Deterrence/Prevention Screening and prevention includes the following:20 In persons with thalassemia trait, confirming the diagnosis is usually

ly easy. In such situations, genetic counseling is necessary, and, if both parents are carriers, a detailed discussion with the couple should include all possible outcomes. These include the 1 in 4 chance of having a severely affected or completely healthy child and a 1 in 2 chance of having a child with heterozygous thalassemia. For thalassemia carriers, confirmation is not that simple. Hemoglobin (Hb) electrophoresis is usually not informative. For this reason, more sophisticated studies are warranted if confirmation is critical. Genetic counseling should be provided for patients with thalassemia if a sibling or a family member is known to be affected. Prenatal DNA testing has been available for several years. The decision to perform prenatal diagnosis in parents known to be at risk for having a child with thalassemia is complex and is usually influenced by several factors, such as religion, culture, education, and the number of children in the family. Genetic counseling by professionals that addresses the details of both the genetic risks and the testing risks involved is expected to help the parents make an informed and intelligent decision concerning the procedure. Unfortunately, such tests are not available in certain areas of the world where they are needed most. Extensive screening programs and prenatal diagnosis has resulted in a significant decline in the incidence of thalassemia in some of the high-risk Mediterranean countries. Successful prevention programs in different parts of the world have resulted in an impressive decline in the number of patients with severe forms of thalassemia. Ferrara, Cyprus, Sardinia, Greece, and the United Kingdom were among the first to report a significant decline in the birth rate of children with thalassemia major. The Cypriot screening program continues to prove a great success, despite the false claim that it is a new form of eugenics.21 Many other regions with more limited resources are following their steps with remarkable success. In addition to the effective prenatal diagnosis adopted in the countries mentioned, other measures such as premarital screening programs, genetic counseling, and restrictions on issuing marriage certificates and licenses also proved to be effective. Because many of the countries where thalassemia prevails are poor and cannot afford sophisticated preventive programs, more practical approaches are clearly needed. Screening of children, pregnant women, and individuals visiting public health facilities is effective in identifying individuals at risk who require further testing. A simple CBC count, with emphasis on the RBC counts and indices, including the mean corpuscular volume (MCV), mean corpuscular Hb (MCH), and RBC distribution width (RDW), is the main component of such screening processes. Persons suspected to be positive for thalassemia are checked for elevated levels of Hb A2, Hb F, or both for confirmation. In some situations, this simple method is not adequate, and further testing, including analyses of globin chain synthesis, must be performed to reach a final diagnosis. Prenatal diagnosis includes the following: Globin chain synthesis, which was once used in postnatal diagnosis, was also used on fetal cells obtained by fetoscopy to screen the fetus. This test reveals imbalanced production of certain globin chains that are diagnostic of thalassemia. Since polymerase chain reaction (PCR) techniques have become available, several new methods are now in use to identify affected babies or carrier individuals accurately and quickly. The DNA material is obtained by chorionic villus sampling (CVS), and mutations that change restriction enzyme cutting sites can be identified.

Because many of the mutations that cause and thalassemia have become known in recent years, identifying such mutations on the amplified -globin gene region is now possible with specific labeled oligonucleotide probes. Some of the new techniques can give accurate results in less than 3 hours. Several publications have shown that prenatal diagnosis of thalassemia and hemoglobinopathies could be achieved by simple methods in routine setting. Capillary electrophoresis on fetal cells has proved to be reliable.22 The same method has also been reported to have an advantage over other methods of Hb E evaluation because it could separate the peaks of Hb A 2 from that of Hb E in patients with Hb E mutations.23 In a study from Yi et al, PCR/ligase detection reaction (LDR) capillary electrophoresis assay for the detection of thalassemia fetal mutation in maternal plasma was shown to be a noninvasive and highly sensitive procedure with good potential.24

Pencegahan / Pencegahan Skrining dan pencegahan meliputi: Pada orang-orang dengan talasemia trait, mengkonfirmasikan diagnosis biasanya mudah. Dalam situasi seperti itu, konseling genetika diperlukan, dan, jika kedua orang tua adalah carrier, suatu diskusi yang terperinci dengan pasangan harus mencakup semua hasil yang mungkin. Ini termasuk 1 dari 4 kesempatan untuk memiliki anak yang berat terkena talasemia atau benar-benar sehat dan 1 dalam 2 kesempatan memiliki anak dengan thalassemia heterozigot. Untuk carrier talasemia , konfirmasi tidak sesederhana itu. Elektroforesis Hemoglobin (Hb) biasanya tidak informatif. Untuk alasan ini, studi lebih canggih dijamin jika konfirmasi kritis. Konseling genetik harus disediakan untuk pasien dengan talasemia jika saudara atau anggota keluarga diketahui terkena. Tes DNA Prenatal telah tersedia selama beberapa tahun. Keputusan untuk melakukan diagnosis pralahir pada orang tua diketahui berisiko memiliki anak dengan talasemia adalah kompleks dan biasanya dipengaruhi oleh beberapa faktor, seperti agama, budaya, pendidikan, dan jumlah anak dalam keluarga. Konseling genetik oleh para profesional yang membahas rincian baik risiko genetik dan risiko pengujian yang terlibat diharapkan dapat membantu orang tua membuat keputusan dan cerdas tentang prosedur. Sayangnya, tes tersebut tidak tersedia di daerah-daerah tertentu dimana mereka yang paling dibutuhkan. program screening yang luas dan diagnosis prenatal telah menghasilkan penurunan yang signifikan dalam insiden thalassemia di beberapa negara-negara Mediterania berisiko tinggi. Langkah-langkah lain seperti program screening pranikah, konseling genetik, dan pembatasan pemberian sertifikat perkawinan dan lisensi juga terbukti efektif. Karena banyak negara di mana terdapat talasemia miskin dan tidak mampu program pencegahan canggih, pendekatan praktis jelas diperlukan. Screening pada anak-anak, ibu hamil, dan individu yang mengunjungi fasilitas kesehatan publik efektif dalam mengidentifikasi individu yang berisiko yang membutuhkan pengujian lebih lanjut. Sebuah hitungan CBC sederhana, dengan penekanan pada jumlah RBC dan indeks, termasuk nilai mean corpuscular volume (MCV), mean corpuscular Hb (MCH), dan luas distribusi RBC (RDW), merupakan komponen utama dari proses screening tersebut. Orang-orang yang diduga menjadi positif untuk thalassemia diperiksa untuk peningkatan kadar HbA2, HbF, atau keduanya untuk konfirmasi. Dalam beberapa situasi, jika metode sederhana tidak memadai, pengujian lebih lanjut, termasuk analisis sintesis globin rantai, harus dilakukan untuk mencapai diagnosis akhir. Diagnosis Prenatal Mutasi thalassemia-, biasanya dapat dideteksi dengan analisis DNA langsung yang diperoleh dari fetus dengan bipsi villus korionik atau cairan amniosentesis, DNA dianalisis dengan metode polymerase chain reaction (PCR) dan metode hibridisasi molekular untuk menentukan adanya thalassemia. Bila kedua pasangan prang tua membawa sifat gen thalassemia minor, diagnosis pranatal thalassemia- homozigot pada bayi yang dikandung dapat dibuat dengan analisis endonuklease restriksi DNA, yang diperoleh dari villus korionik atau cairan amniosentesis. Tidak adanya gen- memastikan diagnosis. Terminasi awal akan mencegah akibat bahaya bagi si ibu, yakni toksemia dan perdarahan hebatpasca partus.

