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Thalassemia Intermedia Medication

  • Author: Hassan M Yaish, MD; Chief Editor: Robert J Arceci, MD, PhD  more...
 
Updated: Oct 01, 2015
 

Medication Summary

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 [PO] or parenterally [eg, intravenously, IV; subcutaneously, SC]). The drugs of choice in current practice are the oral agents deferasirox and deferoxamine administered subcutaneously by infusion pump 5 times per week. Chelation therapy 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 Yersinia 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 authors have also recommended a daily low dose of aspirin as prophylactic treatment to prevent thrombotic events in patients with thalassemia intermedia who underwent a splenectomy.

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Analgesics, Other

Class Summary

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

Acetaminophen (Feverall, Tylenol, Mapap, Acephen)

 

Acetaminophen has an antipyretic effect through action on the hypothalamic heat-regulating center. Although this drug is equal to aspirin in action, acetaminophen is preferred, because it has fewer adverse effects.

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Antihistamines, 1st Generation

Class Summary

Antihistamine agents prevent or ameliorate allergic reactions that are associated with the transfusion of blood products.

Diphenhydramine hydrochloride (Benadryl, Diphenhist, Aler-Cap)

 

Diphenhydramine elicits anticholinergic and sedative effects.

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Chelators

Class Summary

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)

 

Deferoxamine chelates iron from ferritin and hemosiderin but not from transferrin, cytochrome, or hemoglobin (Hb). This agent helps prevent damage to the liver and bone marrow from iron deposition.

Deferasirox (Exjade)

 

Deferasirox is available as a tablet for oral suspension. It is an oral iron-chelating agent that reduces liver iron concentration and serum ferritin levels. Deferasirox binds iron with high affinity in a 2:1 ratio. It is approved for treatment of treat chronic iron overload due to multiple blood transfusions and nontransfusion-dependent thalassemia.

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Antibiotics, Other

Class Summary

Antimicrobial 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, Bactrim DS, Septra DS)

 

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

Gentamicin

 

Gentamicin is an aminoglycoside. This agent is effective against gram-negative aerobic microorganisms.

Penicillin V

 

Penicillin V is the drug of choice (DOC) for prophylaxis in patients with thalassemia who have undergone a splenectomy (erythromycin is used in patients allergic to penicillin). This agent is active against most microorganisms that are considered to be major pathogens in splenectomized patients (ie, streptococcal, pneumococcal, and some staphylococcal microorganisms) but not penicillinase-producing species. Prophylaxis with penicillin V is provided for more than 3 years after splenectomy.

Erythromycin (E.E.S., Ery-Tab, Erythrocin)

 

Erythromycin inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. It is used for the treatment of staphylococcal and streptococcal infections.

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Vitamins, Water-Soluble

Class Summary

Vitamins are compounds that are present in small amounts in food, and they 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, vitamin C allows more iron to be removed.

Folic acid (Folvite)

 

Folic acid is 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, thereby increasing the severity of the original disease process.

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Vitamins, Fat-Soluble

Class Summary

The antioxidant effects of vitamin E have been shown to help in decreasing iron-mediated toxic effects on cells by preventing or decreasing membrane-lipid peroxidation.

Vitamin E (Key-E, Aqua Gem-E, E-Gems, Aquasol E)

 

The mechanism of action (MOA) of vitamin E has been known for many years. In newborn or premature infants, in particular, vitamin E deficiency has resulted in peculiar red blood cell (RBC) 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.

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Corticosteroids

Class Summary

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

Hydrocortisone (Solu-Cortef, Cortef)

 

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

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Vaccines, Inactivated, Bacterial

Class Summary

Patients who have undergone a splenectomy are prone to developing infections with any of 3 common encapsulated organisms (ie, Pneumococcus species [spp], H influenzae, and Meningococcus spp). 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 polyvalent (Pneumovax-23)

 

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

Haemophilus influenza type b vaccine (ActHIB, PedvaxHIB)

 

Haemophilus influenzae type b vaccine is recommended 2 weeks before splenectomy. Patients who have already received their primary vaccination early in life and also received a booster at 12 months or later are usually protected, even though they may benefit from an additional dose before the procedure. The conjugate form is administered in a series of 2-3 doses at ages 2, 4, and 6 months.

