AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Thalassemia was first described in peoples of the Mediterranean region and Southeast Asia. In fact, in Greek, the word thalassemia means sea. The most severe form of beta thalassemia is thalassemia major, or Cooley anemia. The syndrome of Cooley anemia, first described in 1925, is caused by the complete absence of beta-globin gene production. Milder forms of thalassemia have also been recognized and include beta thalassemia intermedia, beta thalassemia minor, and alpha thalassemia. This article focuses only on beta thalassemia major.

Pathophysiology

Normal hemoglobin, hemoglobin A, is composed of 2 beta and 2 alpha subunits. In beta thalassemia major, more than 200 mutations have been described in the beta-globin genes, cause loss of both beta-globin subunits. This leaves the normally paired alpha subunits unpaired. Unpaired subunits are cytotoxic. Normally, compensatory mechanisms are present to protect the cell from the small amounts of unpaired alpha subunits, which may regularly be present; however, in beta thalassemia major, these mechanisms are overwhelmed and more that 95% of red cell precursors undergo cytolysis in the intramedullary space. Mechanisms for this hemolysis include increased apoptosis as well as cell membrane fragility through the action of oxidation of alpha chains into hemochromes, which bind to various red cell membrane proteins making the membrane rigid and fragile.

This ineffective erythropoiesis and profound hemolysis result is a severe anemia that is usually manifest in affected individuals by age 6 months. The physiologic response is to attempt to increase red cell production by expanding the bone marrow space up to 30-fold and/or increase production of non-beta hemoglobin chains such as A2 (delta) and fetal (gamma) hemoglobin. However, despite these mechanisms, erythropoiesis remains ineffective and these patients become transfusion-dependent early in life. In fact, the presence or absence of adequate transfusions significantly impacts the appearance of these patients and the course of the disease.

The classic phenotype of patients with Cooley anemia includes the effects of marrow expansion such as frontal bossing of the skull and abnormalities of sinuses and facial bones producing an appearance described as mongoloid. Growth is retarded, which causes very short stature, and marrow expansion causes thinning of long bones and an increased risk for fractures. Folate deficiency is the result of increased utilization of folic acid in the expanded marrow space. Hepatomegaly and splenomegaly are common due to extramedullary hematopoiesis, which can lead to thrombocytopenia and leukopenia. The high red cell turnover causes increased GI absorption of iron to try to compensate for the ineffective erythropoiesis, which leads to hemochromatosis and accompanying endocrinopathies. Adequate transfusion regimens accelerate the development of hemochromatosis as well as the risk for transfusion-transmitted infections.

Frequency

United States

Cooley anemia occurs in the offspring of 2 heterozygote beta thalassemia parents. Incidence of thalassemia major in the black population of the United States is approximately 20 cases per 100,000 persons.

International

Estimates of incidence rates of heterozygote beta thalassemia are 10% in Italian, Sicilian, and Greek populations; 5% in Southeast Asian populations; and 1.5% in African and American black populations

Mortality/Morbidity

With modern treatment, life expectancy has increased. However, the development of certain complications is inevitable. Untreated patients usually do not survive past the second decade of life. With transfusion therapy, patients can survive to the fifth decade of life.

• Hemosiderosis is a major cause of morbidity and mortality and can occur independently of transfusion therapy; however, it occurs at a younger age with transfusion therapy.
  • Cardiac siderosis resulting from iron overload and long-term transfusion therapy is the most common cause of death when it occurs in patients early in their third decade of life. Cardiac hypertrophy and dilatation, myocarditis, right ventricular hypertrophy, and pulmonary hypertension and restrictive lung disease can occur in children younger than 10 years.
  • Liver dysfunction can be due to hepatitis B or C and hemosiderosis is associated with an elevated prothrombin time and vitamin K malabsorption.
  • Cirrhosis and liver dysfunction due to iron overload usually occurs in elderly patients.
  • Endocrine abnormalities such as diabetes mellitus, thyroid and adrenal dysfunction, and delayed sexual maturation with secondary amenorrhea due to infiltration of the pituitary with iron are known complications of hemosiderosis. Endocrine problems are usually recognized in older children and elderly individuals.
• Overwhelming infection is a common cause of death in children younger than 6 years, especially those who had early splenectomies; immunosuppression and increased susceptibility to infection also occurs as a result of the leukopenia related to hepatosplenomegaly.
• Thalassemia is associated with hypercoagulability (Eldor, 2002).
• Neglected anemia can cause death when standard transfusion protocols are not readily available.

