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Thalassemia (British English: thalassaemia) is a group of inherited autosomal recessive blood disorders that originated in the Mediterranean region. In thalassemia the genetic defect, which could be either mutation or deletion, results in reduced rate of synthesis or no synthesis of one of the globin chains that make up hemoglobin. This can cause the formation of abnormal hemoglobin molecules, thus causing anemia, the characteristic presenting symptom of the thalassemias. Thalassemia is a quantitative problem of too few globins synthesized, whereas sickle-cell disease (a hemoglobinopathy) is a qualitative problem of synthesis of an incorrectly functioning globin. Thalassemias usually result in underproduction of normal globin proteins, often through mutations in regulatory genes. Hemoglobinopathies imply structural abnormalities in the globin proteins themselves.[1] The two conditions may overlap, however, since some conditions that cause abnormalities in globin proteins (hemoglobinopathy) also affect their production (thalassemia). Thus, some thalassemias are hemoglobinopathies, but most are not. Either or both of these conditions may cause anemia. The two major forms of the disease, alpha- and beta- (see below), are prevalent in discrete geographical clusters around the world - it is presumed associated with malarial endemicity in ancient times. Alpha is prevalent in peoples of Western African and South Asian descent. It is nowadays found in populations living in Africa and in the Americas. It is also found in Tharu in the Terai region of Nepal and India.[2] It is believed to account for much lower malaria morbidity and mortality,[3] accounting for the historic ability of Tharus to survive in heavily malarial areas where others could not. Beta thalassemia is particularly prevalent among Mediterranean peoples, and this geographical association is responsible for its naming: Thalassa () is Greek for the sea, Haema () is Greek for blood. In Europe, the highest concentrations of the disease are found in Greece, coastal regions in Turkey, in particular, Aegean Region such as Izmir, Balikesir, Aydin, Mugla, and Mediterranean Region such as Antalya, Adana, Mersin, in parts of Italy, in particular, Southern Italy and the lower Po valley. The major Mediterranean islands (except the Balearics) such as Sicily, Sardinia, Malta, Corsica, Cyprus, and Crete are heavily affected in particular. Other Mediterranean people, as well as those in the vicinity of

the Mediterranean, also have high rates of thalassemia, including people from West Asia and North Africa. Far from the Mediterranean, South Asians are also affected, with the world's highest concentration of carriers (16% of the population) being in the Maldives. The thalassemia trait may confer a degree of protection against malaria, which is or was prevalent in the regions where the trait is common, thus conferring a selective survival advantage on carriers (known as heterozygous advantage), and perpetuating the mutation. In that respect, the various thalassemias resemble another genetic disorder affecting hemoglobin, sickle-cell disease.[4] [5] Contents

1 Etymology 2 Epidemiology 3 Pathophysiology o 3.1 Alpha () thalassemias o 3.2 Beta () thalassemias o 3.3 Delta () thalassemia o 3.4 In combination with other hemoglobinopathies 4 Cause 5 Treatment o 5.1 Medical care o 5.2 Medication o 5.3 Carrier detection 6 Cure o 6.1 Bone Marrow Transplant (BMT) from compatible donor o 6.2 Bone Marrow Transplant (BMT) from haploidentical mother to child 7 Benefits 8 Complications 9 References 10 External links

Etymology From the Greek thalassa ("sea") and -emia ("blood"). The etymology indicates the epidemiology of the disorder in that it commonly occurs in patients of Mediterranean descent. The term was first used in 1932. Epidemiology Generally, thalassemias are prevalent in populations that evolved in humid climates where malaria was endemic. It affects all races, as thalassemias protected these people from malaria due to the blood cells' easy degradation. Thalassemias are particularly associated with people of Mediterranean origin, Arabs (especially Palestinians and people of Palestinian descent), and Asians.[6] The Maldives has the highest incidence of Thalassemia in the world with a carrier rate of 18% of the population. The estimated prevalence is 16% in people from Cyprus, 1%[7] in Thailand, and 3-8% in populations from Bangladesh, China, India, Malaysia and Pakistan. Thalassemias also occur