http://emedicine.medscape.com/article/958850-followup Thalassemia: Follow-up Author: Hassan M Yaish 2010

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/L 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.

Splenectomy is the principal surgical procedure used for many patients with thalassemia. 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 of Postsplenectomy risk of infections with encapsulated organisms and malaria in endemic areas 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/L 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.

Splenektomi adalah prosedur pembedahan utama yang digunakan untuk banyak pasien dengan talasemia. Limpa diketahui mengandung sejumlah besar besi tidak beracun labil (yaitu, fungsi penyimpanan) yang berasal dari penyerapan dari besi dilepaskan. Limpa juga meningkatkan kerusakan RBC dan distribusi besi (yaitu, fungsi scavenger). Fakta-fakta ini harus selalu dipertimbangkan sebelum keputusan dibuat untuk melanjutkan dengan splenektomi. Selain itu, dengan laporan baru tentang kejadian tromboemboli vena (VTEs) setelah splenektomi, salah satu harus hati-hati mempertimbangkan manfaat dan risiko sebelum splenektomi adalah dianjurkan. Limpa bertindak sebagai toko untuk besi tidak beracun, sehingga melindungi seluruh tubuh dari besi ini. Awal pengangkatan limpa dapat membahayakan (sirosis hati telah terjadi pada orang tersebut). Sebaliknya, splenektomi dibenarkan ketika limpa menjadi hiperaktif, menyebabkan kerusakan sel darah merah yang berlebihan dan dengan demikian meningkatkan kebutuhan untuk transfusi darah sering, mengakibatkan akumulasi zat besi lebih banyak. Selanjutnya, jika kolam besi labil dalam limpa menjadi target aksi DFO (yaitu, menghapus kolam renang nonharmful dan meninggalkan satu beracun), splenektomi lebih lanjut dibenarkan. Tujuan dalam dilema membingungkan harus selalu untuk mencapai keseimbangan besi negatif, yang, pada banyak pasien, telah dimungkinkan oleh administrasi terus menerus DFO subkutan. Beberapa kriteria yang digunakan untuk membantu keputusan untuk splenektomi; satu praktis menunjukkan splenektomi yang mungkin bermanfaat pada pasien yang membutuhkan lebih dari 200-250 mL / kg PRBC per tahun untuk mempertahankan tingkat Hb 10 g / dL. Risiko yang terkait dengan splenektomi yang minimal, dan banyak prosedur yang kini dilakukan oleh laparoskopi. Postsplenectomy risiko infeksi dengan organisme encapsulated dan malaria di daerah endemik selalu kekhawatiran. Masalahnya adalah minimal saat ini, karena imunisasi presplenectomy dan antibiotik profilaksis pascaoperasi telah menurun secara signifikan tingkat komplikasi tersebut. Secara tradisional, prosedur ini ditunda bila memungkinkan sampai anak berusia 4-5 tahun atau lebih. perlakuan agresif dengan antibiotik harus selalu diberikan untuk setiap penyakit demam sambil menunggu hasil budaya. Dosis rendah aspirin setiap hari juga bermanfaat ketika jumlah platelet meningkat lebih dari 600.000 / postsplenectomy uL. Lain prosedur operasi pada pasien dengan talasemia parah pada terapi transfusi adalah penempatan garis pusat untuk kemudahan dan kenyamanan administrasi transfusi darah, terapi khelasi, atau keduanya. ... Google Translate for my:SearchesVideosEmailPhone

Thalassemia: Treatment & Medication http://emedicine.medscape.com/article/958850-treatment http://emedicine.medscape.com/article/958850-diagnosis Thalassemia: Differential Diagnoses & Workup Hassan M Yaish2010 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. In an animal study, green tea as antioxidant was shown to inhibit or delay the deposition of hepatic iron in thalassemic mice.16 This prevented iron-induced free radical generation, which has been implicated in liver damage and fibrosis. 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.

The management of patient with thalassemia varies according to the severity of the anemia. heterozygote alpha and beta thalassemia patients are not clinically symptomatic, have only a mild anemia, and are not at risk for iron overload. they should be reassured of the benign nature of the inhherited defect, and when appropriate, counseled regarding the risk of transmitting the defect with child-bearing. thalassemia minor patients should not be placed on long-term iron therapy, and do not require folic acid supplementation. patients with thalassemia intermedia or major who are homozygotes or double heterozygotes for alpha or beta thalassemia will require almost continues medical attention beginning early in childhood. the principal management issues include; 1. Transfusion support 2. The prevention of iron overload 3. the management of hypersplenism Thalassemia major patients represents the greatest challange. Children with homozygous, deletion form of beta thalasssemia (bo/bo) presenrs during first year of life with severe, lifethreatening anemia. their survival depens on a carefully orchestrated program of transfusion and iron chelation therapy to prevent iron overload and tissue toxicity. Treatment for thalassemia includes blood transfusions, surgical removal of the spleen (splenectomy), and iron chelation therapy. Bone marrow transplant using marrow from a matched donor is the most aggressive treatment for thalassemia and the only one considered a cure. The purpose of the transplant is to replace genetically defective bone marrow cells with normal bone marrow cells that help produce normal amounts of both alpha- and beta-globin. Blood transfusions are the primary treatment for beta-thalassemia major and are given frequently in order to maintain an acceptable hemoglobin level. Hemoglobin H disease may also require transfusions but not as commonly as beta-thalassemia major. In beta-thalassemia intermedia, transfusions are not required to maintain an acceptable hemoglobin level. An individual with this condition, however, is unstable and may over time or quite suddenly develop severe anemia. If transfusion is required, the condition is no longer considered betathalassemia intermedia but rather beta-thalassemia major. If the condition improves and no longer requires transfusions, the condition is again categorized as beta-thalassemia intermedia. Folate is usually given along with blood transfusions. The spleen ordinarily removes red blood cells from circulation, so a splenectomy is often performed to keep red blood cells in circulation longer. This procedure may help reduce the need for transfusions in individuals with beta-thalassemia major and prevent transfusions completely in individuals with beta-thalassemia intermedia. The spleen may be removed through a large abdominal incision (open splenectomy) or through a flexible tube inserted in a small hole in the abdominal wall (laparoscopic splenectomy). Pneumococcal vaccine (vaccine against Streptococcus pneumoniae) should be given regularly to individuals who have had a splenectomy, since they are susceptible to infection from this bacterium.

