thalasemia diskel

(Alloanamnesis/Heteroanamnesis tgl 15 Oktober 2011)

A. KETERANGAN UMUM

Nama Penderita : Novianto

Jenis kelamin : Laki-laki

Tempat/Tanggal Lahir : Cimahi, 14 November 1998

Berat Badan : 29 Kg

Alamat : Jl. Sriwijaya No. 66 RT.2 RW.18

Kiriman Dari : Keluarga

Dengan Diagnosis : Thalasemia Mayor

AYAH : Nama : Tn. Rusaid

Umur : 43 tahun

Pendidikan : SMA

Pekerjaan : Pegawai Negeri Sipil

Penghasilan : + Rp 2.500.000/bulan

IBU : Nama : Ny. Sumarsih

Umur : 45 tahun

Pendidikan : S1

Pekerjaan : Pengajar Sekolah Dasar

Penghasilan : + Rp 2.500.000/bulan

Tgl. Masuk : Kamis, 13 Oktober 2011

Tgl. Pemeriksaan : Sabtu, 15 Oktober 2011

B. KELUHAN UTAMA :

Lemah badan

C. ANAMNESIS KHUSUS :

Sejak 2 hari sebelum masuk rumah sakit (11 Oktober 2011) penderita

mengeluh lemah badan semakin lama semakin bertambah berat. Keluhan dirasakan

makin memberat jika pasien beraktivitas berat dan akan berkurang jika pasien

beristirahat.

D. ANAMNESIS UMUM

Keluhan lemah badan disertai penurunan nafsu makan serta sering pusing dan

penglihatan berkunang-kunang yang sering timbul karena pengaruh perubahan

posisi dari berbaring ke duduk, dan duduk ke berdiri.

STATUS RESPONSI PEDIATRI – THALLASEMIABAGIAN PEDIATRI KEL. XXXV-E & F SABTU 15 OKTOBER 2011

Hal 1

Keluhan juga disertai dengan keluhan pucat yang awalnya hanya tampak

pada wajah, semakin lama semakin bertambah pucat. Pada berusia 3 tahun

penderita dikeluhkan Panas badan, karena keluhan tersebut penderita dibawa

berobat ke RS Dustira. Setelah menjalani pemeriksaan fisik dan laboratorium dokter

menyatakan bahwa penderita mengidap penyakit talasemia karena penderita

terlihat sangat pucat. Karena penyakitnya tersebut penderita kemudian disarankan

untuk menjalani transfusi darah setiap keluhan timbul.

Semenjak saat itu hingga saat ini penderta selalu rutin kontrol dan telah

mendapat tranfusi sebanyak 79 kali. Pada mulanya penderita menjalani transfusi

darah setiap 4 bulan sekali dengan jumlah pemberian darah sebanyak 2 labu,

namun pada 3 tahun terakhir frekwensi pemberian transfusi hanya 1 bulan sekali

dengan jumlah pemberian darah sebanyak 2 labu. Penderita terakhir menjalani

transfusi pada tanggal 14 Oktober 2011. Setiap selesai tranfusi keluhan pucat, mata

berkunang-kunang, pusing, mudah lelah dan lemas badan akan jauh berkurang

selain itu penderita merasa lebih segar dan nafsu makan menjadi lebih baik.

Riwayat penyakit serupa di dalam keluarga tidak ada.

Riwayat adanya mimisan ada pada usia 3 tahun. Riwayat bintik-bintik

kemerahan, dan pendarahan gusi tidak ada.

Riwayat adanya luka dan peradangan pada lidah dan mukosa mulut disangkal.

Riwayat panas badan yang lama disangkal

E. ANAMNESIS TAMBAHAN

1. RIWAYAT PERSALINAN

Penderita dilahirkan secara spontan di Bidan, dengan berat badan lahir 3100

gram, dengan masa kehamilan selama 36 minggu. Bayi langsung menangis.

2. RIWAYAT IMUNISASI

Riwayat Imunisasi.

BCG : Usia 1 minggu

DPT : 4 kali, pada usia 2, 3, dan 4 bulan

Polio : 4 kali, pada usia 0, 2, 3, dan 4 bulan

Campak : 1 kali, pada usia 9 bulan

Hepatitis B : 3 kali, pada usia 0, 2 dan 6 bulan

Imunisas

iDasar Ulangan

BCG 1 minggu -


Hal 2

DPT 3 bulan 4 5 20 bulan 6 tahun

Polio 0 2 3 4 20 bulan 6 tahun

Campak 9 bulan -

Hepatitis 0 1 6 -

3. KEADAAN KESEHATAN

Ayah : Sehat

Ibu : Sehat

Saudara : Sehat

Orang yang serumah : Sehat

4. KEPANDAIAN

Berbalik : 4 bulan

Duduk tanpa bantuan : 7 bulan

Duduk tanpa pegangan : 7 bulan

Bicara 1 kata : 9 bulan

Bicara 1 kalimat : 18 bulan

Berjalan 1 tangan dipegang : 9 bulan

Berjalan tanpa dipegang : 12 bulan

Membaca : 5 tahun

Menulis : 5 tahun

Sekolah : 6 tahun

5. GIGI GELIGI

- Pertama : 8 buah gigi Gigi Susu : V IV III II I I II III IV V

susu V IV III II I I II III IV V

- Sekarang : 6 buah gigi Gigi Tetap : 8 7 6 5 4 3 2 1 1 2 3 4 5 6 7 8

tetap 8 7 6 5 4 3 2 1 1 2 3 4 5 6 7 8

6. MAKANAN

UMUR JENIS MAKANAN KUANTITAS

0 – 4 Bulan ASI Eksklusif Sesuka bayi

4 – 6 Bulan ASI Eksklusif Sesuka bayi

6 – 10 Bulan ASI + bubur bayi Sesuka bayi + 2X/hari

10 – 12 Bulan ASI + nasi tim Sesuka bayi + 3X/hari

12 bulan hingga

saat ini

Susu Formula + Nasi &

Makanan Hidangan KlgSesuka anak + 3X/hari


Hal 3

Berdasarkan anamnesa tambahan dapat disimpulkan bahwa asupan makanan yang

didapat anak Albi secara kwantitatif dan kwalitatif cukup

7. PENYAKIT YANG SUDAH DIALAMI

Campak Diare

Bengek

Batuk rejan Demam Tifoid

Eksim

TBC Kuning

Kaligata

Dif teri Cacing

Sakit tenggorokan

Tetanus Kejang

Batuk pilek


Hal 4

PEMERIKSAAN FISIK (TANGGAL 15 OKTOBER 2011)

1. KEADAAN UMUM

Keadaan sakit : Tampak Sakit Ringan

Kesadaran : Composmentis (E4,V5,M6) GCS=15

Sesak : PCH tidak ada, Retraksi tidak ada

Sianosis : Sentral maupun perifer tidak tampak sianosis

Ikterus : Ada

Edema : Pitting edema tidak ada, Anasarka tidak ada

Dehidrasi : Tanpa dehidrasi

Anemi : Tampak Anemis (pucat)

Kejang : Lokal / umum tidak ada, Tonik/klonik tidak ada

Letak paksa (posisi) tubuh : Tidak ada

PENGUKURAN

Umur : 13 Tahun

Berat Badan : 29 Kg

Tinggi Badan : 130 cm

Status Gizi : Normal ( Z Score )

Lingkar Kepala : (-) cm

Lingkar Dada : (-) cm

Lingkar Lengan Atas : (-) cm


Hal 5

TANDA VITAL

Tekanan Darah : 130/70 mmHg

Nadi : 102 x/menit, regular, equal, isi cukup

Respirasi : 32x/menit

Tipe : Abdominothorakal

Suhu : 36,8 C

2. PEMERIKSAAN KHUSUS

1. Kepala

Bentuk Kepala : Normocephal

Rambut : Tidak ada kelainan

Muka : Pucat (-)

