eMedicine Specialties > Pediatrics: General Medicine > Hematology

Thalassemia: Treatment & Medication

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
Contributor Information and Disclosures

Updated: Jul 29, 2009

Treatment

Medical Care

Patients with thalassemia traits do not require medical or follow-up care after the initial diagnosis is made. Iron therapy should not be used unless a definite deficiency is confirmed and should be discontinued as soon as the potential Hb level for that individual is reached. Counseling is indicated in all persons with genetic disorders, especially when the family is at risk of a severe form of disease that may be prevented.

Patients with severe thalassemia require medical treatment, and a blood transfusion regimen was the first measure effective in prolonging life. In the process of experimenting with blood transfusion, it was found to provide patients with many benefits, including reversal of the complications of anemia, elimination of ineffective erythropoiesis and its complications, allowance of normal or near-normal growth and development, and extension of patients' life spans. Blood transfusion should be initiated at an early age when the child is symptomatic and after an initial period of observation to assess whether the child can maintain an acceptable level of Hb without transfusion.

After many years of monitoring transfused patients, the inadequacy of transfusion alone as a therapy became clear. Accumulation of transfused iron and its consequences also needed to be addressed. Chelation therapy was considered after extensive research and many clinical trials. Today, regular blood transfusion combined with well-monitored chelation therapy has become the standard therapy and has drastically changed the outlook for this population of patients.