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

 

Meningococcal vaccine is similar to polyvalent pneumococcal vaccine. This vaccine is used in children older than 2 years who are at risk (eg, complement deficiency, asplenia). Meningococcal vaccine contains a serogroup specific against groups A, C, Y, and W-135 N meningitides.

Pneumococcal 7-valent conjugate vaccine (Prevnar)

 

Pneumococcal 7-valent conjugate vaccine is a 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 over 80% of invasive pneumococcal disease in children younger than 6 years in the United States; they also accounted for 74% of penicillin-nonsusceptible S pneumoniae (PNSP) and 100% of pneumococci with high-level penicillin resistance. The customary age for the first dose of pneumococcal 7-valent conjugate vaccine is 2 months, but it can be administered to infants as young as 6 weeks.

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Erythropoiesis

Class Summary

Hydroxyurea was found to induce erythropoiesis and raise hemoglobin (Hb) levels.[30]

Hydroxyurea (Hydrea, Droxia)

 

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

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Contributor Information and Disclosures
Author

Hassan M Yaish, MD Medical Director, Intermountain Hemophilia and Thrombophilia Treatment Center; Professor of Pediatrics, University of Utah School of Medicine; Director of Hematology, 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, New York Academy of Sciences, American Medical Association, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Michigan State Medical Society

Disclosure: Nothing to disclose.

Chief Editor

Robert J Arceci, MD, PhD Director, Children’s Center for Cancer and Blood Disorders, Department of Hematology/Oncology, Co-Director of the Ron Matricaria Institute of Molecular Medicine, Phoenix Children’s Hospital; Editor-in-Chief, Pediatric Blood and Cancer; Professor, Department of Child Health, University of Arizona College of Medicine

Robert J Arceci, MD, PhD is a member of the following medical societies: American Association for the Advancement of Science, American Association for Cancer Research, American Pediatric Society, American Society of Hematology, American Society of Pediatric Hematology/Oncology

Disclosure: Nothing to disclose.

Acknowledgements

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.

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 Academy of Pediatrics and American Society of Pediatric Hematology/Oncology

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Pharmacy Editor, eMedicine

Disclosure: Nothing to disclose.

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. 2008 Jan. 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. 2008 May-Jun. 40(3):312-6. [Medline].

  4. 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. 2007 Jun 1. 109(11):5027-35. [Medline].

  5. 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. 2006 Oct. 135(1):129-38. [Medline].

  6. 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. 2009 Mar. 144(5):789-93. [Medline].

  7. Musallam KM, Taher AT, Duca L, Cesaretti C, Halawi R, Cappellini MD. Levels of growth differentiation factor-15 are high and correlate with clinical severity in transfusion-independent patients with ß thalassemia intermedia. Blood Cells Mol Dis. 2011 Dec 15. 47(4):232-4. [Medline].

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

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

  10. Preza GC, Ruchala P, Pinon R, et al. Minihepcidins are rationally designed small peptides that mimic hepcidin activity in mice and may be useful for the treatment of iron overload. J Clin Invest. 2011 Dec 1. 121(12):4880-8. [Medline]. [Full Text].

  11. Uzun E, Balcı YI, Yuksel S, Aral YZ, Aybek H, Akdag B. Glomerular and tubular functions in children with different forms of beta thalassemia. Ren Fail. 2015 Sep 12. 1-5. [Medline].

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

  13. Succar J, Musallam KM, Taher AT. Thalassemia and venous thromboembolism. Mediterr J Hematol Infect Dis. 2011. 3(1):e2011025. [Medline]. [Full Text].

  14. 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].

  15. 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].

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

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

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

  19. 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. 2008 Jun. 91(6):889-94. [Medline].

  20. 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. 2008 Jul. 142(1):126-35. [Medline].

  21. 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. 2008 Nov. 100(5):864-70. [Medline].