The overgrowth of bone marrow associated with thalassemia causes increased iron absorption. This increased absorption, especially when combined with the iron added to the body through frequent transfusion, causes an overload of iron in body tissues such as the heart, liver, and glands (hematochromatosis). Iron chelation therapy using the drug deferoxamine removes this extra iron from the body. If the iron is not removed, heart failure and death will eventually result. Iron supplements and oxidative drugs such as sulfonamides should be avoided. Prognosis the predicted outcome of thalassemia depends on the severity of the disease and the degree to which an individual follows the appropriate prescribed treatment. Individuals with beta-thalassemia major (the most severe form of thalassemia), can live into their fifties with blood transfusions, iron chelation therapy, and splenectomy. Without iron chelation therapy, however, survival is limited by the degree of iron overload within the heart, with death often occurring between the ages of 20 and 30. Bone marrow transplant with marrow from a matched donor offers a 54% to 90% survival rate for adults. Almost all babies born with alpha-thalassemia major will die from anemia. There is, however, a small number who may survive after receiving prenatal (intrauterine) blood transfusions. The outlook for patients with HbH depends on the complications from blood transfusions, splenomegaly (splenic enlargement), or splenectomy (splenic removal) and the degree of anemia.
Pengobatan untuk Thalassemia meliputi transfusi darah, operasi pengangkatan limpa (splenektomi), dan terapi khelasi besi. Transplantasi sumsum tulang menggunakan sumsum dari donor yang cocok adalah pengobatan yang paling agresif untuk thalassemia dan satu-satunya dianggap obat. Tujuan dari transplantasi adalah untuk menggantikan sel-sel tulang sumsum genetik rusak dengan sel sumsum tulang normal yang membantu menghasilkan jumlah normal baik-alfa dan beta-globin. Transfusi darah adalah perawatan utama untuk beta-thalassemia utama dan sering diberikan untuk mempertahankan tingkat hemoglobin diterima. Penyakit Hemoglobin H juga mungkin memerlukan transfusi tapi tidak umum sebagai beta-talasemia mayor. Dalam intermedia beta-thalassemia, transfusi tidak diharuskan untuk menjaga tingkat hemoglobin diterima. Seorang individu dengan kondisi ini, bagaimanapun, adalah tidak stabil dan mungkin dari waktu ke waktu atau cukup tiba-tiba mengembangkan anemia berat. Jika transfusi diperlukan, kondisi ini tidak lagi dianggap beta-thalassemia intermedia melainkan thalassemia. Jika kondisi membaik dan tidak lagi membutuhkan transfusi, kondisi ini lagi dikategorikan sebagai beta-thalassemia intermedia. Folat biasanya diberikan bersama dengan transfusi darah. Limpa biasanya menghilangkan sel-sel darah merah dari peredaran, sehingga splenectomy sering dilakukan untuk menjaga sel-sel darah merah dalam sirkulasi lagi. Prosedur ini dapat membantu mengurangi kebutuhan untuk transfusi pada individu dengan thalassemia dan mencegah transfusi sepenuhnya pada individu dengan beta-thalassemia intermedia. Limpa bisa diangkat melalui suatu sayatan perut besar (splenektomi terbuka) atau melalui tabung fleksibel yang dimasukkan ke dalam lubang kecil di dinding perut (laparoskopi splenektomi). Pneumococcal vaksin (vaksin terhadap Streptococcus pneumoniae) harus

diberikan secara teratur untuk individu yang memiliki splenectomy, karena mereka rentan terhadap infeksi dari bakteri ini. Pertumbuhan berlebih dari sumsum tulang yang terkait dengan talasemia menyebabkan peningkatan penyerapan zat besi. Penyerapan ini meningkat, terutama bila dikombinasikan dengan besi yang ditambahkan ke dalam tubuh melalui transfusi sering, menyebabkan kelebihan zat besi dalam jaringan tubuh seperti hati, jantung, dan kelenjar (hematochromatosis). Terapi khelasi besi menggunakan deferoxamine obat menghilangkan zat besi tambahan ini dari tubuh. Jika setrika tidak dihilangkan, gagal jantung dan kematian pada akhirnya akan menghasilkan. suplemen zat besi dan obat-obatan oksidatif seperti sulfonamid harus dihindari.