Mata : Sklera : Ikterik : +/+

Konjungtiva : Anemis : +/+

Pupil : Bulat isokhor

THT : Telinga : Discharge ( – )

Hidung : Sekret ( – )

Tenggorok : Tonsil : T1 – T1 tenang

Pharynx : Tidak Hiperemis

Mulut : Bibir : Sianosis (-)

Gusi : Tidak ada kelainan

Gigi : Tidak ada kelainan

Langit2 : Basah, Tidak ada kelainan

Lidah : Basah bersih, Tidak ada kelainan

2. Leher

Tekanan Vena : Tidak meningkat

Kaku Kuduk : Tidak ada

Lympadenopathy : Tidak ada


Hal 6

R L

L R

R L

3. Dada

a. Dinding Dada/Paru

Depan

Inspeksi : Bentuk dan gerak simetris

Palpasi : Vokal Fremitus normal, kanan = kiri

Perkusi : Sonor kanan = kiri

Auskultasi : VBS kanan = kiri

Ronkhi -/- Wheezing -/-

Belakang

Inspeksi : Bentuk dan gerak simetris

Palpasi : Vokal Fremitus normal, kanan = kiri

Perkusi : Sonor kanan = kiri

Auskultasi : VBS kanan = kiri

Ronkhi -/- Wheezing -/-

b. Jantung

Inspeksi : Ictus cordis tidak terlihat

Palpasi : Ictus cordis teraba

Perkusi : Dalam batas normal

Auskultasi : Bunyi Jantung I dan II murni reguler

Bunyi Jantung tambahan tidak ada

4. Perut

Inspeksi : Datar

Palpasi : Tegang, NT (–) turgor kembali cepat

Hepar : Teraba, 4 cm BAC, 2 cm BPX, tepi

tumpul, permukaan rata, Nyeri tekan

(+) pada perkusi dullness (+)

Lien : Teraba, SCHUFFNER III,

incisura teraba (+)

Perkusi : Dullness & Tympani

Auskultasi : Bising usus (+) normal

5. Genitalia

Jenis Kelamin : Laki-laki

Kelainan : Tidak ada kelainan


I

IV 4

IIIII

VVI

VIIVIII

6 4 cm BAC

5 4 cm BPX

Hal 7

6. Anggota Gerak

Atas

Kulit : Gizi kulit kurang, warna coklat kehitaman

Sendi : Tidak ada kelainan

Otot : Tidak ada kelainan

Refleks : Tidak ada kelainan

Edema : Tidak ditemukan

Palmar Manus : Pucat (+)

Kuku : Tidak ada Kelainan

Lymphadenopathy Axiller (-/-)

Bawah

Kulit : Gizi kulit kurang, warna coklat kehitaman

Sendi : Tidak ada kelainan

Otot : Tidak ada kelainan

Refleks : Refleks fisiologis (+)

Edema : Tidak ditemukan

Palmar Pedis : Pucat (+)

Kuku : Tidak ada Kelainan

Lymphadenopathy Inguinal (-/-)

7. Susunan Saraf

Refleks koma

Refleks cahaya (pupil) : Tidak ada Kelainan

Refleks okulosefalik : Tidak dilakukan pemeriksaan

Refleks kornea : Tidak dilakukan pemeriksaan

Rangsang Meningen : Kaku Kuduk tidak ada

Bruzkinsky I/II/III : Tidak dilakukan pemeriksaan

Kernig : Tidak dilakukan pemeriksaan

Laseque : Tidak dilakukan pemeriksaan

Saraf Otak : Tidak ada kelainan

Motorik : Tidak ada kelainan

Sensorik : Tidak ada kelainan

Vegetatif : Tidak ada kelainan

Refleks Fisiologis : APR : + / +

KPR : + / +

Refleks Patologis : Babinsky : Tidak dilakukan pemeriksaan

Chaddock : Tidak dilakukan pemeriksaan


Hal 8

Gordon : Tidak dilakukan pemeriksaan

Oppenheim : Tidak dilakukan pemeriksaan


Hal 9

PEMERIKSAAN PENUNJANG

A. LABORATIORIUM

DARAH

Hb : 7 gr/dl

Leukosit : 8.8 rb/mm3

Hematokrit : 21.1 %

Eritrosit : 3.4 rb/mm3

Trombosit : 348 rb

MCV : 63.1%

MCH :20.9 %

MCHC : 33.2 %

RDW : 28.7 %

Sediaan Apus Darah Tepi (SADT) : Tidak dilakukan pemeriksaan

- Hitung Jenis :

Netrofil Segmen : 51.3 %

Limfosit : 42.4 %

Monosit : 6 %

URINE

Tidak Dilakukan Pemeriksaan

FESES


B. RONTGEN

Tidak dilakukan pemeriksaan

C. LAIN-LAIN

Tidak dilakukan pemeriksaan

IV. RESUME

Berdasarkan (Hetero & Autoanamnesis) pada tanggal 15 Oktober 2011,

didapatkan keterangan bahwa penderita adalah seorang anak laki-laki usia 13

tahun, BB : 29 kg, TB : 134 cm, status gizi baik, datang ke Poliklinik RS Dustira

dengan keluhan utama fatigue.

Dari anamnesa didapatkan :


Hal 10

Sejak 2 hari sebelum masuk rumah sakit (11 Oktober 2011) penderita

mengeluh fatigue semakin lama semakin bertambah berat. Keluhan dirasakan

makin memberat jika pasien beraktivitas berat dan akan berkurang jika pasien

beristirahat.

Keluhan disertai malaise, anorexia serta mudah lelah. Keluhan juga disertai

keluhan hipotensi orthostatik berupa pusing dan berkunang-kunang pada

perubahan posisi tubuh.

Keluhan juga disertai dengan keluhan pucat yang awalnya hanya tampak

pada wajah, semakin lama semakin bertambah pucat. Pada berusia 3 tahun

penderita dikeluhkan Panas badan, karena keluhan tersebut penderita dibawa

berobat ke RS Dustira. Setelah menjalani pemeriksaan fisik dan laboratorium dokter

menyatakan bahwa penderita mengidap penyakit thalasemia karena penderita

terlihat sangat pucat. Karena penyakitnya tersebut penderita kemudian disarankan

untuk menjalani transfusi darah setiap keluhan timbul.

Semenjak saat itu hingga saat ini penderta selalu rutin kontrol dan telah

mendapat tranfusi sebanyak 79 kali. Pada mulanya penderita menjalani transfusi

darah setiap 4 bulan sekali dengan jumlah pemberian darah sebanyak 2 labu,

namun pada 3 tahun terakhir frekwensi pemberian transfusi hanya 1 bulan sekali

dengan jumlah pemberian darah sebanyak 2 labu. Penderita terakhir menjalani

transfusi pada tanggal 14 Oktober 2011. Setiap selesai tranfusi keluhan pucat, mata

berkunang-kunang, pusing, malaise dan fatigue akan jauh berkurang selain itu

penderita merasa lebih segar dan nafsu makan menjadi lebih baik.

Riwayat thallasemia di dalam keluarga tidak ditemukan. Riwayat keluhan

timbula akibat adanya pendarahan ada pada usia 3 tahun.

Anamnesis makanan : Kuantitas dan Kualitas Cukup

Anamnesis imunisasi : Imunisasi dasar beserta ulangan lengkap.

Dari pemeriksaan fisik didapatkan :

Keadaan Umum : Kesadaran Composmentis dengan GCS = 15

Pasien tampak sakit sedang

Tanda Vital :

Tekanan Darah : 130/70 kali/menit

Nadi : 112 kali/menit, regular, equal, isi cukup

Respirasi : 32 x/menit

Tipe : Abdominothorakal

Suhu : 36,8 C.