  • Blood transfusions
    • Several blood transfusion regimens have been introduced. Of these, one seems practical, less demanding, and more cost-effective than any of the others. This regimen attempts to maintain a pretransfusion Hb level of 9-9.5 g/dL at all times.
    • Like all patients who require long-term regular blood transfusions, patients with thalassemia require a pretransfusion workup. This workup should include RBC phenotype, hepatitis B vaccination (if needed), and hepatitis workup. Iron and folate levels should also be measured.
    • Transfused blood should always be leukocyte poor; 10-15 mL/kg PRBCs at the rate of 5 mL/kg/h every 3-5 weeks is usually adequate to maintain the pretransfusion Hb level needed.
    • Consider administration of acetaminophen and diphenhydramine hydrochloride before each transfusion to minimize febrile or allergic reactions.
    • Patients with documented transfusion reactions may benefit from having RBCs washed with saline or from receiving deglycerolized RBCs.
  • Complications of blood transfusion: The major complications of blood transfusions are those related to transmission of infectious agents or the development of iron overload. Patients with thalassemia major are somewhat prone to develop infection more than normal children, regardless of the transfusion status. Reports of suppressed cell- mediated immunity in such patients, as well as abnormal neutrophil function, are available in the literature. A recent study have shown that accelerated aging of T- lymphocytes in patients with β- thalassemia could play a role in the suppressed cell-mediated immunity that may be translated into increased incidence of infections.5 . A second study has suggested an abnormality in the results of the nitroblue tetrazolium (NBT) test conducted on the neutrophils from patients with thalassemia compared with controls.6   
  • Infectious agents
    • As recently as a few years ago, 25% of transfused patients were exposed to   hepatitis B virus. At present, both immunization and strict screening of potential donors have significantly decreased the incidence. Hepatitis C virus (HCV) is the most common cause of hepatitis in adolescents older than 15 years with thalassemia (risk of exposure was 6%). Because both liver failure and hepatocellular carcinoma occur in 20% of adults with HCV, aggressive combined treatment with pegylated interferon alfa (IFN-alfa) and ribavirin is warranted in patients who contract HCV.7
    • The incidence of transfusion-transmitted HCV is expected to drop significantly because of stricter blood screening now mandated. Data from the Registry of the Thalassemia Clinical Research Network (TCRN) demonstrated how successful the screening for HCV was in reducing the incidence of HCV infection in such patients. The incidence was shown to be only 5% in children younger than 15 years compared to 75% in adults older than 25 years; unfortunately, this is not true in developing countries.
    • Infection with rare organisms that are not considered pathogenic in healthy hosts may cause febrile illness and symptoms of enteritis in patients with iron overload, especially those receiving chelation therapy with DFO. The pathogen Y enterocolitica uses the abundant iron scavenger molecules, known as siderophores, which the microorganism needs but cannot synthesize. Fever without any apparent cause, especially when associated with diarrhea, should be treated with gentamicin and trimethoprim-sulfamethoxazole, even when culture results are negative.
  • Iron overload
    • Even though blood transfusion is supposed to decrease the excessive iron absorption in the GI tracts of patients with thalassemia, patients nevertheless receive large amounts of iron with each blood transfusion. Why patients with excessive iron absorb large amounts of iron from the GI tract is not clear.
    • Many believe that the highly active marrow in these patients is iron deficient and needs large amounts of iron to produce the massive numbers of RBCs usual in this disease. The iron absorbed from the gut by the enterocyte, which coordinates iron uptake and transport into the body with its release from the reticuloendothelial system, is bound to transferrin in the plasma. The erythron claims most of the iron, while other tissues and cells that express transferrin receptors pick most of the rest. Both iron and transferrin enter the cells by endocytosis, forming the labile iron pool that provides iron to the cells and the iron-containing enzymes.
    • The major regulator of iron absorption and use is a protein produced in the liver called hepcidin. It has a negative effect on iron absorption. Hepcidin production is stimulated in several situations such as iron overload and inflammation. As a result, iron is not absorbed in such conditions. On the other hand, when a patient has iron deficiency anemia, hepcidin level is downregulated, so iron is absorbed.
    • In patients with thalassemia who experience iron overload, a high level of hepcidin is expected to prevent iron absorption. However, this is not the case because such patients absorb a significant amount of iron despite their known iron overload status. This action is mediated by a marrow derived factor called growth differentiation factor 15 (GDF15), which abrogates hepcidin-mediated protection against iron absorption in patients with iron overloaded who have increased erythropoiesis, such as those with chronic hemolytic anemias.8
    • As iron accumulates and exceeds body needs, production of apoferritin is accelerated to provide means for storing iron in nontoxic forms as ferritin or hemosiderin. Measuring the ferritin level in the first few years after the diagnosis of thalassemia is usually helpful in detecting iron overload status because ferritin correlates well with total body iron burden at this time. Later on, the correlation becomes poor, since ferritin is produced by hepatocellular damage and it acts as an acute-phase reactant. The ferritin level rises in individuals with hepatitis, infections, and heart failure. When ferritin molecules accumulate further, the protein moiety disintegrates, leaving small iron-concentrated hemosiderin particles; this alone is not harmful, but it may cause release from lysosomes of hydrolytic enzymes that are toxic to the cells.
    • In patients with iron overload, a unique situation develops as a result of the very high saturation of the carrier protein transferrin, approximately 90% or more (reference range for children and adults, 23-34%). A new iron pool, which is not present in healthy individuals, is formed (the nontransferrin-bound or the free serum iron pool), which is probably an expansion of the labile pool.
  • Tissue toxicity in iron overload
    • Peroxidation of cell membrane components by iron in the free pool is probably the major cause of organ damage from excessive iron. This effect was noted to worsen when ascorbic acid was added and was corrected partially by either vitamin E or deferoxamine. Patients with thalassemia with iron overload are typically deficient in vitamin E.
    • The route of iron access to the body and its relation to the development of hemosiderosis have been controversial issues for some time. Many believe that absorption of iron from the bowel is the major factor in the etiology of this condition. The parenchymal tissue damage in the livers of patients with hereditary hemochromatosis and those with thalassemia intermedia who are not receiving transfusions and the lower incidence of liver cirrhosis in heavily transfused patients with aplastic anemia support their claims.
    • This interpretation should not create the wrong impression that transfusional iron is not involved in the etiology of iron overload; on the contrary, every effort should be made to minimize all iron intake from any source in patients at risk whenever possible.
  • Chelation therapy
    • Until recently, patients with thalassemia major who received only transfusion therapy could not survive beyond adolescence, largely because of cardiac complications caused by iron toxicity. The introduction of chelating agents capable of removing excessive iron from the body has dramatically increased life expectancy.
    • When administered in conjunction with blood transfusion regimens, chelation can delay the onset of cardiac disease and, in some patients, even prevent its occurrence.
    • Several chelating agents have been tested, and, although many failed, one particular agent was proven effective and safe. DFO is a complex hydroxylamine with high affinity for iron; it targets the labile pool, the nontransferrin-bound iron (free pool), and the ferritin generated from reticuloendothelial iron.
    • Route of administration is critical in achieving the goal of therapy, which is reaching a negative iron balance (ie, excreting more iron than acquired from both intestinal absorption and transfusion). In the adult, reaching this goal involves removing 35 mg of iron per day.
    • Because the agent is not absorbed in the gut, it must be administered parenterally, whether intramuscularly, intravenously, or subcutaneously. Because of its short half-life, subcutaneous infusion must be prolonged if it is to achieve the stated goal.
    • A total dose of 30-40 mg/kg/d is infused over 8-12 hours during the child's sleep for 5 d/wk by a mechanical pump.
    • If doses larger than those tolerated by the subcutaneous route are needed, the intravenous route may be safely used, especially when a vascular access device is in place.
    • Doses as high as 6-10 g were administered intravenously in selected patients and proved effective in reversing serious iron overload complications.
    • The optimal time to initiate chelation therapy is dictated by the amount of accumulated iron and its accessibility for chelation. This usually occurs after 1-2 years of transfusions. Severe toxicity may develop if chelation is started prematurely. A DFO challenge test is usually helpful in deciding whether a patient is a candidate for chelation.
    • DFO toxicity concerns are as follows:
      • Local reaction at the site of injection is reported in many patients and can occasionally be severe.
      • High-frequency hearing loss has been reported in 30-40% of patients. Other neurosensory complications of chelation therapy include color and night blindness and visual field loss. These complications are frequently reversible and more commonly occur when not enough iron is available for chelation, when aggressive chelation therapy is administered, or when the chelation agent is administered in continuous intravenous infusions in a dose greater than 50 mg/kg/d. For this reason, eye and hearing examinations are to be scheduled every 6-12 months in patients receiving chelation therapy.
      • Pulmonary infiltrates as a complication have been reported in only a few patients.
      • For several reasons and despite all the advantages of DFO, chelation with this agent has been inadequate. In countries where it is needed the most, the high cost of the drug and the supplies needed for its administration make it unavailable for most patients. DFO has been prescribed for only 25,000 of 72,000 patients with thalassemia major receiving blood transfusion worldwide. In the Western world, on the other hand, despite the wide availability of the agent, some patients do not comply because of the unpleasant and cumbersome nature of the regimen. Others who cannot tolerate the drug have to modify the dose or the route or stop use all together.
      • A recent report showed that 105 of 328 patients in North America had to modify their regimen, and 20 patients had to stop taking the agent. For such reasons, the search for more practical chelators (especially the targeted chelators that can more effectively remove iron from specific organs [eg, heart, liver]) has continued to be a major task for the last few decades.
    • Oral chelating agents have been in use in other countries for some time, and newer ones are showing efficacy and some specificity for removing iron more efficiently from certain organs than DFO.
    • Deferasirox (Exjade) is a relatively new oral chelating agent with a long half-life, for this reason it is administered orally once daily. Several studies in the last few years have shown that this agent is as effective as its predecessor, deferoxamine, in reducing ferritin level and tissue iron accumulation. One study with 3.5 years median follow-up has confirmed the efficacy and safety of this agent. A dose of 30 mg/kg/d has resulted in negative iron balance in most patients on chronic blood transfusion.9
    • Deferasirox toxicity concerns include the following:
      • Skin rash
      • Hepatic dysfunction
      • Postmarketing surveillance reports of acute renal failure
      • Cytopenia (eg, agranulocytosis, neutropenia, thrombocytopenia)
      • Auditory disturbances
      • Ocular disturbances
      • Hypersensitivity reactions
    • The previously known oral chelating agent deferiprone (Ferriprox, DFP), which failed when administered alone, is now showing superiority in reducing cardiac iron concentration. DFP is co-administered with DFO or is administered sequentially with DFO. The additive and synergistic effects contribute to significant removal of iron from different organs at risk for siderosis, such as the liver and heart. DFP is currently designated as an orphan drug in the United States.
    • Initially, DFP provided some promising results. However, after a few years of observation and monitoring, the agent was found to be less effective than DFO in preventing organ damage. In addition, some adverse effects such as neutropenia or even agranulocytosis were reported in as many as 8% of patients.
    • More recently, DFP was demonstrated to have efficacy comparable to that of DFO, with minimal adverse effects and better compliance, leading some investigators to reconsider the use of DFP. The drug is now in use in more than 50 countries. Significant improvement based on cardiac MRI findings, indicating a reduction in cardiac iron overload and improved cardiac function, was reported in some studies as a result of DFP therapy. This observation suggests a cardioprotective role of DFP. This observation was recently confirmed by more than one study.
    • Finally, combinations of 2 iron chelators (parenteral DFO plus the oral chelator) have been demonstrated to produce additive and synergistic effects. Such an approach would enable a flexible schedule and improve compliance and overall quality of life.
    • Patients receiving chelation therapy have been demonstrated to have some degree of vitamin C deficiency. This deficiency has been attributed, in part, to increased catabolism. Administration of vitamin C increases the urinary excretion of iron and raises both serum iron and ferritin levels; this is probably related to the fact that vitamin C slows down the conversion of ferritin to hemosiderin, leading to the availability of more chelatable iron. Conversely, vitamin C enhances iron-mediated peroxidation of membrane lipids, leading to significant toxicity, mostly cardiac dysfunction in patients who are receiving large doses of vitamin C supplementation in addition to chelation therapy. For this reason, only small doses should be administered to enhance chelation (3 mg/kg/d at the start of infusion of the chelator). Large doses should be avoided.
  • Vitamin E deficiency: Vitamin E deficiency has been reported in patients with severe thalassemia. Some of the hemolysis in this population was attributed to peroxidation of the RBC membrane lipids by an iron-mediated free radical effect. As an antioxidant, vitamin E is expected to decrease cell toxicity.
  • Folic acid deficiency: This deficiency is a common complication in patients with thalassemia, mainly because of the extreme demand associated with the severe expansion of the marrow. Other causes, such as poor absorption and intake, can also contribute to folate deficiency. For this reason, folic acid (1 mg/d) has been recommended as a supplement for this patient population.
  • Hematopoietic stem cell transplantation
    • HSCT is recommended only for selected patients; it is the only known curative treatment for thalassemia. Poor outcome after HSCT correlates with the presence of hepatomegaly and portal fibrosis and with ineffective chelation prior to transplant. The event-free survival rate for patients who have all 3 features is 59%, compared to 90% for those who lack all 3.
    • Even though blood transfusion is not required after a successful transplant, certain individuals need continued chelation therapy to remove excessive iron. The optimal time to start such treatment is a year after the successful HSCT.
    • Parents and caregivers of patients with severe thalassemia are frequently confronted with a choice between standard therapy and HSCT. The 15-year cardiac disease-free survival rate for patients receiving standard therapy exceeds 90% and is similar for those without risk factors who have undergone HSCT.
    • Long-term outcome for transplant patients, including fertility, is not known. The cost of long-term standard therapy is known to be higher than the cost of transplant. The possibility of developing cancer after HSCT should also be considered. In many centers, the donor has to be a matched sibling with or without a thalassemia trait.
  • Investigational agents known to increase Hb F level: This therapeutic strategy is investigational at this time. Several agents administered to raise the Hb F level have been investigated in patients with severe thalassemia. Unfortunately, the initial results of these studies are not promising.
  • Gene therapy: This therapy is an attractive therapeutic modality, the efficacy of which remains to be demonstrated.