PENCEGAHAN : Karena penyakit ini belum ada obatnya, maka pencegahan dini menjadi hal yang lebih penting dibanding pengobatan. Program pencegahan thalassemia terdiri dari beberapa strategi, yakni : (1) penapisan (skrining) pembawa sifat thalassemia, (2) konsultasi genetik (genetic counseling), dan (3) diagnosis prenatal. Skrining pembawa sifat dapat dilakukan secara prospektif dan retrospektif. Secara prospektif berarti mencari secara aktif pembawa sifat thalassemia langsung dari populasi diberbagai wilayah, edangkan secara retrospektif ialah menemukan pembawa sifat melalui penelusuran keluarga penderita thalassemia (family study). Kepada pembawa sifat ini diberikan informasi dan nasehat-nasehat tentang keadaannya dan masa depannya. Suatu program pencegahan yang baik untuk thalassemia seharusnya mencakup kedua pendekatan tersebut. Program yang optimal tidak selalu dapat dilaksanakan dengan baik terutama di negara-negara sedang berkembang, karena pendekatan prospektif memerlukan biaya yang tinggi. Atas dasar itu harus dibedakan antara usaha program pencegahan di negara berkembang dengan negara maju. Program pencegahan retrospektif akan lebih mudah dilaksanakan di negara berkembang daripada program prospektif. Konsultasi genetik meliputi skrining pasangan yang akan kawin atau sudah kawin tetapi belum hamil. Pada pasangan yang berisiko tinggi diberikan informasi dan nasehat tentang keadaannya dan kemungkinan bila mempunyai anak. Diagnosis prenatal meliputi pendekatan retrospektif dan prospektif. Pendekatan retrospektif, berarti melakukan diagnosis prenatal pada pasangan yang telah mempunyai anak thalssemia, dan sekarang sementara hamil. Pendekatan prospektif ditujukan kepada pasangan yang berisiko tinggi yaitu mereka keduanya pembawa sifat dan sementara baru hamil. Diagnosis prenatal ini dilakukan pada masa kehamilan 8-10 minggu, dengan mengambil sampel darah dari villi khorialis (jaringan ari-ari) untuk keperluan analisis DNA. Dalam rangka pencegahan penyakit thalassemia, ada beberapa masalah pokok yang harus disampaikan kepada masyarakat, ialah : (1) bahwa pembawa sifat thalassemia itu tidak merupakan masalah baginya; (2) bentuk thalassemia mayor mempunyai dampak medikososial yang besar, penanganannya sangat mahal dan sering diakhiri kematian; (3) kelahiran bayi thalassemia dapat dihindarkan. Karena penyakit ini menurun, maka kemungkinan penderitanya akan terus bertambah dari tahun ke tahunnya. Oleh karena itu, pemeriksaan kesehatan sebelum menikah sangat penting dilakukan untuk mencegah bertambahnya penderita thalassemia ini. Sebaiknya semua orang Indonesia dalam masa usia subur diperiksa kemungkinan membawa sifat thalassemia. Pemeriksaaan akan sangat dianjurkan bila terdapat riwayat : (1) ada saudara sedarah yang menderita thalassemia, (2) kadar hemoglobin relatif rendah antara 10-12 g/dl walaupun sudah minum obat penambah darah seperti zat besi, (3) ukuran sel darah merah lebih kecil dari normal walaupun keadaan Hb normal. http://www.rotary-cegah-thalassaemia.com/index.php? option=com_content&view=article&id=15:bagaimana-mencegah-penyakit-thalassemia-padaketurunan-kita&catid=4:artikel&Itemid=7

Saturday, 07 November 2009 15:25 THALASSEMIA Pekan Cegah Thalassemia dr.Moedrik Tamam, SpAK 2009

What is Genetic Testing? Genetic tests use a variety of laboratory techniques to determine if a person has a genetic condition or disease or is likely to get the disease. Individuals may wish to be tested if: 1. There is a family history of one specific disease. 2. They show symptoms of a genetic disorder, 3. Theyr are concerned about passing on a genetic problem to their children. Genetic tests include techniques to examine genes or markers near the genes. Direct testing for diseases such as cystic fibrosis and sickle cell anemia come from an analysis of an individual's specific genes. A technique called linkage analysis, or indirect testing, is used when the gene cannot be directly identified but can be located within a specific region of a chromosome. This testing requires additional DNA from an affected family member for comparison. Because each person's DNA is unique (except for identical twins), genetic tests also can be used for individual identification ("DNA fingerprinting"). Genetic testing is a complex process, and the results depend both on reliable laboratory procedures and accurate interpretation of results. Tests also vary in sensitivity , that is, their ability to detect mutations or to detect all patients who have or will get the disease. Interpretation of test results is often complex even for trained physicians and other health care specialists. When interpreting the results of any genetic test, one must take into account the probability of false positive or false negative test results. Special training is required to be able to analyze and convey information about genetic testing to affected individuals and their families. Types of Genetic Testing Carrier Identification includes genetic tests used by couples whose families have a history of recessive genetic disorders and who are considering having children. Three common tests include those for cystic fibrosis, Tay-Sachs disease, and sickle-cell trait. Prenatal Diagnosis is genetic testing of a fetus. This may occur when there is a risk of bearing a child with genes associated with mental retardation or physical deterioration. Down Syndrome is one of the most common genetic diseases screened by this method. Newborn Screening is frequently done as a preventative health measure. Tests usually have clear benefit to the newborn because treatment is available. Phenylketonuria and congenital hypothyroidism are conditions for which testing is conducted in all 52 states. Late-onset Disorders include adult diseases such as cancer and heart disease. These diseases are complex and have both genetic and environmental causes. Genetic tests may indicate a susceptibility or predisposition for these diseases. There are diseases caused by single genes, such as Huntington's disease, that also are seen later in life and can be tested at any time. Identification of genetic information belonging to a specific individual has received a great deal of press coverage lately. Profiles (aka "DNA fingerprints") are complied from the results of DNA testing for one or more genetic markers to identify unique characteristics of an individual. This information is currently used in legal cases involving paternity and in criminal investigations, and it can be used in time of major accidents, disasters, or wars to identify those who have died. Ethical, Legal, and Social Issues in Genetic Testing Information from genetic testing can affect the lives of individuals and their families. In addition to personal and family issues, genetic disease or susceptibility may have implications for employment and insurance. Therefore, careful consideration in the handling of this information is very important. Critical issues include: Privacy - the rights of individuals to maintain privacy. Some genetic tests are required or strongly encouraged for developing fetuses and newborn babies. If an infant is found to be a carrier or likely to develop or be affected by an inherited

disease, these findings may affect the future employability or insurability of the individual. Informed consent - obtaining permission to do genetic testing. One must have knowledge of the risks, benefits, effectiveness, and alternatives to testing in order to understand the implications of genetic testing. Confidentiality - acknowledgment that genetic information is sensitive and access should to limited to those authorized to receive it. Future access to a person's genetic information also should be limited. http://www.lbl.gov/Education/ELSI/Frames/genetic-testing-f.html