Race

• Beta thalassemia is found in peoples of African and Southeast Asian descent as well as in descendants of Mediterranean countries. Beta thalassemia may be protective against malaria.

Sex

• No predilection is recognized.

Age

• Thalassemia major is evident by 6 months to 1 year after Hgb switching has occurred.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Cooley anemia has a severe clinical course. Many children die in late infancy due to infection. Severe anemia, growth retardation, hepatosplenomegaly, and jaundice usually are the presenting symptoms and findings. Facial and skeletal deformities develop later. Iron overload can present as cardiac, hepatic, and endocrine dysfunction.

• Specific complaints include the following:
• • Pallor, irritability
  • Failure to grow
  • Abdominal swelling
  • Infections
  • Jaundice, dark urine
  • Facial and skeletal deformities
  • Irregular heart beat and cardiac failure
  • Amenorrhea and lack of sexual development
  • Gallstones, usually after age 4 years

Physical

The processes of ineffective erythropoiesis and hemolysis ultimately lead to the physical signs of Cooley anemia. These include the following:

• Evidence of severe anemia
• Development percentiles that are below average
• Progressive hepatosplenomegaly
• Jaundice
• Leg ulcers
• Typical frontal bossing and mongoloid facies, paraspinal deformities, and other skeletal changes; malocclusion and compression fractures of vertebrae
• Cardiomegaly and arrhythmias
• Delayed secondary sexual characteristics

Causes

More than 200 mutations of the beta-globin genes on chromosome 11 can cause thalassemia. These mutations can cause an absence of beta-chain production, ie, beta (0) thalassemia, or diminished beta-chain production, ie, beta (+) thalassemia.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Hemoglobin E thalassemia
Hemoglobin S thalassemia
Sideroblastic anemia

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• CBC, platelet, and reticulocyte count findings show a severe microcytic anemia, thrombocytopenia and leukopenia secondary to hypersplenism, and mild to moderate reticulocytosis.
• Serum folate levels often are low in patients with thalassemia major.
• Coagulation tests (eg, prothrombin time, activated partial thromboplastin time, fibrinogen values, other tests) if patients have increased bleeding.
• Peripheral blood smear findings include microcytic hypochromic RBCs, marked anisocytosis and poikilocytosis, polychromasia, poorly hemoglobinated nucleated RBCs, and basophilic stippling. The number of nucleated RBCs increases following splenectomy.
• Exclude the presence of hepatitis B and C by evaluating for antihepatitis B antibodies and hepatitis B surface antigens or antihepatitis C antibodies.
• LDH and total and indirect (nonconjugated) bilirubin levels are increased because of intramedullary hemolysis. The reticulocyte count is relatively low since hemolysis occurs within the medullary space.
• Urinalysis to evaluate dark brown urine, which results from elevated dipyrrole levels caused by increased heme catabolism.
• For Hgb F and A2 quantitation, only quantitative procedures (eg, ion exchange chromatography for Hgb A2) should be used. Routine Hgb electrophoresis is not sufficiently sensitive to detect small increases in Hgb A2.
• • Variable amounts of Hbg F are observed, ranging from 10-90%
  • Hgb A2 levels vary and can be normal, decreased, or elevated.
• Exclude hemosiderosis by measuring serum iron levels, assessing total body iron concentration (TIBC), measuring ferritin levels, and quantitating hepatic iron stores. Recent studies suggest that quantitating hepatic iron stores may be more accurate than measuring serum ferritin, and a liver biopsy may be performed for accurate analysis. Serum TIBC is low and serum iron and ferritin levels are high in patients with hemosiderosis.
• Liver function test results may be elevated in patients with hepatic siderosis.
• Serum uric acid levels are high in patients with thalassemia major.
• RBC osmotic fragility is decreased secondary to marked hypochromia. This test is rarely performed.
• Use supravital staining (eg, with methyl violet) of peripheral blood to help demonstrate inclusion bodies.
• More definitive tests include quantification of relative alpha- and beta-globin chain synthesis and genetic testing.