in descendants of people from Latin America and Mediterranean countries (e.g. Greece, Italy, Portugal, Spain, and others). Pathophysiology Normal hemoglobin is composed of four protein chains, two and two globin chains arranged into a heterotetramer. Thalassemia patients produce a deficiency of either or globin, unlike sickle-cell disease, which produces a specific mutant form of globin. The thalassemias are classified according to which chain of the hemoglobin molecule is affected. In thalassemias, production of the globin chain is affected, while in thalassemia production of the globin chain is affected. The globin chains are encoded by a single gene on chromosome 11; globin chains are encoded by two closely linked genes on chromosome 16. Thus, in a normal person with two copies of each chromosome, there are two loci encoding the chain, and four loci encoding the chain. Deletion of one of the loci has a high prevalence in people of African or Asian descent, making them more likely to develop thalassemias. Thalassemias are not only common in Africans, but also in Greeks and Italians. Alpha () thalassemias Main article: Alpha-thalassemia The thalassemias involve the genes HBA1[8] and HBA2,[9] inherited in a Mendelian recessive fashion. There are two gene loci and so four alleles. It is also connected to the deletion of the 16p chromosome. Thalassemias result in decreased alpha-globin production, therefore fewer alpha-globin chains are produced, resulting in an excess of chains in adults and excess chains in newborns. The excess chains form unstable tetramers (called Hemoglobin H or HbH of 4 beta chains), which have abnormal oxygen dissociation curves. Beta () thalassemias Main article: Beta-thalassemia Beta thalassemias are due to mutations in the HBB gene on chromosome 11,[10] also inherited in an autosomal-recessive fashion. The severity of the disease depends on the nature of the mutation. Mutations are characterized as either o or thalassemia major if they prevent any formation of chains, the most severe form of thalassemia. Also, they are characterized as + or thalassemia intermedia if they allow some chain formation to occur. In either case, there is a relative excess of chains, but these do not form tetramers: Rather, they bind to the red blood cell membranes, producing membrane damage, and at high concentrations they form toxic aggregates. Delta () thalassemia Main article: Delta-thalassemia

As well as alpha and beta chains present in hemoglobin, about 3% of adult hemoglobin is made of alpha and delta chains. Just as with beta thalassemia, mutations that affect the ability of this gene to produce delta chains can occur[citation needed]. In combination with other hemoglobinopathies Thalassemia can co-exist with other hemoglobinopathies. The most common of these are:

hemoglobin E/thalassemia: common in Cambodia, Thailand, and parts of India; clinically similar to thalassemia major or thalassemia intermedia. hemoglobin S/thalassemia, common in African and Mediterranean populations; clinically similar to sickle cell anemia, with the additional feature of splenomegaly hemoglobin C/thalassemia: common in Mediterranean and African populations, hemoglobin C/o thalassemia causes a moderately severe hemolytic anemia with splenomegaly; hemoglobin C/+ thalassemia produces a milder disease.

Cause

Thalassemia has an autosomal recessive pattern of inheritance Both and thalassemias are often inherited in an autosomal recessive fashion, although this is not always the case. Cases of dominantly inherited and thalassemias have been reported, the first of which was in an Irish family with two deletions of 4 and 11 bp in exon 3 interrupted by an insertion of 5 bp in the -globin gene. For the autosomal recessive forms of the disease, both parents must be carriers in order for a child to be affected. If both parents carry a hemoglobinopathy trait, there is a 25% risk with each pregnancy for an affected child. Genetic counseling and genetic testing is recommended for families that carry a thalassemia trait. There are an estimated 60-80 million people in the world carrying the beta thalassemia trait alone.[citation needed] This is a very rough estimate; the actual number of thalassemia major patients is unknown due to the prevalence of thalassemia in less developed countries.[citation needed] Countries such as India and Pakistan are seeing a large increase of thalassemia patients due to lack of genetic counseling and screening.[citation needed] There is growing concern that thalassemia may become a very serious problem in the next 50 years, one that will burden the

world's blood bank supplies and the health system in general.[citation needed] There are an estimated 1,000 people living with thalassemia major in the United States and an unknown number of carriers.[citation needed] Because of the prevalence of the disease in countries with little knowledge of thalassemia, access to proper treatment and diagnosis can be difficult.[citation needed] Treatment Medical care

Mild thalassemia : patients with thalassemia traits do not require medical or follow-up care after the initial diagnosis is made.[11] Patients with -thalassemia trait should be warned that their blood picture resembles iron deficiency and can be misdiagnosed. They should eschew empirical use of Iron therapy; yet iron deficiency can develop during pregnancy or from chronic bleeding.[12] 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.[13] Severe thalassemia : patients with severe thalassemia require medical treatment, and a blood transfusion regimen was the first measure effective in prolonging life.[11]