Surgical Care

Splenectomy is the principal surgical procedure used for many patients with thalassemia. The spleen is known to contain a large amount of the labile nontoxic iron (ie, storage function) derived from sequestration of the released iron. The spleen also increases RBC destruction and iron distribution (ie, scavenger function). These facts should always be considered before the decision is made to proceed with splenectomy. In addition, with recent reports of venous thromboembolic events (VTEs) after splenectomy, one should carefully consider the benefits and the risks before splenectomy is advocated. The spleen acts as a store for nontoxic iron, thereby protecting the rest of the body from this iron. Early removal of the spleen may be harmful (liver cirrhosis has occurred in such individuals).

Conversely, splenectomy is justified when the spleen becomes hyperactive, leading to excessive destruction of RBCs and thus increasing the need for frequent blood transfusions, resulting in more iron accumulation. Furthermore, if the labile iron pool in the spleen becomes the target for the action of the DFO (ie, removing the nonharmful pool and leaving the toxic one), splenectomy is further justified. The goal in this confusing dilemma should always be to achieve a negative iron balance, which, in many patients, has been possible by continuous administration of subcutaneous DFO.

  • Several criteria are used to aid in the decision for splenectomy; a practical one suggests that splenectomy may be beneficial in patients who require more than 200-250 mL/kg of PRBC per year to maintain an Hb level of 10 g/dL.
  • The risks associated with splenectomy are minimal, and many of the procedures are now performed by laparoscopy. Postsplenectomy risk of infections with encapsulated organisms and malaria in endemic areas is always a concern. The problem is minimal at the present time, since presplenectomy immunizations and postsurgical prophylactic antibiotics have significantly decreased the rates of such complications. Traditionally, the procedure is delayed whenever possible until the child is aged 4-5 years or older. Aggressive treatment with antibiotics should always be administered for any febrile illness while awaiting the results of cultures. Low-dose daily aspirin is also beneficial when the platelet count rises to more than 600,000/µL postsplenectomy.
  • Another surgical procedure in patients with severe thalassemia on transfusion therapy is the placement of a central line for the ease and convenience of administering blood transfusions, chelation therapy, or both.

Consultations

  • Pediatric surgeon
  • Pediatric endocrinologist
  • Pediatric ophthalmologist
  • Pediatric otolaryngologist
  • Pediatric gastroenterologist
  • Pediatric HSCT specialist

Diet

  • A normal diet is recommended, with emphasis on the following supplements: folic acid, small doses of ascorbic acid (vitamin C), and alpha-tocopherol (vitamin E).
  • Iron should not be given, and foods rich in iron should be avoided. Drinking coffee or tea has been shown to help decrease absorption of iron in the gut.

Activity

  • Patients with well-controlled disease are usually fully active.
  • Patients with anemia, heart failure, or massive hepatosplenomegaly are usually restricted according to their tolerances.

Medication

Medications needed for the treatment of various types of thalassemias are nonspecific and only supportive. A list of such medications is provided in this article.

Antipyretics, analgesics

Administration before blood transfusion prevents or decreases febrile reactions.