Imaging Studies

• Conventional radiographs include chest, skull, and sinus films and a skeletal survey, which may demonstrate the "hair-on-end" phenomenon. Findings may include bony expansion, hair-on-end phenomenon, pathological fractures, vertebral collapse, osteopenia, and intrathoracic paraspinal masses.
• Gallbladder imaging and ultrasound evaluation may reveal pigment stones.
• Splenic ultrasound may reveal splenomegaly.
• MRI T2 imaging for iron overload is now being performed in limited centers in the United States.

Other Tests

• Prenatal diagnosis
• • Globin-chain separation by carboxymethyl-cellulose column chromatography can be performed using fetal erythrocytes, which are obtained by fetal blood sampling. In this procedure, a needle is placed percutaneously through the mother's uterus to phlebotomize the umbilical cord.
  • The DNA-based method uses amniotic tissue or chorionic villi sampling. This method is associated with a very low risk of fetal loss, with an error rate in experienced laboratories of less than 1%. The procedure involves placing a catheter into the intrauterine cavity and aspirating a small amount of chorionic villi from the placenta. The DNA makeup of this tissue is identical to that of the fetus.

Histologic Findings

Bone marrow is hypercellular and may show evidence of (1) erythroid hyperplasia; (2) Gaucherlike storage cells due to accumulation of lipids, especially glycolipids, derived from the destruction and large turnover of cells; and (3) alpha-chain aggregates in normoblasts with phase microscopy or supravital stain. Increased iron stores and megaloblastosis secondary to folate deficiency may be present

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The goals of medical therapy are correction of anemia, suppression of erythropoiesis, and inhibition of increased GI iron.