Medication Medical therapy for beta thalassemia primarily involves iron chelation. Deferoxamine is the intravenously or subcutaneously administered chelation agent currently approved for use in the United States. Deferasirox (Exjade) is an oral iron chelation drug also approved in the US in 2005. Deferiprone is an oral iron chelator that has been approved in Europe since 1999 and many other countries. It is available under compassionate use guidelines in the United States. The antioxidant indicaxanthin, found in beets, in a spectrophotometric study showed that indicaxanthin can be reduce perferryl-Hb generated in solution from met-Hb and hydrogen peroxide, more effectively than either Trolox or Vitamin C. Collectively, results demonstrate that indicaxanthin can be incorporated into the redox machinery of -thalassemic RBC and defend the cell from oxidation, possibly interfering with perferryl-Hb, a reactive intermediate in the hydroperoxide-dependent Hb degradation.[14] Carrier detection

A screening policy exists in Cyprus to reduce the incidence of thalassemia, which since the program's implementation in the 1970s (which also includes pre-natal screening and abortion) has reduced the number of children born with the hereditary blood disease from 1 out of every 158 births to almost zero.[15] In Iran as a premarital screening, the man's red cell indices are checked first, if he has microcytosis (mean cell hemoglobin < 27 pg or mean red cell volume < 80 fl), the woman is tested. When both are microcytic their hemoglobin A2 concentrations are measured. If both have a concentration above 3.5% (diagnostic of thalassemia trait) they are referred to the local designated health post for genetic counseling.[16]

In 2008, in Spain, a baby was selectively implanted in order to be a cure for his brother's thalassemia. The child was born from an embryo screened to be free of the disease before implantation with In vitro fertilization. The baby's supply of immunocompatible cord blood

was saved for transplantation to his sister. The transplantation was considered successful.[17] In 2009, a group of doctors and specialists in Chennai and Coimbatore registered the successful treatment of thalassemia in a child using a sibling's umbilical cord blood.[18] Cure Bone Marrow Transplant (BMT) from compatible donor It is possible to be cured, with no more need of blood transfusions, thanks to Bone Marrow Transplantation (BMT) from compatible donor ,invented in the 1980s by Prof. Guido Lucarelli. In low risk young patients,the thalassemia free survival rate is 87%; the mortality risk is 3%. [19] Bone Marrow Transplant (BMT) from haploidentical mother to child If the patient doesnt have an HLA-matched compatible donor, there is another cure called Bone Marrow Transplantation(BMT) from haploidentical mother to child (mismatched donor), in which the donor is the mother. It has been invented in 2002 by Dr. Pietro Sodani. The results are: thalassemia free survival rate 70%,rejection 23% and mortality 7%. The best results are with very young patients. [20] Benefits Epidemiological evidence from Kenya suggests another reason: protection against severe malarial anemia may be the advantage.[21] People diagnosed with heterozygous (carrier) thalassemia have some protection against coronary heart disease.[22] Complications

Iron overload: People with thalassemia can get an overload of iron in their bodies, either from the disease itself or from frequent blood transfusions. Too much iron can result in damage to the heart, liver and endocrine system, which includes glands that produce hormones that regulate processes throughout the body. The damage is characterized by excessive iron deposition. Without adequate iron chelation therapy, almost all patients with beta-thalassemia will accumulate potentially fatal iron levels.[23] Infection: people with thalassemia have an increased risk of infection. This is especially true if the spleen has been removed. Bone deformities: Thalassemia can make the bone marrow expand, which causes bones to widen. This can result in abnormal bone structure, especially in the face and skull. Bone marrow expansion also makes bones thin and brittle, increasing the risk of broken bones. Enlarged spleen: the spleen aids in fighting infection and filters unwanted material, such as old or damaged blood cells. Thalassemia is often accompanied by the destruction of a large number of red blood cells, and the task of removing these cells causes the spleen to enlarge. Splenomegaly can make anemia worse, and it can reduce the life of transfused red blood cells. Severe enlargement of the spleen may necessitate its removal.