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

  23. Memish ZA, Saeedi MY. Six-year outcome of the national premarital screening and genetic counseling program for sickle cell disease and ß-thalassemia in Saudi Arabia. Ann Saudi Med. 2011 May-Jun. 31(3):229-35. [Medline]. [Full Text].

  24. Badens C, Joly P, Agouti I, et al. Variants in genetic modifiers of ß-thalassemia can help to predict the major or intermedia type of the disease. Haematologica. 2011 Nov. 96(11):1712-4. [Medline]. [Full Text].

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

  26. Wood JC, Mo A, Gera A, Koh M, Coates T, Gilsanz V. Quantitative computed tomography assessment of transfusional iron overload. Br J Haematol. 2011 Jun. 153(6):780-5. [Medline].

  27. 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. 2008 Oct. 83(10):781-3. [Medline].

  28. Pennell DJ, Carpenter JP, Roughton M, Cabantchik Z. On improvement in ejection fraction with iron chelation in thalassemia major and the risk of future heart failure. J Cardiovasc Magn Reson. 2011 Sep 12. 13:45. [Medline]. [Full Text].

  29. 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. 2005 Jul. 27(7):380-5. [Medline].

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

  31. Meiler SE, Wade M, Kutlar F, et al. Pomalidomide augments fetal hemoglobin production without the myelosuppressive effects of hydroxyurea in transgenic sickle cell mice. Blood. 2011 Jul 28. 118(4):1109-12. [Medline]. [Full Text].

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

  33. Cappellini MD, Bejaoui M, Agaoglu L, et al. Iron chelation with deferasirox in adult and pediatric patients with thalassemia major: efficacy and safety during 5 years' follow-up. Blood. 2011 Jul 28. 118(4):884-93. [Medline].

  34. Taher AT, Porter J, Viprakasit V, Kattamis A, Chuncharunee S, Sutcharitchan P, et al. Deferasirox reduces iron overload significantly in nontransfusion-dependent thalassemia: 1-year results from a prospective, randomized, double-blind, placebo-controlled study. Blood. 2012 Aug 2. 120(5):970-7. [Medline].

  35. Taher AT, Porter JB, Viprakasit V et al. Deferasirox continues to reduce iron overload in non-transfusion-dependent thalassemia: a one-year, open-label extension to a one-year, randomized double-blind, placebo-controlled study (THALASSA). Poster presented at the 54th American Society of Hematology Annual Meeting and Exposition in Atlanta, GA (8-11 December 2012). Abstract #3258.

  36. 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. 2003 Apr. 77(3):299-303. [Medline].

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

  38. 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].

  39. Graziadei G, Refaldi C, Barcellini W, et al. Does absolute excess of alpha chains compromise the benefit of splenectomy in patients with thalassemia intermedia?. Haematologica. 2012 Jan. 97(1):151-3. [Medline]. [Full Text].

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

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

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

  43. Lai ME, Vacquer S, Carta MP, et al. Thalassemia intermedia is associated with a proatherogenic biochemical phenotype. Blood Cells Mol Dis. 2011 Apr 15. 46(4):294-9. [Medline].

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

  45. The thalassemia syndromes. Nathan DG, Oski FA, eds. Nathan and Oski's Hematology of Infancy and Childhood. 5th ed. Philadelphia, Pa: WB Saunders Co; 1997. Vol 1: 847-9.

  46. The thalassemias. Lilleyman JS, Hann IM, Blanchette V, eds. Pediatric Hematology. 2nd ed. 2000. 316, 325.

  47. Weatherall DJ. Thalassemia. Stamatoyannopoulos G, Nienhuis AW, Majerus PW, Varmus H, eds. The Molecular Basis of Blood Diseases. 2nd ed. Philadelphia, Pa: WB Saunders Co; 1994. 157-206.

  48. Weatherall DJ, Clegg JB. The Thalassemia Syndromes. 3rd ed. Oxford, England: Blackwell Science Publishing Co; 1981.

 
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Peripheral blood film in thalassemia intermedia.
Basophilic stippling in thalassemia intermedia.
Nucleated red blood cell in thalassemia intermedia.
 
 
 
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