Hal 11

Pada pemeriksaan fisik ditemukan tanda-tanda anemia hemolitik berupa sklera

mata ikterik, konjungtiva anemis serta muka, tubuh, dan palmar manus dan pedis

yang tampak pucat. Pada pemeriksaan Abdomen ditemukan Hepatomegali dan

Splenomegali. Pada pemeriksaan hepar melalui palpasi hepar teraba 3 cm BAC,

dan 2 cm BPX dengan konsistensi lunak, permukaan rata, tepi tumpul dan NT yang

negatif, pada perkusi Dullness (+). Pada pemeriksaan Lien ditemukan melalui

palpasi lien teraba membesar SCHUFFNER III dengan incisura yang teraba, pada

perkusi dullness (+).

Tanda-tanda kemungkinan komplikasi gagal jantung tidak ditemukan, hal ini

berdasarkan haemodinamik yang stabil, ukuran jantung yang normal, tidak

terdapatnya edema, dan bunyi jantung yang normal tanpa bunyi jantung tambahan.

Kemungkinan adanya kelainan pada paru tidak ditemukan VF, VBS dalam batas

normal kanan = kiri, Ronkhi & Wheezing tidak ditemukan.

Dari pemeriksaan laboratorium didapatkan :

Pemeriksaan darah : Ditemukan adanya penurunan Hb, & Ht yang cukup

Signifikan (Hb 7 gr/dL, Ht 21,1%)

Ditemukan MCV dan MCH menurun.

Pemeriksaan urin : Tidak dilakukan pemeriksaan

Pemeriksaan feses : Tidak dilakukan pemeriksaan

V. DIAGNOSIS

Diagnosis Banding :

Thallasemia Mayor

Anemia defisiensi besi

Diagnosis Kerja :

Thallasemia Mayor

.

VI. USUL PEMERIKSAAN:

1. SADT

2. Hb-elektroforesis

3. Pungsi sumsum tulang

4. Pemeriksaan kadar biirubun total, indirek, SGOT, SGPT.


Hal 12

VII. TERAPI

Supportive berupa :

Makan gizi seimbang dan diet makanan rendah zat besi

Transfusi PRC 2 labu

Desferioksamin 20-40 mg/kb diberikan melalui Infusion Pump IV dalam

rentang 8-12 jam atau 1 – 2 g IV dengan kecepatan 15 mg/kg/jam

Roborontia :

Asam Askorbat (Vitamin C) 3 mg/kg/hari diberikan bersamaan dengan

Desferioksamin

Alpha-tocopherol (Vitamin E) 200-400 IU/hari PO

Asam Folat 0.4 – 1 mg/hari PO

VIII. PROGNOSIS

Quo ad vitam : ad bonam

Quo ad fuctionam : ad malam


Hal 13

DISKUSI KASUS

Keluhan utama pada pasien ini adalah lemah badan dan pucat, keluhan lemah

badan dan pucat ini biasanya ditemukan pada penyakit thallasemia, anemia

defisiensi besi, anemia megaloblastik, anemia aplastik, leukemia limfoblastik akut.

Pada penyakit thallasemia dikeluhkan pucat serta lemah badan, akibat anemia berat

dan pada pemeriksaan fisik ditemukan hepatosplenomegali. Pada penyakit anemia

defisiensi besi keluhan disertai dengan rasa letih, lemah, dan lesu yang didukung

adanya spoon nail pada pemeriksaan fisik. Pada anemia megaloblastik adanya

keluhan defisit sensoris serta keterlambatan perkembangan, pucat, lemah dan lesu

yang diakibatkan karena kurangnya vitamin B12 dan atau asam folat yang tidak

adekuat biasanya dapat juga diakibatkan karena riwayat BBLSR dan malnutrisi.

Pada anemia aplastik sealin adanya keluhan pucat dan lemah biasanya disertai

adanya perdarahan (purpura, petekie, ekimosis, epistaksis, perdarahan saluran

cerna) pada pemeriksaan fisik, tidak ditemukan adanya hepatosplenomegali dan

limfadenopati sedangkan pada leukemia limfobastik akut keluhan pucat lemah lesu,

disertai dengan adanya panas badan atau infeksi yang berulang.

Pada pasien ini keluhan pucat tidak disertai adanya demam atau infeksi yang

berulang tidak memiliki riwayat BBLSR tidak disertai perdarahan dan pada

pemeriksaan fisik yang ditemukan adalah hepatosplenomegali (+), spoon nail (-),

purpura (-), ptekie (-), ekimosis (-), epistaksis (-), perdarahan saluran cerna (-),

limfadenopati (-)

1. Dari anamnesa yang mendukung ke diagnosis kerja Thallasemia Mayor

adalah :

Adanya keluhan yang mengarah pada anemia pada penderita seperti pucat,

lemah badan, tidak bersemangat dan sering mengeluh capek setelah

beraktivitas, disertai dengan penurunan nafsu makan, mata berkunang, serta

sering pusing.

Adanya riwayat transfusi berulang sejak penderita berusia 3 tahun.

2. Dari pemeriksaan fisik yang mendukung ke diagnosis kerja Thallasemia

Mayor adalah :


Hal 14

Pada pemeriksaan fisik ditemukan tanda-tanda anemia berupa sklera mata

yang ikterik, konjungtiva anemi, serta muka, tubuh, dan palmar manus dan

pedis yang tampak pucat.

Leher: Lymphadepathy servical tidak ditemukan. Lymphadenopathy atau

pembesaran kelenjar getah bening adalah penemuan yang sering ditemukan

pada penyakit infeksi, baik akut ataupun kronis. Pada anak dengan

Thallasemia biasanya dapat ditemukan adanya splenomegali. Splenomegali

sendiri sebagai bagian dari sistem RES biasanya akan timbul sebagai akibat

adanya infeksi, seperti misalnya pada malaria, DHF, dll. Pada kasus

thallasemia biasanya didapat splenomegali tanpa lympadenopathy.

Pada pemeriksaan Abdomen ditemukan Hepatomegali dan Splenomegali.

Pada pemeriksaan hepar melalui palpasi hepar teraba 3 cm BAC, dan 2 cm

BPX dengan konsistensi lunak, permukaan rata, tepi tumpul dan NT yang

positif, pada perkusi Dullness (+). Pada pemeriksaan Lien ditemukan melalui

palpasi lien teraba membesar SCHUFFNER III dengan incisura yang teraba,

pada perkusi dullness (+).

Tanda-tanda kemungkinan komplikasi gagal jantung tidak ditemukan, hal ini

berdasarkan haemodinamik yang stabil, ukuran jantung yang normal, tidak

terdapatnya edema, dan bunyi jantung yang normal tanpa bunyi jantung

tambahan.

3. Dari pemeriksaan Laboratorium yang mendukung diagnosis Thalasemia

Mayor adalah :

Hb : 7 gr/dl


Hematokrit : 21.1 %

Eritrosit : 3.4 rb/mm3

Trombosit : 348 rb

MCV : 63.1%

MCH :20.9 %

MCHC : 33.2 %

RDW : 28.7 %

Sediaan Apus Darah Tepi (SADT) : Tidak dilakukan pemeriksaan

- Hitung Jenis :

Netrofil Segmen : 51.3 %

Limfosit : 42.4 %


Hal 15

Monosit : 6 %

URINE


FESES


Nilai Hb : 7 gr/dl

Nilai normal Hb pada anak usia 6 – 12 tahun adalah 11.5 -15.5 gr/dl (Nelson

textbook of periatrics). Hasil pemeriksaan ini menyokong gejala anemia yang

ditemukan pada pemeriksaan fisik.