Slowed growth rates: anemia can cause a child's growth to slow. Puberty also may be delayed in children with thalassemia. Heart problems: such as congestive heart failure and abnormal heart rhythms (arrhythmias), may be associated with severe thalassemia.[24]

References 1. ^ Hemoglobinopathies and Thalassemias 2. ^ Modiano, G. et al. (1991). "Protection against malaria morbidity: Near-fixation of the -thalassemia gene in a Nepalese population". American Journal of Human Genetics 48 (2): 390397. PMC 1683029. PMID 1990845. 3. ^ Terrenato, L. et al. (1988). "Decreased Malaria Morbidity in the Tharu People Compared to Sympatric Populations in Nepal". Annals of Tropical Medicine and Parasitology 82 (1): 111. PMID 3041928. 4. ^ Weatherall David J, "Chapter 47. The Thalassemias: Disorders of Globin Synthesis" (Chapter). Lichtman MA, Kipps TJ, Seligsohn U, Kaushansky K, Prchal, JT: Williams Hematology, 8e: http://www.accessmedicine.com/content.aspx?aID=6123722. 5. ^ Mayoclinic. http://www.mayoclinic.com/health/thalassemia/DS00905/DSECTION=complications. Retrieved 20 September 2011. 6. ^ E. Goljan, Pathology, 2nd ed. Mosby Elsevier, Rapid Review Series. 7. ^ http://www.dmsc.moph.go.th/webrOOt/ri/Npublic/p04.htm 8. ^ Online 'Mendelian Inheritance in Man' (OMIM) 141800 9. ^ Online 'Mendelian Inheritance in Man' (OMIM) 141850 10. ^ Online 'Mendelian Inheritance in Man' (OMIM) 141900 11. ^ a b "Pediatric Thalassemia Treatment & Management". Medical Care. Open Publishing. 30 April 2010. Retrieved 27 September 2011. 12. ^ Claude Owen Burdick. "Separating Thalassemia Trait and Iron Deficiency by Simple Inspection". American Society for Clinical Pathology. Retrieved 27 September 2011. 13. ^ * Harrison's Principles of Internal Medicine 17th Edition. McGraw-Hill medical. September 2008. pp. 776. ISBN 0-07-164114-9. 14. ^ Tesoriere L, Allegra M, Butera D, Gentile C, Livrea MA (July 2006). "Cytoprotective effects of the antioxidant phytochemical indicaxanthin in betathalassemia red blood cells". Free Radical Research 40 (7): 75361. DOI:10.1080/10715760600554228. PMID 16984002. 15. ^ Leung TN, Lau TK, Chung TKh (April 2005). "Thalassaemia screening in pregnancy". Current Opinion in Obstetrics & Gynecology 17 (2): 12934. DOI:10.1097/01.gco.0000162180.22984.a3. PMID 15758603. 16. ^ Samavat A, Modell B (November 2004). "Iranian national thalassaemia screening programme". BMJ (Clinical Research Ed.) 329 (7475): 11347. DOI:10.1136/bmj.329.7475.1134. PMC 527686. PMID 15539666. 17. ^ Spanish Baby Engineered To Cure Brother 18. ^ His sister's keeper: Brother's blood is boon of life, Times of India, 17 September 2009 19. ^ HLA-matched sibling bone marrow transplantation for -thalassemia major, Blood Journal, 3 February 2011 20. ^ T cell-depleted hla-haploidentical stem cell transplantation in thalassemia young patients., Pediatric Reports , 22 June 2011

21. ^ Wambua S, Mwangi TW, Kortok M et al. (May 2006). "The Effect of +Thalassaemia on the Incidence of Malaria and Other Diseases in Children Living on the Coast of Kenya". PLoS Medicine 3 (5): e158. DOI:10.1371/journal.pmed.0030158. PMC 1435778. PMID 16605300. 22. ^ Tassiopoulos S, Deftereos S, Konstantopoulos K et al. (2005). "Does heterozygous beta-thalassemia confer a protection against coronary artery disease?". Annals of the New York Academy of Sciences 1054: 46770. DOI:10.1196/annals.1345.068. PMID 16339699. 23. ^ Cianciulli P (October 2008). "Treatment of iron overload in thalassemia". Pediatr Endocrinol Rev 6 Suppl 1: 20813. PMID 19337180. 24. ^ "Thalassemia Complications". Thalassemia. Open Publishing. Retrieved 27 September 2011.

Talasemia
Dari Wikipedia bahasa Indonesia, ensiklopedia bebas Belum Diperiksa Langsung ke: navigasi, cari

Thalassaemia
Klasifikasi dan bahan-bahan eksternal ICD-10 ICD-9 MedlinePlus eMedicine MeSH D56. 282.4 000587 ped/2229 radio/686 D013789

Pola penurunan sifat genetik pada penderita talasemia.