Acetaminophen (Tylenol, Tempra, Panadol)

Antipyretic effect through action on hypothalamic heat-regulating center. Action equal to that of aspirin but preferred because does not have adverse effects of aspirin.

Adult

325-650 mg/dose PO prior to blood transfusion

Pediatric

10-15 mg/kg/dose PO prior to blood transfusion

Rifampin decreases analgesic effect; barbiturates increase hepatic toxicity

Pregnancy

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

Precautions

Large doses in patients who abuse alcohol may result in hepatic toxicity; some preparations contain 7-10% alcohol

Antihistamines

Administration prior to blood transfusion may decrease or prevent allergic reactions.


Diphenhydramine hydrochloride (Benadryl)

Antihistamine with anticholinergic and sedative effects.

Adult

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

Pediatric

1 mg/kg/dose PO/IV or 5 mg/kg/d PO/IV divided q6h

Potentiates effects of CNS depressants and MAOIs

Documented hypersensitivity; newborn and premature infants; breastfeeding mothers; acute attacks of asthma; glaucoma; stenotic peptic ulcer (because of atropinelike effect)

Pregnancy

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

Precautions

Causes drowsiness; should not be used when situation requires state of alertness; dryness in mouth; urticaria; chills; hypotension

Chelating agents

These agents are used to chelate excessive iron from the body in patients with iron overload.


Deferoxamine mesylate (Desferal)

Chelates iron from ferritin or hemosiderin but not from transferrin, cytochrome, or Hb.

Adult

20-40 mg/kg/d SC infusions through infusion pump over 8-12 h
After blood transfusion: 1-2 g IV at slow rate of 15 mg/kg/h

Pediatric

Administer as in adults

May cause loss of consciousness when administered with prochlorperazine

Documented hypersensitivity; renal failure; anuria; hemochromatosis; children <5 y with very little iron deposition

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

Rapid IV infusion may cause hypotension, urticaria, and flushing; hearing and visual disturbances; infection with Y enterocolitica; reddish discoloration of urine; GI adverse effects include abdominal discomfort, nausea, vomiting, and diarrhea, which may add to the symptoms of acute iron toxicity; flushing and fever are reported


Deferasirox (Exjade)

Tab for PO susp. PO 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 patient weighing 40 kg] and serum ferritin level consistently >1000 mcg/L).

Adult

Initial: 20 mg/kg PO qd on empty stomach 30 min ac; calculate dose to nearest whole tablet
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

Data limited; do not take with aluminum-containing antacids

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

Corticosteroids

Some patients may develop local reaction at the site of DFO injection. Hydrocortisone in the DFO solution may help to reduce the reaction.


Hydrocortisone (Solu-Cortef, Cortef, Hydrocortone)

Anti-inflammatory action. Both Na succinate (Solu-Cortef) and Na phosphate (Cortef) forms used for IV infusion, but not Na acetate form (Hydrocortone).

Adult

10-20 mg IV/SC added to chelating solution

Pediatric

Administer as in adults

Decreases hypoglycemic effect of insulin; phenobarbital, phenytoin, and rifampin increase rate of metabolism

Although corticosteroids have many known contraindications, in this small dose, no adverse effects are expected; however, that the corticosteroid is administered as part of a long-term almost daily treatment requires that serious consideration be given to any condition that may represent a contraindication for corticosteroids; documented hypersensitivity; systemic fungal infection; tuberculosis; peptic ulcer; because of its benzyl alcohol content, not recommended for newborns

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

Hyperthyroidism; liver cirrhosis; ulcerative colitis; hypertension; osteoporosis; abrupt withdrawal may cause adrenal insufficiency

Antibacterial combinations

Certain antibacterial agents are known to be effective against organisms that often cause infection in patients with iron overload who also are receiving DFO therapy. Although rare in healthy patients, Y enterocolitica requires siderophores; thus, infections with this pathogen occur with relative frequency in patients with thalassemia. Appropriate therapy is a combination of trimethoprim-sulfamethoxazole (TMP/SMX) and gentamicin. Patients who require splenectomy need to receive prophylactic penicillin to prevent fulminating sepsis, especially those younger than 5 years. Many recommend that older patients receive prophylactic antibiotics for at least 3 years after splenectomy.


Trimethoprim-sulfamethoxazole (TMP/SMX, Bactrim, Septra)

In combination with gentamicin, DOC for infections by Y enterocolitica.

Adult

160 mg TMP/800 mg SMZ PO q12h for 10-14 d

Pediatric

<2 months: Contraindicated
>2 months: 8-10 mg/kg/d PO/IV divided q12h; dose usually based on TMP component

Potentiates effect of warfarin, prolonging PT; may cause thrombocytopenia when given in combination with thiazides; increases concentration of methotrexate; potentiates effect of phenytoin

Documented hypersensitivity; infants <2 mo; G-6-PD deficiency; megaloblastic anemia; porphyria

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

Discontinue at first appearance of skin rash or sign of adverse reaction; obtain CBCs 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 leucovorin 5-15 mg/d PO); caution in folate deficiency (eg, those with chronic alcoholism, elderly patients, 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 TMP-SMZ; caution in renal or hepatic impairment (perform urinalyses and renal function tests during therapy); administer fluids to prevent crystalluria and stone formation


Gentamicin (Garamycin)

Aminoglycoside known to be effective against gram-negative microorganisms. Dosing regimens are numerous; adjust dose based on CrCl and changes in volume of distribution.

Adult

3-6 mg/kg/d IV divided q8h

Pediatric

6-7.5 mg/kg/d IV divided q8h

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

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

Monitor drug levels closely in patients with renal impairment; narrow therapeutic index (not intended for long-term therapy); caution in renal failure (not on dialysis), myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission; adjust dose in renal impairment


Penicillin V (Pen-Vee, Veetids, V-Cillin K)

DOC for postsplenectomy prophylaxis; erythromycin used in patients allergic to penicillin. Active against most microorganisms considered to be major offenders in splenectomized patients, namely, streptococcal, pneumococcal, and some staphylococcal microorganisms, but not penicillinase-producing species.

Adult

250 mg PO bid

Pediatric

<5 years: 125 mg PO bid
>5 years: Administer as in adults

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

Pregnancy

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

Precautions

Patients with asthma may be allergic to penicillin; PO route not adequate for treatment of severe infection; when treating streptococcal infection, minimum of 10-d dose should be administered

Vitamins

Several vitamins are required, as either supplements or enhancers of the chelating agent.