Nilai Leukosit sebesar ini menandakan kemungkinan adanya komorbiditas

dengan penyakit infeksi, kemungkinan besar infeksi bakteri.

MCV : 63.1%

MCHC : 33.2 %

Nilai MCV dan MCHC ini menyokong jenis dari anemia yang dialami penderita.


Hal 16

TEORI

THALASSEMIA

BATASAN

Golongan penyakit yang bersifat keturunan (herediter) yang ditandai dengan adanya

defisiensi pembentukan rantai globin spesifik dari Hb.

KLASIFIKASI

Thalasemia Mayor

Thalasemia Intermidia

Thalasemia Minor

ETIOLOGI

Defesiensi rantai globin yang bersifat herediter.

KRITERIA DIAGNOSIS

Anamnesis

Pucat, gangguan pertumbuhan

Riwayat keluarga

Pemeriksaan fisik

Facies Cooley pada anak yang lebih besar, ikterik ringan, hepatosplenomegali

tanpa lympadenopathy.

Labolatorium

Anemia berat (< Hb <3 g/dL atau 4 g/dL)

Morfologi eritrosit: gambaran hemolitik (anisositosis, poikilositosis, polikromasi,

sel target, normoblast)

Dapat terjadi leikopenia dan trobositopenia

Retikulosit meningkat

MCV rendah (<65 fl), MCHC menurun

Hb F atau Hb A2 meningkat

Sumsum tulang aktivitas eritropoesis meningkat

DIAGNOSIS BANDING


Hal 17

Hemoglobinasi

Anemia Defesiensi Besi

Anemia disentopoetik kongenital

PEMERIKSAAN PENUNJANG

Hb, leukosit, trombosit, hitung jenis, morfologi darah tepi, retikulosit.

Indeks eritrosit: MCV, MCHC

Hb-lektroforesis

Punksi sumsum tulang

PENYULIT

Hemosiderosis

TERAPI

Umum

Makanan gizi seimbang

Dietetik

Makanan, obat yang banyak mengandung zat besi sebaiknya dihindarkan

Khusus

Dapat dicoba transplantasi sumsum tulang.

PRC 10-15 mL/kbBB setiap 4 mgg mengatasi anemia, sehingga kadar Hb >

10 g/dL. Bila tedapat tanda gagal jantung, pernah ada kelainan jantung atau

Hb < 5 g/dL maka dosis untuk satu kali pemberian tidak boleh lebih dari

transfusi darah, diberikan O2 dengan kecepatan 2-4 L/mnt.

Iron Chelating Agent (desferioksamin) mengatasi kelebihan Fe dalam

jaringan tubuh dosis 4 mg/kg/hr, s.k. 10-12 jam/hr, selama 5 hari dalam 1

minggu.

Splenektomi

Dilakukan bila didapat hipersplenisme atau jarak pemberian transfusi yang

makin pendek.

Asam folat 1 mg/hr p.o.


Hal 18

Thalassemia

Author: Hassan M Yaish, MD, Associate Professor of Pediatrics, University of Utah School of Medicine, Pediatric Hematologist/Oncologist, Department of Pediatrics, Primary Children's Medical Center

INTRODUCTIONBackground: The thalassemias are inherited disorders of hemoglobin (Hb) synthesis. Their clinical severity varies widely, ranging from asymptomatic forms to severe or even fatal entities. The name Mediterranean anemia, which Whipple introduced, is misleading because the condition can be found in any part of the world. As described below, different types of thalassemia are more endemic to certain geographic regions.

In 1925, Thomas Cooley, a Detroit pediatrician, described a severe type of anemia in children of Italian origin. He noted abundant nucleated red blood cells (RBCs) in the peripheral blood, which he initially thought was erythroblastic anemia, an entity that von Jaksh described earlier. Before long, Cooley realized that erythroblastemia is neither specific nor essential in this disorder and that the term erythroblastic anemia was nothing but a diagnostic catchall. Although Cooley was aware of the genetic nature of the disorder, he failed to investigate the apparently healthy parents of the affected children.

In Europe, Riette described Italian children with unexplained mild hypochromic and microcytic anemia in the same year Cooley reported the severe form of anemia later named after him. In addition, Wintrobe and coworkers in the United States reported a mild anemia in both parents of a child with Cooley anemia. This anemia was similar to the one that Riette described in Italy. Only then was Cooley's severe anemia recognized as the homozygous form of the mild hypochromic and microcytic anemia that Riette and Wintrobe described. This severe form was then labeled as thalassemia major and the mild form as thalassemia minor. The word thalassemia is a Greek term derived from thalassa, which means "the sea" (referring to the Mediterranean), and emia, which means "related to blood."

These initial patients are now recognized to have been afflicted with thalassemia. In the following few years, different types of thalassemia that involved polypeptide chains other than chains were recognized and described in detail.

In recent years, the molecular biology and genetics of the thalassemia syndromes have been described in detail, revealing the wide range of mutations encountered in each type of thalassemia (see Image 3). b thalassemia alone can arise from any of more than 150 mutations.

Pathophysiology: The thalassemias are inherited disorders of Hb synthesis that result from an alteration in the rate of globin chain production. A decrease in the rate of production of a certain globin chain or chains (, , , ) impedes Hb synthesis and creates an imbalance with the other, normally produced globin chains.

Because 2 types of chains ( and non-) pair with each other at a ratio close to 1:1 to form normal Hbs, an excess of the normally produced type is present and accumulates in the cell as an unstable product, leading to the destruction of the cell. This imbalance is the hallmark of all forms of thalassemia. For this reason, most thalassemias are not considered hemoglobinopathies because the globin chains are normal in structure and because the defect is limited to a decreased rate of production of these normal chains. However, thalassemic hemoglobinopathies exist, as discussed below (see Molecular pathology).

The type of thalassemia usually carries the name of the underproduced chain or chains. The reduction varies from a slight decrease to a complete absence of production. For example, when chains are produced at a lower rate, the thalassemia is termed +, whereas -0 thalassemia indicates a complete absence of production of chains from the involved allele.

The consequences of impaired production of globin chains ultimately result in the deposition of less Hb into each RBC, leading to hypochromasia. The Hb deficiency causes RBCs to be smaller, leading to the classic hypochromic and microcytic picture of thalassemia. This is true in almost all anemias caused by impairment in production of either of the 2 main components of Hb: heme or globin. However, this does not occur in the silent carrier state, since both Hb level and RBC indices remain normal.

In the most common type of thalassemia trait, the level of Hb A2 (d2/a2) is usually elevated. This is due to the increased use of chains by the excessive free chains, which results from a lack of adequate chains with which to pair. The gene, unlike and genes, is known to have a


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physiologic limitation in its ability to produce adequate chains; by pairing with the chains, chains produce Hb A2 (approximately 2.5-3% of the total Hb).

Some, but not all, of the excessive a chains are used to form Hb A2 with the chains, while the remaining chains precipitate in the cells, reacting with cell membranes, intervening with normal cell division, and acting as foreign bodies, leading to destruction of RBCs. The degree of toxicity caused by the excessive chains varies according to the type of such chains (eg, the toxicity of chains in b thalassemia is more prominent than the toxicity of chains in a thalassemia).

In other types of thalassemia traits, the mutation is not limited to the b gene but extends to the adjacent gene; thus, no elevation of the Hb A2 level is expected; instead, chains are activated, resulting in an elevated Hb F level (another abnormal finding on Hb electrophoresis in thalassemias). The thalassemia types associated with elevated levels of both Hbs A2 and F are less common.