Apa Pengujian genetik? --------------tes genetik menggunakan berbagai teknik laboratorium untuk menentukan apakah seseorang memiliki kondisi genetik atau penyakit atau mungkin untuk mendapatkan penyakit. Individu mungkin ingin diuji apabila: 1. Ada riwayat keluarga satu penyakit tertentu. 2. Mereka menunjukkan gejala gangguan genetik, 3. Theyr prihatin tentang kelulusan pada masalah genetik untuk anak-anak mereka. Tes genetik meliputi teknik-teknik untuk memeriksa gen atau penanda dekat gen. Langsung pengujian untuk penyakit seperti cystic fibrosis dan anemia sel sabit datang dari analisis gen spesifik individu. teknik yang disebut analisis linkage, atau pengujian tidak langsung, digunakan ketika gen tidak bisa langsung teridentifikasi namun dapat ditemukan dalam suatu wilayah tertentu dari suatu kromosom. Tes ini membutuhkan DNA tambahan dari anggota keluarga yang terkena untuk perbandingan. Karena DNA setiap orang adalah unik (kecuali kembar identik), tes genetik juga dapat digunakan untuk identifikasi individu ("DNA fingerprinting"). pengujian genetika adalah suatu proses yang kompleks, dan hasil tergantung baik pada prosedur laboratorium yang handal dan akurat interpretasi hasil. Tes juga bervariasi dalam sensitivitas, yaitu, kemampuan mereka untuk mendeteksi mutasi atau untuk mendeteksi semua pasien yang telah atau akan mendapatkan penyakit ini. Interpretasi hasil uji seringkali rumit bahkan untuk dokter terlatih dan ahli kesehatan lainnya. Ketika menafsirkan hasil tes genetik, orang harus memperhitungkan kemungkinan hasil palsu positif atau palsu tes negatif. Pelatihan khusus diperlukan untuk dapat menganalisis dan menyampaikan informasi tentang tes genetik untuk individu yang terkena dan keluarga mereka. Jenis Pengujian genetik Carrier Identifikasi termasuk tes genetik digunakan oleh pasangan yang keluarganya memiliki riwayat gangguan genetik resesif dan yang mempertimbangkan memiliki anak. Tiga tes umum termasuk untuk cystic fibrosis, penyakit Tay-Sachs, dan sifat sel sabit. Diagnosis Prenatal pengujian genetik janin. Hal ini dapat terjadi ketika ada risiko melahirkan anak dengan gen yang terkait dengan keterbelakangan mental atau kerusakan fisik. Down Syndrome adalah salah satu penyakit genetik yang paling umum disaring oleh metode ini. Newborn Screening sering dilakukan sebagai ukuran kesehatan preventif. Tes biasanya memiliki manfaat yang jelas pada bayi baru lahir karena pengobatan tersedia. Fenilketonuria dan hipotiroidisme kongenital adalah kondisi dimana pengujian dilakukan di semua 52 negara bagian. Akhir-onset Gangguan termasuk penyakit dewasa seperti kanker dan penyakit jantung. Penyakit ini sangat kompleks dan memiliki kedua penyebab genetik dan lingkungan. tes genetik mungkin menandakan adanya kerentanan atau kecenderungan untuk penyakit ini. Ada penyakit yang disebabkan oleh gen tunggal, seperti penyakit Huntington, yang juga terlihat di kemudian hari dan dapat diuji setiap saat. Identifikasi informasi genetik milik individu tertentu telah menerima banyak liputan pers

akhir-akhir ini. Profil (alias "sidik jari DNA") adalah memenuhi dari hasil tes DNA untuk satu atau lebih penanda genetik untuk mengidentifikasi karakteristik unik individu. Informasi ini saat ini digunakan dalam kasus-kasus hukum yang melibatkan ayah dan investigasi kriminal, dan dapat digunakan dalam waktu kecelakaan besar, bencana, atau perang untuk mengidentifikasi mereka yang telah meninggal. Etika, Hukum, dan Isu Sosial dalam Pengujian genetik Informasi dari pengujian genetik dapat mempengaruhi kehidupan individu dan keluarga mereka. Selain masalah-masalah pribadi dan keluarga, penyakit genetik atau kepekaan mungkin memiliki implikasi untuk pekerjaan dan asuransi. Oleh karena itu, pertimbangan cermat dalam penanganan informasi ini sangat penting. isu-isu Kritis meliputi: * Privasi - hak-hak individu untuk menjaga privasi. Beberapa tes genetik diperlukan atau sangat dianjurkan untuk janin berkembang dan bayi yang baru lahir. Jika bayi ditemukan untuk menjadi carrier atau mungkin mengembangkan atau dipengaruhi oleh penyakit bawaan, temuan tersebut dapat mempengaruhi masa depan atau dipertanggungkan dipekerjakan individu. * Informed consent - mendapatkan izin untuk melakukan pengujian genetik. Seseorang harus memiliki pengetahuan tentang risiko, manfaat, efektivitas, dan alternatif untuk pengujian untuk memahami implikasi dari pengujian genetik. * Kerahasiaan - pengakuan bahwa informasi genetik sensitif dan akses harus dapat terbatas pada apa yang berwenang untuk menerimanya. akses Masa Depan untuk informasi genetik seseorang juga harus dibatasi.