Serum level of vitamin C is low in patients with thalassemia major, likely due to increased consumption in the face of iron overload.


Ascorbic acid (Vitamin C, Cebid, Vita-C, Ce-Vi-Sol, Cecon, Dull-C)

Delays conversion of transferrin to hemosiderin, thus making iron more accessible to chelation.

Adult

3 mg/kg/d PO administered with SC deferoxamine infusion

Pediatric

Administer as in adults

Decreases effects of warfarin and fluphenazine; increases aspirin levels; enhances urinary iron excretion

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Larger doses may induce cardiac toxicity in patients on chelation therapy who have iron overload; caution in patients with preexisting renal calculi


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

An antioxidant. Prevents iron-mediated toxicity caused by peroxidation of cell membrane lipids, reducing extent of accompanying hemolysis. Protects polyunsaturated fatty acids in membranes from attack by free radicals and protects RBCs against hemolysis. Demonstrated to be deficient in patients with iron overload receiving chelation therapy.

Adult

200-400 IU/d PO

Pediatric

1 IU/kg/d PO

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

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Vitamin E may induce vitamin K deficiency; necrotizing enterocolitis may occur when large doses of vitamin E are administered


Folic acid (Folvite)

Required for DNA synthesis; therefore in great demand in these patients because of increased cellular turnover. Deficient in most patients with chronic hemolysis.

Adult

0.4-1 mg/d PO

Pediatric

1 mg/d PO

Increases phenytoin metabolism; PO contraceptives impair folate metabolism, depleting levels

Pernicious anemia; aplastic anemia

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Benzyl alcohol may be contained in some IV products as a preservative (associated with a fatal gasping syndrome in premature infants); resistance to treatment may occur in deficiencies of other vitamins

Vaccines

Splenectomized patients are usually prone to developing infections with the encapsulated organisms such as pneumococci, Haemophilus influenzae, and meningococcal organisms. For this reason, such patients now are immunized against these organisms 1-2 wk prior to the procedure to prevent infections.


Pneumococcal polyvalent vaccine, 23-valent (Pneumovax)

Polyvalent polysaccharide vaccine (PS23) contains 23 serotypes that cause 70% of invasive infections. This vaccine should not be given to children <2 y. In rare cases in which splenectomy is required in children <2 y and no previous vaccination has been given, conjugate type (PCV7), which contains only 7 serotypes, is required.

Adult

0.5 mL IM/SC once

Pediatric

<2 years: Immunity may not be conferred; antibody response poor in this age group
>2 years: 0.5 mL IM/SC as single dose 1-2 wk before splenectomy; repeat dose after 5 y for high-risk children (eg, functional or anatomic asplenia, conditions associated with rapid antibody decline after initial vaccination)

Immunosuppressive agents (large amounts of corticosteroids, antimetabolites, alkylating agents, cytotoxic agents) may reduce effectiveness; therapy with immunoglobulin preparations is likely to block active immunity induced with pneumococcal vaccination (withhold for 3 mo after discontinuation of immunoglobulin therapy)

Documented hypersensitivity to any component or thimerosal; severe or even moderate febrile illness; thrombocytopenia or any coagulation disorder that contraindicates IM injection unless potential benefit clearly outweighs risk of administration

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

If administered with other vaccines required before splenectomy, administer in different syringes and at different sites; use of pneumococcal conjugate vaccine does not replace use of 23-valent pneumococcal polysaccharide vaccination in children > 2 y with sickle cell disease, asplenia, HIV infection, chronic illness, or those who are immunocompromised; caution in coagulation disorders; caution with moderate or severe illness with or without fever; may cause arthralgia, fever, urticaria, Guillain-Barré syndrome (rare)


Haemophilus b conjugate vaccine (ActHIB, HibTITER, PedvaxHIB)

Used for routine immunization of children against invasive diseases caused by H influenzae type b. Decreases nasopharyngeal colonization. The CDC's Advisory Committee on Immunization Practices (ACIP) recommends that all children receive one of the conjugate vaccines licensed for infant use beginning routinely at age 2 mo.
Conjugate form usually given in series of 3 doses at ages 2, 4, and 6 mo. Patients who have already received primary vaccine and booster dose at age 12 mo or older are usually protected and do not require further vaccination prior to splenectomy.

Adult

Not indicated

Pediatric

Regimens vary depending on product; the use of HibTITER is the example that follows:
2-6 months: 0.5 mL IM q2mo for 3 doses
7-11 months: 0.5 mL IM q2mo for 2 doses if previously unvaccinated
12-14 months: 0.5 mL IM once if previously unvaccinated
Booster dose: All children receive 0.5 mL at age 15 mo or at least 2 mo after last dose of immunization series; for children aged 15-71 mo and previously unvaccinated, 0.5 mL IM is given only once

Immunosuppressive agents (large amounts of corticosteroids, antimetabolites, alkylating agents, cytotoxic agents) may reduce effectiveness

Documented hypersensitivity; immunosuppressed children or those receiving immunosuppressive therapy; IV/ID/SC administration

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

If given with other vaccines required before splenectomy, administer in different syringes and at different sites; delay immunization upon evidence of febrile illness; may cause local erythema, swelling, or tenderness; risk of H influenzae type b infections increases the week after vaccination; cause-effect relationship with observed postvaccine Guillain-Barré syndrome has not been established; serious adverse reactions should be reported to US Department of Health and Human Services (800-822-7967)


Quadrivalent meningococcal vaccine (Menomune-A/C/Y/W-135)

Used only in children >2 y. Serogroup specific against groups A, C, Y, and W-135 Neisseria meningitidis.

Adult

Pediatric

<2 years: Contraindicated
>2 years: 0.5 mL SC; consider revaccination after 2-3 y

Adequate immunologic response may not be obtained if immunosuppressed; do not give concurrently with whole-cell pertussis or whole-cell typhoid vaccines because of combined endotoxin content

Documented hypersensitivity; children <2 y

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 headache, chills, or fever


Pneumococcal 7-valent conjugate vaccine (Prevnar)

Sterile solution of saccharides of capsular antigens of S 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 can be given to infants as young as 6 wk. Preferred sites of IM injection are anterolateral aspect of the thigh in infants or deltoid muscle of upper arm in toddlers and young children. Do not inject vaccine in gluteal area or areas that may contain a major nerve trunk or blood vessel. A 3-dose series, 0.5 mL each, is initiated in infants aged 7-11 mo (4 wk apart; third dose after first birthday).
Children aged 12-23 mo are given 2 doses (2 mo apart). Children >24 mo through 9 y are given 1 dose. Minor illnesses, such as a mild upper respiratory tract infection, with or without low-grade fever, are not generally considered contraindications.