In the severe forms, such as thalassemia major or Cooley anemia, the same pathophysiology applies with substantial exaggeration. The significant excess of free a chains caused by the deficiency of chains causes destruction of the RBC precursors in the bone marrow (ie, ineffective erythropoiesis).

Globin chain production

To understand the genetic changes that result in thalassemia, one should be familiar with the physiologic process of globin chain production in the healthy individual. The globin chain as a unit is a major building block for Hb: together with heme, it produces the Hb molecule (heme plus globin equals Hb). Two different pairs of globin chains form a tetrameric structure with a heme moiety in the center. All normal Hbs are formed from 2 -like chains and 2 non- chains. Various types of Hb are formed, depending on the types of chains pairing together. Such Hbs exhibit different oxygen-binding characteristics, normally related to the oxygen delivery requirement at different developmental stages in human life.

In embryonic life, chains (- like chains) combine with chains to produce Hb Portland (2/2) and with chains to produce Hb Gower-1 (2/2).

Subsequently, when a chains are produced, they form Hb Gower-2, pairing with e chains (2/2). Fetal Hb is composed of 2/2 and the primary adult Hb (Hb A) of 2/2. A third physiologic Hb, known as Hb A2, is formed by 2/2 chains (see Image 1).

Genetic changes

All the genes that control the production of globin chains lie within 1 of 2 clusters located on 2 different chromosomes. Chromosome 11 is the site of 5 functional -like globin genes arranged in a link cluster over 60 kilobases (kb). From left to right (5'-3'), they are /-G/-A//. -G and -A differ by only one amino acid (alanine vs glycine).

A critical control region of the d-globin gene (promoter) is known to be defective; it inhibits messenger RNA (mRNA) processing, resulting in only a small amount of Hb A2 (2/2) production, which thus accounts for less than 3% of total Hb in adult RBCs.

The -like globin gene cluster is located on chromosome 16 and consists of 3 functional genes. From left to right (5'-3'), the genes are /2/1.

Understanding the structure of the globin genes, how they are regulated to produce globin chains, and how the chains pair together to produce the various Hbs is critical for appreciating the different pathologic changes of this process that result in thalassemia.

Molecular biology

Each globin gene consists of a string of nucleotide bases divided into 3 coding sequences, termed exons, and 2 noncoding regions, known as introns or intervening sequences (IVS; see Image 2). Three other regions, known as regulatory regions, also exist in the 5' noncoding or flanking region of each globin gene.

The first is the promoter, which plays a major role in the transcription of the structural genes. The second region is the enhancer, which has an important role in promoting erythroid-specific gene expression, as well as in coordinating the changes in globin gene activity at different stages of development (embryonal, fetal, adult). Enhancers can influence gene expression, despite being located some distance away from the gene itself, and, unlike the promoter, they can stimulate transcription irrespective of their orientation relative to the transcription start site. Finally, master regulatory sequences, known as locus control regions (in the -globin gene family) and HS40 (in the a gene complex), are responsible for activating the genes in erythroid cells.

Each of these regulatory sequences has a modular structure that consists of short nucleotide motifs that act as binding sites for transcriptional activator or suppressor molecules. Such molecules activate or suppress gene expression in different cell types at different stages of development. A certain gene is transcribed by an initiation complex formed of certain proteins and a number of


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transcription factors, which interact with binding sites on the promoters and other regulatory sequences of the relevant genes.

When a gene is transcribed, mRNA is synthesized from one of the gene's DNA strands by the action of RNA polymerase. The initial product is a large mRNA precursor. Both exons and introns are initially present on this mRNA precursor; the introns are ultimately subsequently eliminated, and the exons are spliced together in the nucleus. At this stage, the mRNA, which has also been modified at both 5' and 3' ends, moves to the cytoplasm to act as a template for the production of globin chains.

Carrier molecules (transfer RNA [tRNA]) transport amino acids to the mRNA template. Each amino acid has a specific tRNA, which also contains 3 bases (anticodon), complimentary to the mRNA codons for that amino acid. The position of each amino acid in the globin chain is thus established by its corresponding triplet code (codon) in the globin gene. The cytidine, uridine, and guanosine (CUG) codon, for example, encodes the amino acid leucine, while the adenosine, adenosine, and adenosine (AAA) codon encodes lysine. When a tRNA molecule carries the initial amino acid to the template, directed by codon-anticodon base pairing, globin chain synthesis begins.

Once the first tRNA is in place, a complex is formed between several protein initiation factors and the subunit of the ribosome that is to hold the growing peptide chains together on the mRNA as it is translated. A second tRNA moves in alongside, and a new amino acid is bound to the first with a peptide bond, resulting in a peptide chain 2 amino acids long. This process continues from left to right until a specific codon for termination is reached. At this point, the completed peptide chain drops off the ribosome-mRNA complex and the ribosomal subunits are recycled. The globin chain is now ready to join a heme molecule and 3 other globin chains to form an Hb molecule.

The developmental switches from embryonic to fetal and then to adult Hb production are synchronized throughout the different organs of hematopoiesis (yolk sack, liver, bone marrow), which function at various stages of development. Even though the mechanism of such switches is not clearly understood, the globin gene promoter is known to contain information that specifies developmental stages of transcription.

Molecular pathology

To date, more than 1000 inherited mutations that affect either the structure or synthesis of the - and -globin chains are known. Mutations that result in b or a thalassemia are similar in principle but different in their patterns. Presently, more than 200 molecular defects known to downregulate the expression of b globin have been characterized. Such defects result in various types of b thalassemia.

Major deletions in thalassemia are unusual (in contrast to thalassemia), and most of the encountered mutations are single base changes, small deletions, or insertions of 1-2 bases at a critical site along the gene (see Image 3). These mutations occur in both exons and introns. For example, in a non-sense mutation, a single base change in the exon generates a stop codon in the coding region of the mRNA, resulting in premature termination of globin chain synthesis. This termination leads to the production of short, nonviable chains.

Conversely, in the frame shift mutation, 1 or more bases on the exon are lost or inserted, resulting in a change in the reading frame of the genetic code or the production of a new stop codon.

RNA-splicing mutations are fairly common and represent a large portion of all mutations that result in thalassemia. These mutations corrupt the splicing process. The importance of precise splicing in the quantitative production of stable functional mRNA cannot be overemphasized.

Slippage by even one nucleotide changes the reading frame of the mRNA. Both ends of the RNA introns (at the junction with the exons) have specific consensus sequences; these motifs include GT in the 5' (left end or donor site) consensus sequence and AG in the 3' (right end or acceptor site) consensus sequence. Such sequences are obligatory for correct splicing, and a single substitution at the invariant GT or AG sequence prevents splicing altogether and results in -0 or -0 thalassemia. Mutations in the other members of the consensus sequences, although still highly conserved, result in variable degrees of ineffective b-globin production, causing milder types of thalassemia.

Mutations in exon sequences may activate a cryptic splice site. For example, in exon 1 of the -globin gene, a consensus sequence that resembles a sequence in IVS-1 has been identified as the site for several distinct mutations, resulting in a gene that carries the features of both thalassemia and hemoglobinopathy simultaneously (quantitatively and qualitatively abnormal Hb production). This type of mutation represents a clear link between the thalassemias and the hemoglobinopathies, and, accordingly, these are labeled thalassemic hemoglobinopathies.

Thus, mutations at codon 19 (A to G), 26 (G to A), and 27 (G to T)—all in exon 1—result in reduced production of mRNA (thalassemia) because of inefficient splicing and an amino acid substitution encoded by the mRNA that is spliced and translated (albeit inefficiently) into protein. The resulting abnormal Hbs are Malay, E, and Knossos, respectively.