1. Thalassemia- (gangguan pembentukan rantai ) Sindrom thalassemia- disebabkan oleh delesi pada gen globin pada kromosom 16 terdapat 2 gen globin pada tiap kromosom 16) dan nondelesi seperti gangguan mRNA pada penyambungan gen yang menyebabkan rantai menjadi lebih panjang dari kondisi normal. Faktor delesi terhadap empat gen globin dapat dibagi menjadi empat, yaitu: a. Delesi pada satu rantai (Silent Carrier / -Thalassemia Trait 2) (-/) Gangguan pada satu rantai globin sedangkan tiga lokus globin yang ada masih bisa menjalankan fungsi normal sehingga tidak terlihat gejala-gejala bila ia terkena thalassemia. b. Delesi pada dua rantai (-Thalassemia Trait 1) (--/ atau -/-) Pada tingkatan ini terjadi penurunan dari HbA2 dan peningkatan dari HbH dan terjadi manifestasi klinis ringan seperti anemia kronis yang ringan dengan eritrosit hipokromik mikrositer dan MCV ( mean corpuscular volume) 60-75 fl. c. Delesi pada tiga rantai (HbH disease) (--/-) Delesi ini disebut juga sebagai HbH disease (4) yang disertai anemia hipokromik mikrositer, basophylic stippling, heinz bodies, dan retikulositosis. HbH terbentuk dalam jumlah banyak karena tidak terbentuknya rantai sehingga rantai tidak memiliki pasangan dan kemudian membentuk tetramer dari rantai sendiri (4). Dengan banyak terbentuk HbH, maka HbH dapat mengalami presipitasi dalam eritrosit sehingga dengan mudah eritrosit dapat dihancurkan. Penderita dapat tumbuh sampai dewasa dengan anemia sedang (Hb 8-10 g/dl) dan MCV ( mean corpuscular volume) 60-70 fl. d. Delesi pada empat rantai (Hidrops fetalis/Thalassemia major) (--/--) e. Delesi ini dikenal juga sebagai hydrops fetalis. Biasanya terdapat banyak Hb Barts (4) yang disebabkan juga karena tidak terbentuknya rantai sehingga rantai membentuk tetramer sendiri menjadi4. Manifestasi klinis dapat berupa ikterus, hepatosplenomegali, dan janin yang sangat anemis. Kadar Hb hanya 6 g/dl dan pada elektroforesis Hb menunjukkan 80-90% Hb Barts, sedikit HbH, dan tidak dijumpai HbA atau HbF. Biasanya bayi yang mengalami kelainan ini akan mati beberapa jam setelah kelahirannya. 2. Thalassemia- (gangguan pembentukan rantai ) Thalassemia- disebabkan oleh mutasi pada gen globin pada sisi pendek kromosom 11. a. Thalassemia o Pada thalassemiao, tidak ada mRNA yang mengkode rantai sehingga tidak dihasilkan rantai yang berfungsi dalam pembentukan HbA b. Thalassemia + Pada thalassemia+, masih terdapat mRNA yang normal dan fungsional namun hanya sedikit sehingga rantai dapat dihasilkan dan HbA dapat dibentuk walaupun hanya sedikit. Sedangkan secara klinis thalassemia dibagi menjadi 2 golongan, yaitu a. Thalasemia Mayor Terjadi bila kedua orang tuanya membawa gen pembawa sifat thalassemia. Gejala penyakit muncul sejak awal masa kanak-kanak dan biasanya penderita hanya bertahan hingga umur sekitar 2 tahun. Penderita bercirikan : o Lemah o Pucat

o Perkembangan fisik tidak sesuai dengan umur o Berat badan kurang o Tidak dapat hidup tanpa transfusi transfusi darah seumur hidupnya. b. Thalasemia minor/trait Gejala yang muncul pada penderita Thalasemia minor bersifat ringan, biasanya hanya sebagai pembawa sifat. Istilah Thalasemia trait digunakan untuk orang normal namun dapat mewariskan gen thalassemia pada anak-anaknya:ditandai oleh splenomegali, anemia berat, bentuk homozigot. Pada anak yang besar sering dijumpai adanya: Gizi buruk Perut buncit karena pembesaran limpa dan hati yang mudah diraba Aktivitas tidak aktif karena pembesaran limpa dan hati (Hepatomegali ), Limpa yang besar ini mudah ruptur karena trauma ringan saja Gejala khas adalah: Gejala khas adalah: Bentuk muka mongoloid yaitu hidung pesek, tanpa pangkal hidung, jarak antara kedua mata lebar dan tulang dahi juga lebar. Keadaan kuning pucat pada kulit, jika sering ditransfusi, kulitnya menjadi kelabu karena penimbunan besi

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. Dosing Interactions Contraindications Precautions Adult 325-650 mg/dose PO prior to blood transfusion Pediatric 10-15 mg/kg/dose PO prior to blood transfusion Dosing Interactions Contraindications Precautions Rifampin decreases analgesic effect; barbiturates increase hepatic toxicity Dosing Interactions Contraindications Precautions Documented hypersensitivity Dosing Interactions Contraindications Precautions 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. Dosing Interactions Contraindications Precautions 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

Dosing Interactions Contraindications Precautions Potentiates effects of CNS depressants and MAOIs Dosing Interactions Contraindications Precautions Documented hypersensitivity; newborn and premature infants; breastfeeding mothers; acute attacks of asthma; glaucoma; stenotic peptic ulcer (because of atropinelike effect) Dosing Interactions Contraindications Precautions 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. Dosing Interactions Contraindications Precautions 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 Dosing Interactions Contraindications Precautions May cause loss of consciousness when administered with prochlorperazine Dosing Interactions Contraindications Precautions Documented hypersensitivity; renal failure; anuria; hemochromatosis; children <5 y with very little iron deposition Dosing Interactions Contraindications

Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions 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). Dosing Interactions Contraindications Precautions 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 Dosing Interactions Contraindications Precautions Data limited; do not take with aluminum-containing antacids Dosing Interactions Contraindications Precautions Documented hypersensitivity Dosing Interactions Contraindications Precautions Pregnancy B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals Precautions Common adverse effects include diarrhea, nausea, abdominal pain, headache, pyrexia, cough, and rash; may increase serum creatinine and hepatic enzyme levels; decrease dose with

persistent elevation of serum creatinine level; may cause auditory and visual disturbances; slight decreases in serum copper and zinc levels may occur; dissolve tab completely in water, orange juice, or apple juice and drink resulting susp immediately (do not swallow tab whole, do not chew or crush); measure serum ferritin levels monthly and adjust dose every 3-6 mo based on serum ferritin trends 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). Dosing Interactions Contraindications Precautions Adult 10-20 mg IV/SC added to chelating solution Pediatric Administer as in adults Dosing Interactions Contraindications Precautions Decreases hypoglycemic effect of insulin; phenobarbital, phenytoin, and rifampin increase rate of metabolism Dosing Interactions Contraindications Precautions 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 Dosing Interactions Contraindications Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions 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. Dosing Interactions Contraindications Precautions 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 Dosing Interactions Contraindications Precautions Potentiates effect of warfarin, prolonging PT; may cause thrombocytopenia when given in combination with thiazides; increases concentration of methotrexate; potentiates effect of phenytoin Dosing Interactions Contraindications Precautions Documented hypersensitivity; infants <2 mo; G-6-PD deficiency; megaloblastic anemia; porphyria Dosing Interactions Contraindications Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions 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 TMPSMZ; 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. Dosing Interactions Contraindications Precautions Adult 3-6 mg/kg/d IV divided q8h Pediatric 6-7.5 mg/kg/d IV divided q8h Dosing Interactions Contraindications Precautions 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) Dosing Interactions Contraindications Precautions Documented hypersensitivity Dosing Interactions Contraindications Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions 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. Dosing Interactions Contraindications Precautions Adult 250 mg PO bid Pediatric