• Transfusion protocols
• • A regular transfusion protocol is recommended. Recent studies recommend RBC transfusion when the Hgb level is less than 9.5 g/dL. This therapy appears to be a reasonable compromise that is effective in reducing ineffective erythropoiesis and the other pathophysiologic consequences of thalassemia, which can also slow the rate of iron overload. Three different transfusion protocols have been used, described as follows:
    • Conservative therapy: Transfuse conservatively and only when the Hgb level falls below 6-8 g/dL or if the patient is symptomatic. This transfusion protocol has recently fallen out of favor with many physicians because it lacks many of the long-term benefits observed with hypertransfusion.
    • Hypertransfusion/high transfusion: The treatment of choice is to transfuse often enough to keep the Hgb level greater than 10 g/dL and the hematocrit value greater than 30%. This therapy protocol suppresses endogenous erythroid activity, helps prevent marrow expansion, and reduces dietary iron absorption.
    • Supertransfusion: Transfuse often enough to keep the hematocrit level greater than 35%, resulting in 2-3 units being transfused every 2-4 weeks. This may become the protocol of the future, but not enough data are currently available on long-term benefits. Hypertransfusion and supertransfusion regimens help maintain a higher Hgb and hematocrit level but are associated with a high incidence of hemosiderosis.
  • Benefits include the following:
    • Patients experience fewer intercurrent infections.
    • Patients live a more active lifestyle.
    • Patients have less cardiomegaly and hepatosplenomegaly.
    • Fewer bone changes and orthodontic problems occur.
  • Unfortunately, regular transfusions do not appear to correct the deficient pubertal growth spurt.
• Avoidance of iron toxicity
• • The hypertransfusion regimen actually reduces ineffective erythropoiesis, thus reducing iron absorption. This benefit may be offset by iron administered via increased transfusions (1 g of Hgb contains 3.46 mg of iron).
  • Patients should receive chelation therapy in combination with an adequate transfusion regimen to delay/prevent hemochromatosis and should begin during the first decade (usually at 3 y). Chelation has been shown to reduce hepatic iron stores, decrease hepatic fibrosis, and improve growth. Beneficial effects on endocrine and cardiac complications are less dramatic. Deferoxamine remains the most commonly used agent, while deferiprone is also used. A target hepatic iron concentration of less than 15 mg/g should be maintained. Other chelators are also being investigated, and the role of the recently approved oral agent deferasirox (Exjade) remains to be determined.
  • Several options are available for monitoring iron stores. These include measuring serum ferritin levels, quantitating hepatic iron via liver biopsy performed under ultrasonic guidance, performing magnetic spectroscopy, and performing magnetic resonance imaging. Recent evidence suggests that serum ferritin levels are not always reliable for assessing iron stores. Liver biopsies with ultrasonic guidance are safe, and, when analyzed, findings provide an accurate assessment of iron stores. Magnetic spectroscopy is available in only 4 centers worldwide, but it may be comparable to liver biopsy for assessing iron load. Also, because iron deposition in tissues may vary, this will likely be the most reliable method for determining total body iron in the future. Magnetic resonance imaging is not a reliable method for assessing iron stores.
• Antibiotics
  • Treat febrile illnesses with broad-spectrum antibiotics after obtaining blood and urine culture results.
  • Penicillin prophylaxis is warranted as usual in postsplenectomy patients.
• Bone marrow transplantation
  • This is the only current potentially curative treatment for beta thalassemia.
  • Previously, only young, low-risk patients without evidence of liver damage were able to benefit from transplant; however, advances in conditioning regimens have now allowed higher-risk, young patients to be successfully transplanted more than 90% of the time.
  • Early reports of so-called minitransplants with nonmyeloablative conditioning regimens suggest this may be an effective option as well, but currently remains under investigation.
  • Improved immunosuppression and supportive care have also allowed some patients to be successfully transplanted with matched, unrelated donors with success rates comparable to standard allogeneic transplant from matched, related donors.
  • Outcome is likewise worse for those older than 16 years.
• Other and future therapies
  • Augmentation of fetal hemoglobin synthesis with hydroxyurea and 5-Azacitidine has not been consistently shown to be effective at this time, but additional agents that can increase fetal hemoglobin synthesis are being sought.
  • Baseline erythropoietin levels are higher in patients with thalassemia major than in healthy controls, but case reports exist of decreased transfusion requirements in patients treated with recombinant human erythropoietin with or without concomitant hydroxyurea.
  • The role of bisphosphonates is being delineated, but they may help prevent osteopenia/osteoporosis often seen in patients with Cooley anemia.
  • Efforts in gene therapy have not been shown to be effective yet, but it still remains an area of investigation and potential promise.

Surgical Care

• Permanent indwelling catheter
• Splenectomy
• • This may not be necessary if the child has been maintained on an aggressive transfusion protocol.
  • Indications are that massive hepatomegaly causes hypersplenism, which aggravates anemia, thrombocytopenia, and leukopenia and increases transfusion requirements.
  • All patients who undergo splenectomy should receive vaccinations for the encapsulated organisms (eg, Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis).
  • The procedure should be deferred until the patient is aged 6 years to reduce the incidence of overwhelming infection.

Consultations

• Genetic counselor
• Hematologist to help manage transfusions, crises such as hypersequestration, folate deficiency, and monitoring and management of iron overload
• Surgeon to manage complications such as cholelithiasis
• Psychiatrist to manage adjustment to failure of growth, sexual maturation, and disability due to iron overload

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

No specific medications are used to treat this hereditary disorder. The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Chelating agents

Used as an adjunct in the management of severe iron intoxication.

