoglobin. 2009;33(1):75-80. [Medline].

3. Harteveld CL, Refaldi C, Cassinerio E, Cappellini MD, Giordano PC. Segmental duplications involving the alpha-globin gene cluster are causing beta-thalassemia intermedia phenotypes in beta-thalassemia heterozygous patients. Blood Cells Mol Dis. May-Jun 2008;40(3):312-6. [Medline].

4. Finkenstedt A, Bianchi P, Theurl I, Vogel W, Witcher DR, Wroblewski VJ, et al. Regulation of iron metabolism through GDF15 and hepcidin in pyruvate kinase deficiency. Br J Haematol. Mar 2009;144(5):789-93. [Medline].

5. [Guideline] Gibson BE, Todd A, Roberts I, et al. Transfusion guidelines for neonates and older children. Br J Haematol. Feb 2004;124(4):433-53. [Medline].

6. Origa R, Galanello R, Ganz T, Giagu N, Maccioni L, Faa G, et al. Liver iron concentrations and urinary hepcidin in beta-thalassemia. Haematologica. May 2007;92(5):583-8. [Medline]. [Full Text].

7. Cappellini MD, Grespi E, Cassinerio E, Bignamini D, Fiorelli G. Coagulation and splenectomy: an overview. Ann N Y Acad Sci. 2005;1054:317-24. [Medline].

8. Dunn J, Khan S, Ariff B, Strickland N, Al-Nahhas A. Pulmonary emboli and extramedullary haematopoiesis in beta-thalassaemia intermedia. Nucl Med Rev Cent East Eur. 2008;11(1):34-6. [Medline].

9. Karimi M, Khanlari M, Rachmilewitz EA. Cerebrovascular accident in beta-thalassemia major (beta-TM) and beta-thalassemia intermedia (beta-TI). Am J Hematol. Jan 2008;83(1):77-9. [Medline].

10. Morris CR, Gladwin MT, Kato GJ. Nitric oxide and arginine dysregulation: a novel pathway to pulmonary hypertension in hemolytic disorders. Curr Mol Med. Nov 2008;8(7):620-32. [Medline].

11. Parker TM, Ward LM, Johnston DL, Ventureya E, Klaassen RJ. A case of Moyamoya syndrome and hemoglobin E/beta-thalassemia. Pediatr Blood Cancer. Mar 2009;52(3):422-4. [Medline].

12. Metarugcheep P, Chanyawattiwongs S, Srisubat K, Pootrakul P. Clinical silent cerebral infarct (SCI) in patients with thalassemia diseases assessed by magnetic resonance imaging (MRI). J Med Assoc Thai. Jun 2008;91(6):889-94. [Medline].

13. Westerman M, Pizzey A, Hirschman J, et al. Microvesicles in haemoglobinopathies offer insights into mechanisms of hypercoagulability, haemolysis and the effects of therapy. Br J Haematol. Jul 2008;142(1):126-35. [Medline].

14. Goldschmidt N, Spectre G, Brill A, et al. Increased platelet adhesion under flow conditions is induced by both thalassemic platelets and red blood cells. Thromb Haemost. Nov 2008;100(5):864-70. [Medline].

15. Singer ST, Ataga KI. Hypercoagulability in sickle cell disease and beta-thalassemia. Curr Mol Med. Nov 2008;8(7):639-45. [Medline].

16. Aessopos A, Kati M, Farmakis D. Heart disease in thalassemia intermedia: a review of the underlying pathophysiology. Haematologica. May 2007;92(5):658-65. [Medline].

17. Hankins JS, McCarville MB, Loeffler RB, et al. R2* magnetic resonance imaging of the liver in patients with iron overload. Blood. May 14 2009;113(20):4853-5. [Medline].

18. Deborah Chirnomas S, Geukes-Foppen M, Barry K, Braunstein J, Kalish LA, Neufeld EJ, et al. Practical implications of liver and heart iron load assessment by T2*-MRI in children and adults with transfusion-dependent anemias. Am J Hematol. Oct 2008;83(10):781-3. [Medline].

19. Karimi M, Darzi H, Yavarian M. Hematologic and clinical responses of thalassemia intermedia patients to hydroxyurea during 6 years of therapy in Iran. J Pediatr Hematol Oncol. Jul 2005;27(7):380-5. [Medline].

20. Koren A, Levin C, Dgany O, Kransnov T, Elhasid R, Zalman L, et al. Response to hydroxyurea therapy in beta-thalassemia. Am J Hematol. May 2008;83(5):366-70. [Medline].

21. Cappellini MD. Long-term efficacy and safety of deferasirox. Blood Rev. Dec 2008;22 Suppl 2:S35-41. [Medline].

22. Atichartakarn V, Angchaisuksiri P, Aryurachai K, Chuncharunee S, Thakkinstian A. In vivo platelet activation and hyperaggregation in hemoglobin E/beta-thalassemia: a consequence of splenectomy. Int J Hematol. Apr 2003;77(3):299-303. [Medline].

23. Blendis LM, Modell CB, Bowdler AJ. Some effects of splenectomy in thalassaemia major. Br J Haematol. Sep 1974;28(1):77-87. [Medline].

24. Sanefuji M, Ohga S, Kira R, et al. Moyamoya syndrome in a splenectomized patient with beta-thalassemia intermedia. J Child Neurol. Jan 2006;21(1):75-7. [Medline].