<5 years: 125 mg PO bid >5 years: Administer as in adults Dosing Interactions Contraindications Precautions Probenecid may increase effectiveness by decreasing clearance; tetracyclines are bacteriostatic, causing decrease in effectiveness of penicillins when administered concurrently Dosing Interactions Contraindications Precautions Documented hypersensitivity Dosing Interactions Contraindications Precautions 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. Dosing Interactions Contraindications Precautions Adult 3 mg/kg/d PO administered with SC deferoxamine infusion Pediatric Administer as in adults Dosing Interactions Contraindications Precautions Decreases effects of warfarin and fluphenazine; increases aspirin levels; enhances urinary iron excretion Dosing Interactions

Contraindications Precautions None reported Dosing Interactions Contraindications Precautions 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. Dosing Interactions Contraindications Precautions Adult 200-400 IU/d PO Pediatric 1 IU/kg/d PO Dosing Interactions Contraindications Precautions Mineral oil decreases absorption of vitamin E; vitamin E delays absorption of iron and increases effects of anticoagulants Dosing Interactions Contraindications Precautions IV use in infants Dosing Interactions Contraindications Precautions 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.

Dosing Interactions Contraindications Precautions

Adult 0.4-1 mg/d PO Pediatric 1 mg/d PO Dosing Interactions Contraindications Precautions Increases phenytoin metabolism; PO contraceptives impair folate metabolism, depleting levels Dosing Interactions Contraindications Precautions Pernicious anemia; aplastic anemia Dosing Interactions Contraindications Precautions 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. Dosing Interactions Contraindications Precautions 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) Dosing Interactions Contraindications Precautions 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) Dosing Interactions Contraindications Precautions 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 Dosing Interactions Contraindications Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions 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-Barr 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. Dosing Interactions Contraindications Precautions 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 Dosing Interactions Contraindications Precautions Immunosuppressive agents (large amounts of corticosteroids, antimetabolites, alkylating agents, cytotoxic agents) may reduce effectiveness Dosing Interactions Contraindications Precautions Documented hypersensitivity; immunosuppressed children or those receiving immunosuppressive therapy; IV/ID/SC administration Dosing Interactions Contraindications Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions 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-Barr 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. Dosing Interactions Contraindications Precautions Adult Pediatric <2 years: Contraindicated >2 years: 0.5 mL SC; consider revaccination after 2-3 y Dosing Interactions Contraindications Precautions 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 Dosing

Interactions Contraindications Precautions Documented hypersensitivity; children <2 y Dosing Interactions Contraindications Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions May cause 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. Dosing Interactions Contraindications Precautions 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 Dosing Interactions Contraindications Precautions 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) Dosing Interactions Contraindications Precautions 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) Dosing Interactions Contraindications Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions For IM use only (do not administer IV under any circumstances); take special care to prevent injection into or near a blood vessel or nerve; caution in patients with possible history of latex sensitivity (packaging contains dry natural rubber); use of pneumococcal conjugate vaccine does not replace use of 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.17 Improvement of pulmonary hypertension following hydroxyurea has also been observed.18 Hydroxyurea (Droxia, Hydrea) Inhibitor of deoxynucleotide synthesis. Dosing Interactions Contraindications Precautions 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 Dosing Interactions Contraindications Precautions 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 Dosing Interactions Contraindications Precautions Documented hypersensitivity; severe anemia or bone marrow suppression (ie, WBC counts of <2500, platelets <100,000/mL Dosing Interactions Contraindications Precautions Pregnancy D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus Precautions Caution in renal impairment; for sickle cell, monitor blood count q2wk and adjust dose accordingly (ie, discontinue if hematologic toxicity occurs, then resume after recovery by reducing dose associated with hematologic toxicity by 2.5 mg/kg/d); hematologic toxicity is defined as neutrophils <2000/mL, platelets <80,000/mL, hemoglobin <4.5 g/dL, and reticulocytes <80,000/mL (if Hbg <9 g/dL) 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.19 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). Dosing Interactions Contraindications Precautions 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

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

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.

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.

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.

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.

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.

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

Somatropin

http://emedicine.medscape.com/article/958850-diagnosis

Thalassemia: Differential Diagnoses & Workup

Author: Hassan M Yaish, MD

2010 Laboratory Studies

Laboratory studies in thalassemia include the following:

The CBC count and peripheral blood film examination results are usually sufficient to suspect the diagnosis. Hemoglobin (Hb) evaluation confirms the diagnosis in thalassemia, Hb H disease, and Hb E/ thalassemia. o In the severe forms of thalassemia, the Hb level ranges from 2-8 g/dL.
o

Mean corpuscular volume (MCV) and mean corpuscular Hb (MCH) are significantly low, but, unlike thalassemia trait, thalassemia major is associated with a markedly elevated RDW, reflecting the extreme anisocytosis. The WBC count is usually elevated in thalassemia major; this is due, in part, to miscounting the many nucleated RBCs as leukocytes. Leukocytosis is usually present, even after excluding the nucleated RBCs. A shift to the left is also encountered, reflecting the hemolytic process. Platelet count is usually normal, unless the spleen is markedly enlarged. Peripheral blood film examination reveals marked hypochromasia and microcytosis, hypochromic macrocytes that represent the polychromatophilic cells, nucleated RBCs, basophilic stippling, and occasional immature leukocytes, as shown below.

o o

Peripheral blood film in Cooley anemia.

Supra vital stain in hemoglobin H disease that reveals Heinz bodies (golf ball appearance).
Hb electrophoresis usually reveals an elevated Hb F fraction, which is distributed heterogeneously in the RBCs of patients with thalassemia, Hb H in patients with Hb H disease, and Hb Bart in newborns with thalassemia trait. In -0 thalassemia, no Hb A is usually present; only Hb A2 and Hb F are found. Iron studies are as follows:
o o o

Serum iron level is elevated, with saturation reaching as high as 80%. The serum ferritin level, which is frequently used to monitor the status of iron overload, is also elevated. However, an assessment

using serum ferritin levels may underestimate the iron concentration in the liver of a transfusion-independent patient with thalassemia.