Adult

Not indicated

Pediatric

Series initiated at age 2 months: 0.5 mL IM x 3 doses at 4-8 wk intervals, followed by a fourth dose of 0.5 mL at age 12-15 mo; administer fourth dose 2 mo or later following the third dose
Series initiated at age 7-11 months: 0.5 mL IM x 2 doses at 4 wk intervals, followed by third dose after 1-year birthday, separate second and third dose by at least 2 mo
Series initiated at age 12-23 months: 0.5 mL IM x 2 doses administered 2 mo apart
Administration of pneumococcal polysaccharide-23 (PPV-23) and pneumoccal-7 (PCV-7) vaccines should follow the schedule below for patients undergoing splenectomy at a young age.
Age 24-59 months and 4 PCV-7 doses were previously given:
PPV-23: 1 dose at 24 mo, 6-8 wk after last PCV-7; repeat 3-5 y later
Age 24-59 months and 1-3 PCV-7 doses were previously given:
Initiated at age 2-9 years: 0.5 mL IM once
PCV-7: 1 dose
PPV-23: 1 dose 6-8 wk after PCV-7; repeat 3-5 y later
Age 24-59 months and 1 PPV-23 was previously given:
PCV-7: 2 doses given 6-8 w apart
PPV-23: Repeat 3-5 y later
Age 24-59 months and no PPV-23 or PCV-7 previously given:
PCV-7: 2 doses given 6-8 w apart
PPV-23: 1 dose 6-8 wk after PCV-7; repeat 3-5 y later

Effects may decrease with immunosuppressive agents (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 PPV-23 and reduce efficacy (do not administer within 6-8 wk of vaccine)

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

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 PPV-23 in children >24 mo with sickle cell disease, asplenia, HIV infection, chronic illness, or those who are immunocompromised; caution in patients with coagulation disorders

Antineoplastic agent

Some patients may respond to hydroxyurea and subsequently decrease or eliminate transfusion requirements. Patients with homozygous or heterozygous XmnI polymorphism were found to respond favorably in one study.10 Improvement of pulmonary hypertension following hydroxyurea has also been observed.11


Hydroxyurea (Droxia, Hydrea)

Inhibitor of deoxynucleotide synthesis.

Adult

15 mg/kg/d PO (range 10-20 mg/kg/d) initially; may increase by increments of 5 mg//kg/d q12wk; not to exceed 35 mg/kg/d

Pediatric

Administer as in adults

Coadministration with fluorouracil or cytarabine can increase risk for 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

Documented hypersensitivity; severe anemia or bone marrow suppression (ie, WBC counts of <2500,
platelets <100,000/mL

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)

Growth Hormone

Excessive chelation with deferoxamine may cause growth retardation. Growth hormone may be effective in increasing growth rate in all thalassemic patient particularly the ones with growth hormone deficiency.12


Somatropin (Saizen, Genotropin, Humatrope, Norditropin, Tev-Tropin)

Human growth hormone produced by recombinant DNA technology (mouse C127 cell line). Elicits anabolic and anticatabolic influence on various cells including: myocytes, hepatocytes, adipocytes, lymphocytes, and hematopoietic cells. Exerts activity on specific cell receptors including insulinlike growth factor-1 (IGF-1).

Adult


Pediatric

0.18-0.3 mg/kg/wk SC divided into 6-7 injections; not to exceed 0.7 mg/kg/wk during puberty
Depot: 1.5 mg/kg/month or 0.75 mg/kg SC q2wk

Limited data available; none reported

Documented hypersensitivity; sensitivity to benzyl alcohol; active neoplasia; acute critical illness following open heart or abdominal surgery, multiple accidental trauma, or acute respiratory failure

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

Rotate injection sites; may cause moderate fluid retention and arthralgias (treat symptomatically or reduce dose by 50%); discontinue for up to 5 d for severe toxicity (may reinitiate at 50% of original dose), discontinue permanently is toxicity not resolved with 5 d or recurs; may cause allergic reaction, acute pancreatitis, or glucose intolerance; caution with renal or hepatic impairment

More on Thalassemia

Overview: Thalassemia
Differential Diagnoses & Workup: Thalassemia
Treatment & Medication: Thalassemia
Follow-up: Thalassemia
Multimedia: Thalassemia
References
[ CLOSE WINDOW ]

References

  1. Joly P, Lacan P, Garcia C, Couprie N, Francina A. Identification and molecular characterization of four new large deletions in the beta-globin gene cluster. Blood Cells Mol Dis. Mar 6 2009;[Medline].

  2. Deborah Chirnomas S, Geukes-Foppen M, Barry K, 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].

  3. Hankins JS, McCarville MB, Loeffler RB, et al. R2* magnetic resonance imaging of the liver in patients with iron overload. Blood. Mar 4 2009;[Medline].

  4. Lucarelli G, Galimberti M, Polchi P, et al. Marrow transplantation in patients with thalassemia responsive to iron chelation therapy. N Engl J Med. Sep 16 1993;329(12):840-4. [Medline].

  5. Gharagozloo M, Bagherpour B, Tahanian M, et al. Premature senescence of T lymphocytes from patients with beta-thalassemia major. Immunol Lett. Jan 29 2009;122(1):84-8. [Medline].

  6. Ghaffari J, Vahidshahi K, Kosaryan M, Parvinnejad N, Mahdavi M, Karami H. Nitroblue tetrazolium test in patients with beta-thalassemia major. Saudi Med J. Nov 2008;29(11):1601-5. [Medline].

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

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

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

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

  11. Karimi M, Borzouee M, Mehrabani A, Cohan N. Echocardiographic finding in beta-thalassemia intermedia and major: absence of pulmonary hypertension following hydroxyurea treatment in beta-thalassemia intermedia. Eur J Haematol. Mar 2009;82(3):213-8. [Medline].

  12. Geffner ME, Karlsson H. Use of recombinant human growth hormone in children with thalassemia. Horm Res. Jan 2009;71 Suppl 1:46-50. [Medline].