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The flanking regions of the -globin gene are also sites for various mutations. A single base substitution that involves the promoter element, for example, can downregulate -globin gene transcription, resulting in a mild form of b thalassemia. Conversely, a mutation that affects the 3' end of the -globin mRNA can interfere with its processing, resulting in a severe form of thalassemia.

Clearly, many different thalassemia mutations exist, and compound heterozygosity is frequently encountered. The resulting laboratory findings may lead to confusion. An example is the patient who manifests symptoms of thalassemia major without an elevated Hb A2 level. The explanation for such a situation is often co-inheritance of and thalassemia. / thalassemia further is divided into /+ or /-0.

In the first type, a misalignment in the / genes during meiosis results in the production of fused / genes, a process responsible for the production of an Hb variant termed Hb Lepore.

The fused / gene is under the control of a -globin gene promoter region (the gene promoter is deleted in the process). Because the gene promoter carries mutations that lead to ineffective transcription, the fused / chains are produced in limited amounts, resulting in thalassemia. This is in addition to the hemoglobinopathy.

Conversely, in /-0 thalassemia, a large deletion occurs in the -globin gene cluster, removing both the and the genes, which can also extend to involve all globin genes on chromosome 11, thus producing , , , and -0 thalassemia.

Cellular pathophysiology

The basic defect in all types of thalassemia is imbalanced globin chain synthesis (see Molecular biology). However, the consequences of accumulation of the excessive globin chains in the various types of thalassemia are different. In b thalassemia, excessive a chains, unable to form Hb tetramers, precipitate in the RBC precursors and, in one way or another, produce most of the manifestations encountered in all of the b thalassemia syndromes; this is not the situation in a thalassemia.

The excessive chains in a thalassemia are chains earlier in life and chains later in life. Because such chains are relatively soluble, they are able to form homotetramers that, although relatively unstable, nevertheless remain viable and able to produce soluble Hb molecules such as Hb Bart (4 chains) and Hb H (4 chains). These basic differences in the 2 main types of thalassemia are responsible for the major differences in their clinical manifestations and severity.

a chains that accumulate in the RBC precursors are insoluble, precipitate in the cell, interact with the membrane (causing significant damage), and interfere with cell division. This leads to excessive intramedullary destruction of the RBC precursors. In addition, the surviving cells that arrive in the peripheral blood with intracellular inclusion bodies (excess chains) are subject to hemolysis; this means that both hemolysis and ineffective erythropoiesis cause anemia in the person with thalassemia.

The ability of some RBCs to maintain the production of chains, which are capable of pairing with some of the excessive a chains to produce Hb F, is advantageous. Binding some of the excess chains undoubtedly reduces the symptoms of the disease and provides additional Hb with oxygen-carrying ability.

Furthermore, increased production of Hb F, in response to severe anemia, adds another mechanism to protect the RBCs in persons with b thalassemia. The elevated Hb F level increases oxygen affinity, leading to hypoxia, which, together with the profound anemia, stimulates the production of erythropoietin. As a result, severe expansion of the ineffective erythroid mass leads to severe bone expansion and deformities. Both iron absorption and metabolic rate increase, adding more symptoms to the clinical and laboratory manifestations of the disease. The large numbers of abnormal RBCs processed by the spleen, together with its hematopoietic response to the anemia if untreated, results in massive splenomegaly, leading to manifestations of hypersplenism.

If the chronic anemia in these patients is corrected with regular blood transfusions, the severe expansion of the ineffective marrow is reversed. However, by doing so, another source of iron is added, which, together with the excessive iron absorption normally present in such cases, leads to a state of iron overload. Most nonheme iron in healthy individuals is bound tightly to its carrier protein, transferrin. In iron overload conditions, such as severe thalassemia, the transferrin becomes saturated, and free iron is found in the plasma. This iron is harmful since it provides the material for the production of hydroxyl radicals and additionally accumulates in various organs, such as the heart, endocrine glands, and liver, resulting in significant damage to these organs.

By understanding the etiology of the symptoms in thalassemia, one can appreciate that certain modifiers may result in the development of milder types of thalassemia. Factors that may reduce the degree of globin chain imbalance are expected to modify the severity of the symptoms; co-inheritance of thalassemia, the presence of higher Hb F level, or the presence of a milder thalassemia mutation all typically ameliorate the symptoms of thalassemia.

Malaria hypothesis


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In 1949, Haldane suggested a selective advantage for survival in individuals with the thalassemia trait in regions where malaria is endemic. He argued that lethal RBC disorders such as thalassemia, sickle cell disease, and G-6-PD deficiency are present almost exclusively in tropical and subtropical regions of the world. The incidence of these genetic mutations in a certain population thus reflects the balance between the premature death of homozygotes and the increased fitness of heterozygotes.

For instance, in thalassemia, the frequency of the gene is greater than 1% in the Mediterranean Basin, India, Southeast Asia, North Africa, and Indonesia; it is very uncommon in other parts of the world. a thalassemia may be the most common single gene disorder in the world (5-10% in the Mediterranean, 20-30% in West Africa, approximately 68% in the South Pacific); however, the gene prevalence in Northern Europe and Japan is less than 1%.

The mechanism of protection against malaria is not clear. Hb F in cells has been demonstrated to retard the growth of the malaria parasite, and, by virtue of its high level in infants with b thalassemia trait, the fatal cerebral malaria known to kill infants in these areas may be prevented. The RBCs of patients with Hb H disease have also shown a suppressive effect on the growth of the parasites. This effect is not observed in a thalassemia trait.

Classification of thalassemia

A large number of thalassemic syndromes are currently known; each involves decreased production of one globin chain or more, which form the different Hbs normally found in RBCs. The most important types in clinical practice are those that affect either a or b chain synthesis.

thalassemia

Several forms of a thalassemia are known in clinical practice. The most common forms are as follows:

Silent carrier thalassemia: This is a fairly common type of subclinical thalassemia, usually found by chance among various ethnic populations, particularly African American, while the child is being evaluated for some other condition. As pointed out above (see Genetic changes), 2 genes are located on each chromosome 16, giving a thalassemia the unique feature of gene duplication (see Image 2). This duplication is in contrast to only one -globin gene on chromosome 11.

In the silent carrier state, one of the a genes is usually absent, leaving only 3 of 4 genes (aa/ao). Patients are hematologically healthy, except for occasional low RBC indices.

In this form, the diagnosis cannot be confirmed based on Hb electrophoresis results, which are usually normal in all a thalassemia traits. More sophisticated tests are necessary to confirm the diagnosis. One may look for hematologic abnormalities in family members (eg, parents) to support the diagnosis. A CBC in one parent that demonstrates hypochromia and microcytosis in the absence of any explanation is frequently adequate evidence for the presence of thalassemia.

thalassemia trait: This trait is characterized by mild anemia and low RBC indices. This condition is typically caused by the deletion of 2 a (a) genes on one chromosome 16 (aa/oo) or one from each chromosome (ao/ao). This condition is encountered mainly in Southeast Asia, the Indian subcontinent, and some parts of the Middle East. The ao/ao form is much more common in black populations because the doubly deleted (oo) form of chromosome 16 is rare in this ethnic group.

Hb H disease: This condition, which results from the deletion or inactivation of 3 globin genes (oo/ao), represents thalassemia intermedia, with mildly to moderately severe anemia, splenomegaly, icterus, and abnormal RBC indices. When peripheral blood films stained with supravital stain or reticulocyte preparations are examined, unique inclusions in the RBCs are usually observed. These inclusions represent b chain tetramers (Hb H), which are unstable and precipitate in the RBC, giving it the ap pearance of a golf ball. These inclusions are termed Heinz bodies (see Image 4).

thalassemia major: This condition is the result of complete deletion of the a gene cluster on both copies of chromosome 16 (oo/oo), leading to the severe form of homozygous a thalassemia, which is usually incompatible with life and results in hydrops fetalis unless intrauterine blood transfusion is given.

thalassemia

Similar to thalassemia, several clinical forms of thalassemia are recognized; some of the more common forms are as follows:

Silent carrier thalassemia: Similar to patients who silently carry thalassemia, these patients have no symptoms, except for possible low RBC indices. The mutation that causes the thalassemia is very mild and represents a + thalassemia.