25. Cunningham MJ, Macklin EA, Neufeld EJ, et al. Complications of beta-thalassemia major in North America. Blood. Jul 1 2004;104(1):34-9. [Medline].

26. Davison SM, Kelly DA. Management strategies for hepatitis C virus infection in children. Paediatr Drugs. 2008;10(6):357-65. [Medline].

27. Aessopos A, Kati M, Meletis J. Thalassemia intermedia today: should patients regularly receive transfusions?. Transfusion. May 2007;47(5):792-800. [Medline].

28. Gardenghi S, Marongiu MF, Ramos P, et al. Ineffective erythropoiesis in beta-thalassemia is characterized by increased iron absorption mediated by down-regulation of hepcidin and up-regulation of ferroportin. Blood. Jun 1 2007;109(11):5027-35. [Medline].

29. Lagos P, Lagona E, Kattamis C. Serum ferritin in beta-thalassaemia intermedia. Lancet. Jan 26 1980;1(8161):204-5. [Medline].

30. Lilleyman JS, Hann IM, Blanchette V. The thalassemia. In: Pediatric Hematology. 2000:316, 325.

31. Luyendijk W, Went L, Schaad HD. Spinal cord compression due to extramedullary hematopoiesis in homozygous thalassemia. Case report. J Neurosurg. Feb 1975;42(2):212-6. [Medline].

32. McIntosh N. Beneficial effects of transfusing a patient with non–transfusion-dependent thalassaemia major. Arch Dis Child. Jun 1976;51(6):471-2. [Medline].

33. Nathan DG, Oski FA. The thalassemia. In: Nathan and Oski's Hematology of Infancy and Childhood. Vol 1. Philadelphia, Pa: WB Saunders Co; 1997:847-9.

34. Nick H, Acklin P, Lattmann R, et al. Development of tridentate iron chelators: from desferrithiocin to ICL670. Curr Med Chem. Jun 2003;10(12):1065-76. [Medline].

35. Origa R, Galanello R, Ganz T, et al. Liver iron concentrations and urinary hepcidin in beta-thalassemia. Haematologica. May 2007;92(5):583-8. [Medline].

36. Pippard MJ, Callender ST, Warner GT, Weatherall DJ. Iron absorption and loading in beta-thalassaemia intermedia. Lancet. Oct 20 1979;2(8147):819-21. [Medline].

37. Weatherall DJ. Thalassemia. In: Stamatoyannopoulos G, et al, eds. The Molecular Basis of Blood Diseases. Philadelphia, Pa: WB Saunders Co; 1944:157-206.

38. Weatherall DJ, Clegg JB. The Thalassemia Syndromes. Oxford, England: Blackwell Science Publishing Co; 1981.

39. Weizer-Stern O, Adamsky K, Amariglio N, et al. Downregulation of hepcidin and haemojuvelin expression in the hepatocyte cell-line HepG2 induced by thalassaemic sera. Br J Haematol. Oct 2006;135(1):129-38. [Medline].

Keywords

beta thalassemia intermedia, β thalassemia intermedia, beta thalassemia major, β thalassemia major, beta thalassemia trait, β thalassemia trait, hemoglobin, Hb, Hb level, globin chain synthesis, erythropoiesis, iron overload, hepcidin, anemia, growth retardation, failure to thrive, bone fractures, enlarged spleen, splenomegaly, pulmonary embolism, pulmonary hypertension, Moyamoya disease, cerebral infarction, enlarged spleen, treatment, diagnosis

Contributor Information and Disclosures

Author

Hassan M Yaish, MD, Professor of Pediatrics, University of Utah School of Medicine; Director of Hematology Services, Medical Director, Mountain States Hemophilia and Thrombophilia Treatment Center; Pediatric Hematologist/Oncologist, Department of Pediatrics, Primary Children's Medical Center
Hassan M Yaish, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Michigan State Medical Society, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Medical Editor

J Martin Johnston, MD, Associate Professor of Pediatrics, Mercer University School of Medicine; Director of Pediatric Hematology/Oncology, Backus Children's Hospital; Consulting Oncologist/Hematologist, St Damien's Pediatric Hospital
J Martin Johnston, MD is a member of the following medical societies: American Society of Pediatric Hematology/Oncology
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

James L Harper, MD, Associate Professor, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, Associate Chairman for Education, Department of Pediatrics, University of Nebraska Medical Center; Assistant Clinical Professor, Department of Pediatrics, Creighton University; Director, Continuing Medical Education, Children's Memorial Hospital; Pediatric Director, Nebraska Regional Hemophilia Treatment Center
James L Harper, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Federation for Clinical Research, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Council on Medical Student Education in Pediatrics, and Hemophilia and Thrombosis Research Society
Disclosure: Nothing to disclose.

CME Editor

Helen SL Chan, MBBS, FRCP(C), FAAP, Senior Scientist, Research Institute; Professor, Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Canada
Helen SL Chan, MBBS, FRCP(C), FAAP is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Society of Hematology, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

Chief Editor

Robert J Arceci, MD, PhD, King Fahd Professor of Pediatric Oncology, Professor of Pediatrics, Oncology and the Cellular and Molecular Medicine Graduate Program, Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine
Robert J Arceci, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Pediatric Society, American Society of Hematology, and American Society of Pediatric Hematology/Oncology
Disclosure: Nothing to disclose.

© 1994- by Medscape.
All Rights Reserved
(http://www.medscape.com/public/copyright)