  13. [Guideline] Langlois S, Ford JC, Chitayat D, et al. Carrier screening for thalassemia and hemoglobinopathies in Canada. J Obstet Gynaecol Can. Oct 2008;30(10):950-71. [Medline].

  14. Cowan RS. Moving up the slippery slope: mandated genetic screening on Cyprus. Am J Med Genet C Semin Med Genet. Feb 15 2009;151C(1):95-103. [Medline].

  15. Srivorakun H, Fucharoen G, Sae-Ung N, Sanchaisuriya K, Ratanasiri T, Fucharoen S. Analysis of fetal blood using capillary electrophoresis system: a simple method for prenatal diagnosis of severe thalassemia diseases. Eur J Haematol. Feb 17 2009;[Medline].

  16. Winichagoon P, Svasti S, Munkongdee T, et al. Rapid diagnosis of thalassemias and other hemoglobinopathies by capillary electrophoresis system. Transl Res. Oct 2008;152(4):178-184. [Medline].

  17. Barnett CF, Hsue PY, Machado RF. Pulmonary hypertension: an increasingly recognized complication of hereditary hemolytic anemias and HIV infection. JAMA. Jan 23 2008;299(3):324-31. [Medline].

  18. 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].

  19. El-Beshlawy A, Youssry I, El-Saidi S, et al. Pulmonary hypertension in beta-thalassemia major and the role of L-carnitine therapy. Pediatr Hematol Oncol. Dec 2008;25(8):734-43. [Medline].

  20. 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].

  21. 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].

  22. 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].

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

  24. Fung EB, Harmatz PR, Lee PD, et al. Increased prevalence of iron-overload associated endocrinopathy in thalassaemia versus sickle-cell disease. Br J Haematol. Nov 2006;135(4):574-82. [Medline].

  25. De Sanctis V, Borsari G, Brachi S, Govoni M, Carandina G. Spermatogenesis in young adult patients with beta-thalassaemia major long-term treated with desferrioxamine. Georgian Med News. Mar 2008;74-7. [Medline].

  26. Atichartakarn V, Angchaisuksiri P, Aryurachai K, et al. 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].

  27. Beutler E, Hoffbrand AV, Cook JD. Iron deficiency and overload. Hematology (Am Soc Hematol Educ Program). 2003;40-61. [Medline].

  28. Borgna-Pignatti C, Vergine G, Lombardo T, et al. Hepatocellular carcinoma in the thalassaemia syndromes. Br J Haematol. Jan 2004;124(1):114-7. [Medline].

  29. Cao A, Rosatelli C, Galanello R, et al. The prevention of thalassemia in Sardinia. Clin Genet. Nov 1989;36(5):277-85. [Medline].

  30. Cappellini MD, Cohen A, Piga A, et al. A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia. Blood. May 1 2006;107(9):3455-62. [Medline].

  31. Cario H, Janka-Schaub G, Janssen G, et al. Recent developments in iron chelation therapy. Klin Padiatr. May-Jun 2007;219(3):158-65. [Medline].

  32. Centis F, Tabellini L, Lucarelli G, et al. The importance of erythroid expansion in determining the extent of apoptosis in erythroid precursors in patients with beta-thalassemia major. Blood. Nov 15 2000;96(10):3624-9. [Medline].

  33. Chakravarti A, Verma V, Kumaria R, Dubey AP. Anti HCV seropositivity among multi transfused patients with beta-thalassemia. J indian Med Assoc. 2005;103(2):64-66. [Medline].

  34. Christoforidis A, Haritandi A, Tsatra I, et al. Four-year evaluation of myocardial and liver iron assessed prospectively with serial MRI scans in young patients with beta-thalassaemia major: comparison between different chelation regimens. Eur J Haematol. Jan 2007;78(1):52-7. [Medline].

  35. 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].

  36. De Virgiliis S, Cossu P, Toccafondi C, et al. Effect of subcutaneous desferrioxamine on iron balance in young thalassemia major patients. Am J Pediatr Hematol Oncol. Spring 1983;5(1):73-7. [Medline].

  37. dos Santos CO, Costa FF. AHSP and beta-thalassemia: a possible genetic modifier. Hematology. 2005;10(2):57-61. [Medline].

  38. Fucharoen S, Ketvichit P, Pootrakul P, et al. Clinical manifestation of beta-thalassemia/hemoglobin E disease. J Pediatr Hematol Oncol. Nov-Dec 2000;22(6):552-7. [Medline].

  39. 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].

  40. Gilman JG, Huisman TH, Abels J. Dutch beta 0-thalassaemia: a 10 kilobase DNA deletion associated with significant gamma-chain production. Br J Haematol. Feb 1984;56(2):339-48. [Medline].

  41. Haldane JBS. The rate of mutation of human genes. In: Proceedings of the VIII International Congress on Genetics and Heredity. 1949;267.

  42. Hershko C, Weatherall DJ. Iron-chelating therapy. Crit Rev Clin Lab Sci. 1988;26(4):303-45. [Medline].

  43. Kazazian HH Jr. The thalassemia syndromes: molecular basis and prenatal diagnosis in 1990. Semin Hematol. Jul 1990;27(3):209-28. [Medline].

  44. Kazazian HH Jr, Boehm CD. Molecular basis and prenatal diagnosis of beta-thalassemia. Blood. Oct 1988;72(4):1107-16. [Medline].

  45. Kontoghiorghes GJ. Deferasirox: uncertain future following renal failure fatalities, agranulocytosis and other toxicities. Expert Opin Drug Saf. May 2007;6(3):235-9. [Medline].

  46. Lilleyman JS, Hann IM, Blanchette V. The thalassemia. Pediatr Hematol. 2000;307-327.

  47. Lorey F. Asian immigration and public health in California: thalassemia in newborns in California. J Pediatr Hematol Oncol. Nov-Dec 2000;22(6):564-6. [Medline].

  48. Mentzer WC Jr. Differentiation of iron deficiency from thalassaemia trait. Lancet. Apr 21 1973;1(7808):882. [Medline].

  49. Nagel RL, Roth EF Jr. Malaria and RBC genetic defects. Blood. Sep 1989;74(4):1213-21. [Medline].

  50. Nathan DG, Gunn RB. Thalassemia: the consequences of unbalanced hemoglobin synthesis. Am J Med. Nov 1966;41(5):815-30. [Medline].