Complete RBC phenotype, hepatitis screen, folic acid level, and human leukocyte antigen (HLA) typing are recommended before initiation of blood transfusion therapy.

Imaging Studies
Skeletal survey and other imaging studies reveal classic changes of the bones that are usually encountered in patients who are not regularly transfused. The striking expansion of the erythroid marrow widens the marrow spaces, thinning the cortex and causing osteoporosis. These changes, which result from the expanding marrow spaces, usually disappear when marrow activity is halted by regular transfusions. Osteoporosis and osteopenia may cause fractures, even in patients whose conditions are wellcontrolled. In addition to the classic "hair on end" appearance of the skull, shown below, which results from widening of the diploic spaces and observed on plain radiographs, the maxilla may overgrow, which results in maxillary overbite, prominence of the upper incisors, and separation of the orbit. These changes contribute to the classic "chipmunk facies observed in patients with thalassemia major

The classic "hair on end" appearance on plain skull radiographs of a patient with Cooley anemia.
Other bony structures, such as ribs, long bones, and flat bones, may also be sites of major deformities. Plain radiographs of the long bones may reveal a lacy trabecular pattern. Changes in the pelvis, skull, and spine become more evident during the second decade of life, when the marrow in the peripheral bones becomes inactive while more activity occurs in the central bones. Compression fractures and paravertebral expansion of extramedullary masses, which could behave clinically like tumors, more frequently occur during the second decade of life. MRI and CT scanning are usually used in diagnosing such complications. Chest radiography is used to evaluate cardiac size and shape. MRI and CT scanning can be used as noninvasive means to evaluate the amount of iron in the liver in patients receiving chelation therapy. A newer noninvasive procedure involves measuring the cardiac T2 with cardiac magnetic resonance (CMR). This procedure has shown decreased values in cardiac T2 due to iron deposit in the heart. Unlike liver MRI, which usually correlates very well with the iron concentration in the liver measured using percutaneous liver biopsy samples and the serum

ferritin level, CMR does not correlate well with the ferritin level, the liver iron level, or echocardiography findings. This suggests that cardiac iron overload cannot be estimated with these surrogate measurements. This is also true in measuring the response to chelation therapy in patients with iron overload. The liver is clear of iron loading much earlier than the heart, which also suggests that deciding when to stop or reduce treatment based on liver iron levels is misleading. The relationship between hepatic and myocardial iron concentration was assessed by T2-MRI in patients receiving chronic transfusion.3 A poor correlation was noted, and approximately 14% of patients with cardiac iron overload were identified who had no matched degree of hepatic hemosiderosis. Left ventricular ejection fraction was insensitive for detecting high myocardial iron. For this reason, cardiac evaluation should be addressed separately. Hepatic iron content (HIC) obtained by liver biopsy, cardiac function tests obtained by echocardiography measurements, and multiple gated acquisition scan (MUGA) findings were compared to the results of iron measurements on R2-MRI in the liver and heart.4 Various iron overload patients were involved in the study that revealed that R2-MRI was strongly associated with HIC (weakly but significantly with ferritin level) and represents an excellent noninvasive method to evaluate iron overload in the liver and heart and to monitor response to chelation therapy.

Other Tests
The following tests may be indicated:

ECG and echocardiography are performed to monitor cardiac function. HLA typing is performed for patients for whom bone marrow transplantation is considered. Eye examinations, hearing tests, renal function tests, and frequent blood counts are required to monitor the effects of deferoxamine (DFO) therapy and the administration of other chelating agents (see Treatment, Medication).

Procedures
Bone marrow aspiration is needed in certain patients at the time of the initial diagnosis to exclude other conditions that may manifest as thalassemia major. Liver biopsy is used to assess iron deposition and the degree of hemochromatosis. However, using liver iron content as a surrogate for evaluation of cardiac iron is misleading. Many studies have shown very poor correlation between the two; hence, cardiac evaluation for the presence of iron overload needs to be addressed separately. Measurement of urinary excretion of iron after a challenge test of DFO is used to evaluate the need to initiate chelation therapy and reflects the amount of iron overload.

Histologic Findings

All severe forms of thalassemia exhibit hyperactive marrow with erythroid hyperplasia and increased iron stores in marrow, liver, and other organs. In the untreated person with severe disease, extramedullary hematopoiesis in unusual anatomic sites is one of the known complications. Erythroid hyperplasia is observed in bone marrow specimens. Increased iron deposition is usually present in marrow, as depicted in the image below, liver, heart, and other tissues.

Excessive iron in a bone marrow preparation.

Staging
Some use a relevant staging system based on the cumulative numbers of blood transfusions given to the patient to grade cardiac-related symptoms and determine when to start chelation therapy in patients with thalassemia major or intermedia. In this system, patients are divided into 3 groups. The first group contains those who have received fewer than 100 units of packed RBCs (PRBCs) and are considered to have stage I disease. These patients are usually asymptomatic; their echocardiograms reveal only slight left ventricular wall thickening, and both the radionuclide cineangiogram and the 24-hour ECG findings are normal. Patients in the second group (stage II patients) have received 100-400 units of blood and may report slight fatigue. Their echocardiograms may demonstrate left ventricular wall thickening and dilatation but normal ejection fraction. The radionuclide cineangiogram findings are normal at rest but show no increase or fall in ejection fraction during exercise. Atrial and ventricular beats are usually noticed on the 24-hour ECG. Finally, in stage III patients, symptoms range from palpitation to congestive heart failure, decreased ejection fraction on echocardiogram, and normal cineangiogram results or decreased ejection fraction at rest, which falls during exercise. The 24-hour ECG reveals atrial and ventricular premature beats, often in pairs or in runs.

A second classification, introduced by Lucarelli, is used for patients with severe disease who are candidates for hematopoietic stem cell transplantation (HSCT).5 This classification is used to assess risk factors that predict outcome and prognosis and addresses 3 elements: (1) degree of hepatomegaly, (2) presence of portal fibrosis in liver biopsy sample, and (3) effectiveness of chelation therapy prior to transplantation. If one of these elements is unfavorable prior to HSCT, the chance of event-free survival is significantly poorer than in patients who have neither hepatomegaly nor fibrosis and whose condition responds well to chelation (class 1 patients). The event-free survival rate after allogeneic HSCT for class 1 patients is 90%, compared with 56% for those with hepatomegaly and fibrosis and whose condition responds poorly to chelation (class 3).