Talasemia merupakan salah satu jenis anemia hemolitik dan merupakan penyakit keturunan yang diturunkan secara autosomal yang paling banyak dijumpai di Indonesia dan Italia.[rujukan?] Enam sampai sepuluh dari setiap 100 orang Indonesia membawa gen penyakit ini. Kalau sepasang dari mereka menikah, kemungkinan untuk mempunyai anak penderita talasemia berat adalah 25%, 50% menjadi pembawa sifat (carrier) talasemia, dan 25% kemungkinan bebas talasemia[1]. Sebagian besar penderita talasemia adalah anak-anak usia 0 hingga 18 tahun.

Daftar isi

1 Klasifikasi talasemia o 1.1 Talasemia alfa 1.1.1 Delesi pada empat rantai alfa 1.1.2 Delesi pada tiga rantai alfa 1.1.3 Delesi pada dua rantai alfa 1.1.4 Delesi pada satu rantai alfa o 1.2 Talasemia beta 2 Mutasi talasemia dan resistensi terhadap malaria 3 Uji talasemia pra-kelahiran 4 Pencegahan dan pengobatan 5 Referensi 6 Pranala luar

Klasifikasi talasemia
Pada talasemia terjadi kelainan pada gen-gen yang mengatur pembentukan dari rantai globin sehingga produksinya terganggu. Gangguan dari pembentukan rantai globin ini akan mengakibatkan kerusakan pada sel darah merah yang pada akhirnya akan menimbulkan

pecahnya sel darah tersebut. Berdasarkan dasar klasifikasi tersebut, maka terdapat beberapa jenis talasemia, yaitu talasemia alfa, beta, dan delta.

Talasemia alfa
Pada talasemia alfa, terjadi penurunan sintesis dari rantai alfa globulin. Dan kelainan ini berkaitan dengan delesi pada kromosom 16. Akibat dari kurangnya sintesis rantai alfa, maka akan banyak terdapat rantai beta dan gamma yang tidak berpasangan dengan rantai alfa. Maka dapat terbentuk tetramer dari rantai beta yang disebut HbH dan tetramer dari rantai gamma yang disebut Hb Barts. Talasemia alfa sendiri memiliki beberapa jenis[2].
Delesi pada empat rantai alfa

Dikenal juga sebagai hydrops fetalis. Biasanya terdapat banyak Hb Barts. Gejalanya dapat berupa ikterus, pembesaran hepar dan limpa, dan janin yang sangat anemis. Biasanya, bayi yang mengalami kelainan ini akan mati beberapa jam setelah kelahirannya atau dapat juga janin mati dalam kandungan pada minggu ke 36-40. Bila dilakukan pemeriksaan seperti dengan elektroforesis didapatkan kadar Hb adalah 80-90% Hb Barts, tidak ada HbA maupun HbF.
Delesi pada tiga rantai alfa

Dikenal juga sebagai HbH disease biasa disertai dengan anemia hipokromik mikrositer. Dengan banyak terbentuk HbH, maka HbH dapat mengalami presipitasi dalam eritrosit sehingga dengan mudah eritrosit dapat dihancurkan. Jika dilakukan pemeriksaan mikroskopis dapat dijumpai adanya Heinz Bodies.
Delesi pada dua rantai alfa

Juga dijumpai adanya anemia hipokromik mikrositer yang ringan. Terjadi penurunan dari HbA2 dan peningkatan dari HbH.
Delesi pada satu rantai alfa

Disebut sebagai silent carrier karena tiga lokus globin yang ada masih bisa menjalankan fungsi normal.

Talasemia beta
Disebabkan karena penurunan sintesis rantai beta. Dapat dibagi berdasarkan tingkat keparahannya, yaitu talasemia mayor, intermedia, dan karier. Pada kasus talasemia mayor Hb sama sekali tidak diproduksi. Mungkin saja pada awal kelahirannya, anak-anak talasemia mayor tampak normal tetapi penderita akan mengalami anemia berat mulai usia 3-18 bulan. Jika tidak diobati, bentuk tulang wajah berubah dan warna kulit menjadi hitam. Selama hidupnya penderita akan tergantung pada transfusi darah. Ini dapat berakibat fatal, karena efek sampingan transfusi darah terus menerus yang berupa kelebihan zat besi (Fe)[3]. Salah satu ciri fisik dari penderita talasemia adalah kelainan tulang yang berupa tulang pipi masuk ke dalam dan batang hidung menonjol (disebut gacies cooley), penonjolan dahi dan jarak kedua mata menjadi lebih jauh, serta tulang menjadi lemah dan keropos[4].