  51. Nathan DG, Oski FA. The thalassemia. In: Hematology of Infancy and Childhood. Vol 1. Philadelphia, Pa: WB Saunders Co;1998:783-879, 811-886.

  52. 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].

  53. Olivieri NF, Brittenham GM, Matsui D, et al. Iron-chelation therapy with oral deferipronein patients with thalassemia major. N Engl J Med. Apr 6 1995;332(14):918-22. [Medline].

  54. 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].

  55. Orkin SH, Kazazian HH Jr. The mutation and polymorphism of the human beta-globin gene and its surrounding DNA. Annu Rev Genet. 1984;18:131-71. [Medline].

  56. Pakbaz Z, Fischer R, Fung E, et al. Serum ferritin underestimates liver iron concentration in transfusion independent thalassemia patients as compared to regularly transfused thalassemia and sickle cell patients. Pediatr Blood Cancer. Sep 2007;49(3):329-32. [Medline].

  57. Pakpaz FR, Fung E, Harmatz P. Serum ferritin underestimates the liver iron concentration. Pediatric Blood and Cancer. 2004;42:497.

  58. Pan LL, Eng HL, Kuo CY, et al. Usefulness of brilliant cresyl blue staining as an auxiliary method of screening for alpha-thalassemia. J Lab Clin Med. Feb 2005;145(2):94-7. [Medline].

  59. Peters TJ, Raja KB, Simpson RJ, Snape S. Mechanisms and regulation of intestinal iron absorption. Ann N Y Acad Sci. 1988;526:141-7. [Medline].

  60. Piomelli S, Danoff SJ, Becker MH, et al. Prevention of bone malformations and cardiomegaly in Cooley''s anemia by early hypertransfusion regimen. Ann N Y Acad Sci. Nov 20 1969;165(1):427-36. [Medline].

  61. Pippard MJ, Callender ST, Weatherall DJ. Intensive iron-chelation therapy with desferrioxamine in iron-loading anaemias. Clin Sci Mol Med. Jan 1978;54(1):99-106. [Medline].

  62. Premawardhena A, Fisher CA, Fathiu F, et al. Genetic determinants of jaundice and gallstones in haemoglobin E beta thalassaemia. Lancet. Jun 16 2001;357(9272):1945-6. [Medline].

  63. Reich S, Buhrer C, Henze G, et al. Oral isobutyramide reduces transfusion requirements in some patients with homozygous beta-thalassemia. Blood. Nov 15 2000;96(10):3357-63. [Medline].

  64. Ross J, Pizarro A. Human beta and delta globin messenger RNAs turn over at different rates. J Mol Biol. Jul 5 1983;167(3):607-17. [Medline].

  65. Roy CN, Enns CA. Iron homeostasis: new tales from the crypt. Blood. Dec 15 2000;96(13):4020-7. [Medline].

  66. Singer ST, Wu V, Mignacca R, et al. Alloimmunization and erythrocyte autoimmunization in transfusion- dependent thalassemia patients of predominantly asian descent. Blood. Nov 15 2000;96(10):3369-73. [Medline].

  67. Tanner MA, Galanello R, Dessi C, et al. A randomized, placebo-controlled, double-blind trial of the effect of combined therapy with deferoxamine and deferiprone on myocardial iron in thalassemia major using cardiovascular magnetic resonance. Circulation. Apr 10 2007;115(14):1876-84. [Medline].

  68. Thein SL. Dominant beta thalassaemia: molecular basis and pathophysiology. Br J Haematol. 1992;80(3):273-7. [Medline].

  69. Vichinsky EP. Reports of proceedings: 1999 international conference on E-Beta thalassemia. J Pediatr Hematol Oncol. 2000;22:6:550.

  70. Voskaridou E, Terpos E, Spina G, et al. Pamidronate is an effective treatment for osteoporosis in patients with beta-thalassaemia. Br J Haematol. Nov 2003;123(4):730-7. [Medline].

  71. Weatherall DJ. Thalassemia. In: Stamatoyannopoulos G et al, eds. The Molecular Basis of Blood Diseases. 1944:157-206.

  72. Weatherall DJ. Thalassemia. In: The Thalassemia Syndromes. 1981.

  73. Wintrobe MM, Mathews E. Familial hematopoietic disorder in Italian adolescents and adults resembling Mediterranean disease (thalassemia). JAMA. 1940;114:1530-4.

[ CLOSE WINDOW ]

Further Reading

[ CLOSE WINDOW ]

Keywords

Mediterranean anemia, Cooley anemia, anemia, erythroblastemia, hypochromic anemia, microcytic anemia, α thalassemia, alpha thalassemia, β thalassemia, beta thalassemia, thalassemia syndromes, Hb synthesis, thalassemic hemoglobinopathy, β thalassemia major, beta thalassemia major, globin chain, Hb production, hemoglobin synthesis, hypochromasia, thalassemia minor, β+ thalassemia, beta+ thalassemia, β-0 thalassemia, beta-0 thalassemia, hypochromasia, Hb A2, Hb F, RNA-splicing mutations, Hb Malay, Hb E, Hb Knossos, Hb Lepore, red blood cell precursors, bone expansion, iron absorption

transferrin, malaria, Heinz bodies, hydrops fetalis, silent carrier β thalassemia, silent carrier beta thalassemia, cis deletion, reticulocyte, splenomegaly, frontal bossing, dental malocclusion, iron deficiency anemia, fetal Hb, HPFH, chipmunk facies, chelation, extramedullary hematopoiesis, left ventricular wall thickening, hematopoietic stem cell transplantation, HSCT, hepatitis, deferoxamine, DFO, ferritin, deferiprone, DFP, L1, vitamin C deficiency, hepatomegaly, portal fibrosis, labile iron pool, splenectomy, chorionic villus sampling, CVS, Hb H disease, Hb Constant Spring, Hb CS

[ CLOSE WINDOW ]

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

Max J Coppes, MD, PhD, MBA, Senior Vice President, Children's National Medical Center (Center for Cancer and Blood Disorders); Director, Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center; Professor of Medicine, Oncology, and Pediatrics, Georgetown University
Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American Association for Cancer Research, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

 
 
HONcode

We subscribe to the
HONcode principles of the
Health On the Net Foundation

All material on this website is protected by copyright, Copyright© 1994- by Medscape.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.