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thalassemia trait: Patients have mild anemia, abnormal RBC indices, and abnormal Hb electrophoresis results with elevated levels of Hb A2, Hb F, or both. Peripheral blood film examination usually reveals marked hypochromia and microcytosis (without the anisocytosis usually encountered in iron deficiency anemia), target cells, and faint basophilic stippling (see Image 6). The production of chains from the abnormal allele varies from complete absence to variable degrees of deficiency.

Thalassemia intermedia: This condition is usually due to a compound heterozygous state, resulting in anemia of intermediate severity, which typically does not require regular blood transfusions.

thalassemia associated with chain structural variants: The most significant condition in this group of thalassemic syndromes is the Hb E/ thalassemia, which may vary in its clinical severity from as mild as thalassemia intermedia to as severe as thalassemia major.

Thalassemia major (Cooley anemia): This condition is characterized by transfusion-dependent anemi a, massive splenomegaly , bone deformities, growth retardation, and peculiar facies in untreated individuals, 80% of whom die within the first 5 years of life from complications of anemia. Examination of a peripheral blood preparation in such patients reveals severe hypochromia and microcytosis, marked anisocytosis, fragmented RBCs, hypochromic macrocytes, polychromasia, nucleated RBCs, and, on occasion, immature leukocytes (see Image 5).

Frequency:

In the US: Because of immigration to the United States from all parts of the world and the intermarriages that have taken place over the years, all types of thalassemia occur in any given part of the country. However, until recently, the number of patients with severe forms of both b and a thalassemia has been very limited. For this reason, finding more than 2-5 patients with the very severe forms in any pediatric hematology center is unusual (except for in the few referral centers in the United States).

However, this situation is changing rapidly in certain parts of the country. In the last 10 years, Asian immigration has been steadily increasing. According to the Federal Census Bureau, in 1990, 6.9 million Asians were in the United States, twice that reported in the 1980 Census count. The prevalence of various thalassemia syndromes in this population is very high. b and a thalassemia, as well as Hb E/ thalassemia, are currently on the rise in the state of California as a result of the large concentration of Asian immigrants in that part of the country.

The interaction between Hb E ( chain variant) and b thalassemia (both very common among Southeast Asians) has created the Hb E/b thalassemia entity, which is now believed to be the most common thalassemia disorder in many regions of the world, including coastal North America, thus replacing b thalassemia major in frequency. For this reason, the cord-blood screening program for detection of hemoglobinopathy in California has recently been modified to include the detection of Hb H disease. In California alone, 10-14 new cases of b thalassemia major and Hb E/ thalassemia and 40 cases of neonatal Hb H disease are detected annually.

Internationally: Worldwide, 15 million people have clinically apparent thalassemic disorders. Reportedly, disorders worldwide, and people who carry thalassemia in India alone number approximately 30 million. These facts confirm that thalassemias are among the most common genetic disorders in humans; they are encountered among all ethnic groups and in almost every country around the world.

Certain types of thalassemia are more common in specific parts of the world. thalassemia is much more common in Mediterranean countries such as Greece, Italy, and Spain. Many Mediterranean islands, including Cyprus, Sardinia, and Malta, have a significantly high incidence of severe thalassemia, constituting a major public health problem. For instance, in Cyprus, 1 in 7 individuals carries the gene, which translates into 1 in 49 marriages between carriers and 1 in 158 newborns expected to have thalassemia major. As a result, preventive measures established and enforced by public health authorities have been very effective in decreasing the incidence among their populations. thalassemia is also common in North Africa, the Middle East, India, and Eastern Europe. Conversely, thalassemia is more common in Southeast Asia, India, the Middle East, and Africa.

Mortality/Morbidity:

thalassemia major is a mortal disease, and virtually all affected fetuses are born with hydrops fetalis as a result of severe anemia. Several reports exist of newborns with thalassemia major who survived after receiving intrauterine blood transfusions. Such patients require extensive medical care thereafter, including regular blood transfusions and chelation therapy, similar to patients with thalassemia major. Morbidity and mortality remain high among such patients. In the rare reports of newborns with thalassemia major born without hydrops fetalis who survived without intrauterine transfusion, high level of Hb Portland, which is a normally functioning embryonic Hb, is thought to be the cause for the unusual clinical course.


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Patients with Hb H disease also require close monitoring. They may require frequent or only occasional blood transfusions, depending on the severity of the condition. Some patients may require splenectomy. Morbidity is usually related to the anemia, complications of blood transfusions, massive splenomegaly in some patients, or the complications of splenectomy in others.

In patients with various types of thalassemia, mortality and morbidity vary according to the severity of the disease and the quality of care provided. Severe cases of b thalassemia major are fatal if not treated. Heart failure due to severe anemia or iron overload is a common cause of death in affected persons. Liver disease, fulminating infection, or other complications precipitated by the disease or by its treatment are some of the causes of morbidity and mortality in the severe forms of thalassemia. Morbidity and mortality are not limited to untreated persons; those receiving well-designed treatment regimens also may be susceptible to the various complications of the disease. Organ damage due to iron overload, chronic serious infections precipitated by blood transfusions, or complications of chelation therapy, such as cataracts, deafness, or infections with unusual microorganisms (eg, Yersinia enterocolitica), are all considered potential complications.

Race: Although thalassemia occurs in all races and ethnic groups, certain types of thalassemia are more common in some ethnic groups than in others (see Frequency). thalassemia is common in southern Europe, the Middle East, India, and Africa. thalassemia is more common in Southeast Asia; nevertheless, it is also seen in other parts of the world. Furthermore, specific mutations of the same type of thalassemia are more common among certain ethnic groups than others; this facilitates the screening and diagnostic processes, since certain probes for the more common mutations in a particular region are usually readily available.

The thalassemia trait in Africa is usually not of the cis deletion on chromosome 16, unlike the condition in Southeast Asia, which is associated with complete absence of the a gene on one chromosome. When both parents have the cis deletion, the fetus may develop hydrops fetalis. For this reason, hydrops fetalis is not a risk in the African population, while it remains a risk for Southeast Asian population.

Sex: Both sexes are equally affected with thalassemia.

Age: Despite thalassemia's inherited nature, age at onset of symptoms varies significantly. In thalassemia, clinical abnormalities in patients with severe cases and hematologic findings in carriers are evident at birth. Unexplained hypochromia and microcytosis in a neonate are highly suggestive of the diagnosis (see Image 7). However, in the severe forms of thalassemia, symptoms may not be evident until the second half of the first year of life; until that time, the production of -globin chains and their incorporation into fetal Hb can mask the condition.

Milder forms of thalassemia are frequently discovered by chance and at various ages. Many patients with an apparent homozygous thalassemia condition (ie, hypochromasia, microcytosis, electrophoresis negative for Hb A, evidence that both parents are affected) may show no significant symptoms or anemia for several years. Almost all such patients' conditions are categorized as b thalassemia intermedia during the course of their disease. This situation usually results when the patient has a milder form of the mutation, is a compound heterozygote for + and -0 thalassemia, or has other compound heterozygosity.

CLINICALHistory: The history in patients with thalassemia varies significantly, depending on the severity of the condition and the age at the time of diagnosis.

In most patients with thalassemia traits, no unusual signs or symptoms are encountered.