Drug Name	Deferasirox (Exjade)
Description	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). Excretion in feces.
Adult Dose	Initial: 20 mg/kg PO qd on empty stomach 30 min ac 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 Dose	<2 years: Not established <2 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Data limited; do not take with aluminum-containing antacids
Pregnancy	B - Usually safe but benefits must outweigh the risks.
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

Drug Name	Ascorbic acid (Ascorbicap, Dull-C)
Description	Low doses increase urinary excretion of iron in response to deferoxamine. Higher doses (eg, 500 mg/d) may cause cardiac decompensation due to mobilization of iron from reticuloendothelial cells to parenchymal cells in the heart.
Adult Dose	100-200 mg/d PO
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Decreases effects of warfarin and fluphenazine; increases aspirin levels
Pregnancy	A - Safe in pregnancy
Precautions	Category C if given in doses higher than RDA; prolonged high doses may cause renal calculi, especially in patients with diabetes

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Provide oral folic acid.
• Monitor for iron overload.
• Monitor transfusion therapy.

Deterrence/Prevention

• Genetic counseling and population screening should be considered in high-risk populations because diagnostic and predictive capabilities have progressed far beyond therapeutic successes.

Prognosis

• Life expectancy for patients is the early part of the third decade of life and is limited by complications of iron overload. Results of new techniques of aggressive long-term iron chelation are not yet available; longer follow-up is needed to determine if overall survival is improved.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to recognize the need for a blood transfusion or transfusing too aggressively to achieve an Hgb level that is inappropriately high for a patient with chronic anemia
• Failure to treat infections and failure to provide penicillin prophylaxis to children who have undergone splenectomy
• Failure to control iron overload

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Bunn HF, Forget BG. The Beta Thalassemias In: Bunn HF, Forget BG, eds. Hemoglobin: Molecular, Genetic and Clinical Aspects. 2nd ed. Philadelphia, Pa: WB Saunders; 1986:. 333-71.
• Chaidos A, Makis A, Hatzimichael E, et al. Treatment of beta-thalassemia patients with recombinant human erythropoietin: effect on transfusion requirements and soluble adhesion molecules. Acta Haematol. 2004;111(4):189-95.
• Davis BA, Porter JB. Long-term outcome of continuous 24-hour deferoxamine infusion via indwelling intravenous catheters in high-risk beta-thalassemia. Blood. Feb 15 2000;95(4):1229-36. [Medline].
• Eldor A, Rachmilewitz EA. The hypercoagulable state in thalassemia. Blood. Jan 1 2002;99(1):36-43.
• Giardini C, Lucarelli G. Bone marrow transplantation for beta-thalassemia. Hematol Oncol Clin North Am. Oct 1999;13(5):1059-64, viii. [Medline].
• Kohli-Kumar M, Marandi H, Keller MA, et al. Use of hydroxyurea and recombinant erythropoietin in management of homozygous beta0 thalassemia. J Pediatr Hematol Oncol. Dec 2002;24(9):777-8.
• Makis AC, Chaliasos N, Hatzimichael EC, Bourantas KL. Recombinant human erythropoietin therapy in a transfusion-dependent beta-thalassemia major patient. Ann Hematol. Aug 2001;80(8):492-5.
• Miller ST, Sleeper LA, Pegelow CH. Prediction of adverse outcomes in children with sickle cell disease. N Engl J Med. Jan 13 2000;342(2):83-9. [Medline].
• Olivieri NF. The beta-thalassemias. N Engl J Med. Jul 8 1999;341(2):99-109. [Medline].
• Rodgers GP, Saunthararajah Y. Advances in experimental treatment of beta-thalassaemia. Expert Opin Investig Drugs. May 2001;10(5):925-34.
• Rund D, Rachmilewitz E. New trends in the treatment of beta-thalassemia. Crit Rev Oncol Hematol. Feb 2000;33(2):105-18. [Medline].
• Rund D, Rachmilewitz E. Beta-thalassemia. N Engl J Med. Sep 15 2005;353(11):1135-46.
• Schrier SL, Angelucci E. New strategies in the treatment of the thalassemias. Annu Rev Med. 2005;56:157-71.
• Thein SL. Beta-thalassemia. Baillieres Clin Haematol. Mar 1998;11(1):91-126. [Medline].

Article Last Updated: Jun 21, 2006