Mutasi talasemia dan resistensi terhadap malaria

Walaupun sepintas talasemia terlihat merugikan, penelitian menunjukkan kemungkinan bahwa pembawa sifat talasemia diuntungkan dengan memiliki ketahanan lebih tinggi terhadap malaria. Hal tersebut juga menjelaskan tingginya jumlah karier di Indonesia. Secara teoritis, evolusi pembawa sifat talasemia dapat bertahan hidup lebih baik di daerah endemi malaria seperti di Indonesia[5].

Uji talasemia pra-kelahiran

Wanita hamil yang mempunyai risiko mengandung bayi talasemia dapat melakukan uji untuk melihat apakan bayinya akan mederita talasemia atau tidak. Di Indonesia, uji ini dapat dilakukan di Yayasan Geneka Lembaga Eijkman di Jakarta. Uji ini melihat komposisi gengen yang mengkode Hb.

Pencegahan dan pengobatan

Untuk mencegah terjadinya talasemia pada anak, pasangan yang akan menikah perlu menjalani tes darah, baik untuk melihat nilai hemoglobinnya maupun melihat profil sel darah merah dalam tubuhnya. Peluang untuk sembuh dari talasemia memang masih tergolong kecil karena dipengaruhi kondisi fisik, ketersediaan donor dan biaya. Untuk bisa bertahan hidup, penderita talasemia memerlukan perawatan yang rutin, seperti melakukan tranfusi darah teratur untuk menjaga agar kadar Hb di dalam tubuhnya 12 gr/dL dan menjalani pemeriksaan ferritin serum untuk memantau kadar zat besi di dalam tubuh. Penderita talesemia juga diharuskan menghindari makanan yang diasinkan atau diasamkan dan produk fermentasi yang dapat meningkatkan penyerapan zat besi di dalam tubuh. Dua cara yang dapat ditempuh untuk mengobati tasalemia adalah transplantasi sumsum tulang belakang dan teknologi sel punca (stem cell)[6]. Pada tahun 2009, seorang penderita talasemia dari India berhasil sembuh setelah memperoleh donor sum-sum tulang belakang dari adiknya tapi akibatnya adiknya mengalami kelumpuhan total setelah melakukan tranplantasi tersebut dan adiknya juga mengalami amnesia parsial. Sehingga Ia meninggal pada tahun 2011 karna tranplantasi tersebut. Ini bukan berarti pendonor akan meninggal setelah tranplantasi, kemungkinan yang paling pasti adalah pendonor akan mengalami amnesia parsial jika kadar kecocokan sum-sum tulang belakang lebih dari 50% sedangkan jika kurang dari 50% akan mengalami kelumpuhan. Berbeda dengan mereka yang merupakan saudara satu kandung, resiko yang akan didapat adalah menderita amnesia parsial dan juga mengalami kelumpuhan total.

Referensi
1. ^ Susan A. Orshan (2007). Maternity, Newborn, and Women's Health Nursing: Comprehensive Care Across the Life Span. Lippincott Williams & Wilkins. ISBN 978-0-78174254-2. 2. ^ Anupam Sachdeva, M. R. Lokeshwar (2006). Hemoglobinopathies. Jaypee Brothers Medical Publisher. ISBN 81-8061-669-X.

3. ^ Robert S. Hillman, Kenneth A. Ault, Henry M. Rinder (2005). Hematology in clinical practice: a guide to diagnosis and management. McGraw-Hill Professional. ISBN 978-0-07-144035-6. 4. ^ Howard A. Pearson, M.D., Lauren C. Berman, M.S.W., Allen C. Crocker, M.D. (1997). "Thalassemia Intermedia: A Region I Conference". THE GENETIC RESOURCE 11 (2). 5. ^ Martin H. Steinberg (2001). Disorders of hemoglobin: genetics, pathophysiology, and clinical management. Cambridge University Press. ISBN 978-0-521-63266-9. 6. ^ Suraksha Agrawal (2003). "Stem Cell Transplantation in Thalassemia". Int J Hum Genet 3 (4): 205-208.