Some patients, especially those with somewhat more severe forms of the disease, manifest some pallor and slight icteric discoloration of the sclerae with splenomegaly, leading to slight enlargement of the abdomen. An affected child's parents or caregivers may report these symptoms. However, some rare types of thalassemia trait are caused by a unique mutation, resulting in truncated or elongated chains, which combine abnormally with a chains, producing insoluble dimers or tetramers. The outcome of such insoluble products is a severe hemolytic process that needs to be managed like thalassemia intermedia or, in some cases, thalassemia major.

The diagnosis is usually suspected in children with an unexplained hypochromic and microcytic picture, especially those who belong to one of the ethnic groups at risk. For this reason, physicians should always inquire about the patient's ethnic background, family history of hematologic disorders, and dietary history.

Thalassemia should be considered in any child with hypochromic microcytic anemia that does not respond to iron supplementation.

In more severe forms, such as thalassemia major, the symptoms vary from extremely debilitating in patients who are not receiving transfusions to mild and almost asymptomatic in those receiving regular transfusion regimens and closely monitored chelation therapy.


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Children with thalassemia major usually demonstrate none of the initial symptoms until the later part of the first year of life (when chains are needed to pair with chains to form Hb A, after chains production is turned off). However, in occasional children younger than 3-5 years, the condition may not be recognized because of the delay in cessation of Hb F production.

Patients with Hb E/ thalassemia may present with severe symptoms and a clinical course identical to that of patients with thalassemia major. Alternatively, patients with Hb E/ thalassemia may run a mild course similar to that of patients with thalassemia intermedia or minor. This difference in severity has been described among siblings from the same parents. Some of the variation in severity can be explained based on the different genotypes, such as the type of thalassemia gene present (ie, + or -0), the co-inheritance of an a thalassemia gene, the high level of Hb F, or the presence of a modifying gene.

Patients with heterozygous or homozygous Hb E are usually slightly anemic, with hypochromasia and microcytosis, and are usually asymptomatic.

If further studies are not performed, benign homozygous Hb E is usually misdiagnosed as Hb E/ thalassemia, a condition that is frequently severe.

In thalassemia, the hematologic abnormalities are clearly evident in newborns with mild or moderate forms of the disease. Lethal clinical consequences and physical deformities encountered at the time of birth are the rule in severe homozygous thalassemia.

In thalassemia, symptoms of anemia start when the chain production is switched off and the chains fail to form in adequate numbers.

Manifestations of anemia include extreme pallor and enlarged abdomen due to hepatosplenomegaly.

o Patients' typical reports may lead a physician who is not familiar with the condition to a first impression of acute leukemia.

o This impression is supported by the large spleen, which leads to thrombocytopenia, and by the high WBC count and immature WBCs seen on the peripheral blood film due to the extreme activity of the marrow.

o To support the impression of acute leukemia further, the elevated level of reticulocytes expected in all hemolytic anemias does not occur, despite the severe hemolysis; this anomaly is due to the massive splenomegaly and the ineffective erythropoiesis that prevents the release of the cells from the bone marrow. Evidence of hemolysis is usually present, with elevated indirect bilirubin level, high lactate dehydrogenase (LDH) level, and low level of haptoglobin.

Bony changes may be severe, resulting in a characteristic radiologic picture (see Imaging Studies, Image 9). These changes are caused by massive expansion of the bone due to the ineffective erythroid production.

The ineffective erythropoiesis also creates a state of hypermetabolism associated with fever and failure to thrive.

Occasionally, gout due to hyperuricemia may be encountered.

Iron overload is one of the major causes of morbidity in all patients with severe forms of thalassemia, regardless of whether they are regularly transfused.

o In transfused patients , heavy iron turnover from transfused blood is usually the cause; in nontransfused patients, this complication is usually deferred until puberty (if the patient survives to that age).

o Increased iron absorption is the cause in nontransfused patients , but the reason behind this phenomenon is not clear. Many believe that, despite the iron overload state in these patients and the increased iron deposits in the bone marrow, the requirement for iron to supply the overwhelming production of ineffective erythrocytes is tremendous, causing significant increases in GI absorption of iron.

o Bleeding tendency, increased susceptibility to infection, and organ dysfunction are all associated with iron overload.

Poor growth in patients with thalassemia is due to multiple factors and affects patients with well- controlled disease as well as those with uncontrolled disease.

Patients may develop symptoms that suggest diabetes, thyroid disorder, or other endocrinopathy; these are rarely the presenting reports.

Physical:

Patients with thalassemia minor rarely demonstrate any physical abnormalities . Because the anemia is never severe and, in most instances, the Hb level is not less than 9-10 g/dL, pallor and splenomegaly are rarely observed.


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In patients with severe forms of thalassemia, the findings upon physical examination vary widely, depending on how well the disease is controlled.

o Children who are not receiving transfusions have a physical appearance so characteristic that an expert examiner can often make a spot diagnosis.

o In Cooley's original 4 patients, the stigmata of severe untreated b thalassemia major included the following: Severe anemia, with an Hb level of 3-7g/dL Massive hepatosplenomegaly Severe growth retardation Bony deformities

o These stigmata are typically not observed; instead, patients look healthy. Any complication they develop is usually due to adverse effects of the treatment (transfusion or chelation).

o Bony abnormalities, such as frontal bossing, prominent facial bones, and dental malocclusion, are usually striking.

o Severe pallor, slight to moderately severe jaundice, and marked hepatosplenomegaly are almost always present.

Complications of severe anemia are manifested as intolerance to exercise, heart murmur, or even signs of heart failure.

Growth retardation is a common finding, even in patients whose disease is well controlled by chelation therapy.

Patients with signs of iron overload may also demonstrate signs of endocrinopathy caused by iron deposits. Diabetes and thyroid or adrenal disorders have been described in these patients.

In patients with severe anemia who are not receiving transfusion therapy, neuropathy or paralysis may result from compression of the spine or peripheral nerves by large extramedullary hematopoietic masses.

Causes: Thalassemias are inherited disorders caused by various gene mutations. The clinical expression and severity are subject to numerous factors that may either mask the condition or exaggerate the symptoms, leading to a more severe disease.

DIFFERENTIALSAnemia, Acute Anemia, Chronic Hydrops Fetalis Pyruvate Kinase Deficiency Thalassemia Thalassemia Intermedia

Other Problems to be Considered:

The differential diagnoses of thalassemic states in general depend on the age of the child at the time of presentation, the type of thalassemia and its severity, and, in severe cases, whether it is treated and well controlled. Furthermore, the form of thalassemia then has to be identified once the thalassemic condition is suspected because of the numerous thalassemic conditions.

Congenital dyserythropoietic anemia is a condition that may mimic severe forms of thalassemia in children. A bone marrow examination, Hb electrophoresis, and other tests reveal the diagnosis. Diamond-Blackfan anemia may also resemble severe forms of thalassemia in young infants.

The thalassemia trait is similar to the thalassemia trait. Both traits should be differentiated from iron deficiency anemia, which is the most common cause of hypochromasia and microcytosis in children and should be excluded before considering thalassemia. A child with presumed iron deficiency anemia that has not responded to adequate iron treatment is a good candidate for thalassemia workup.

In thalassemia, elevated levels of Hb A2, F, or both are usually helpful in confirming the diagnosis. However, in thalassemia, the Hb electrophoresis results are usually normal; in this case, and in cases in which iron study results are also nondiagnostic, nonspecific tests may help to differentiate iron deficiency anemia or anemia of chronic inflammation from thalassemia. Free erythrocyte protoporphyrin (FEP) levels are usually elevated in patients with iron deficiency or anemia of chronic inflammation but not with thalassemia. The soluble transferrin receptors (sTfR) levels are high in patients with iron deficiency but not in those with anemia of chronic infection or thalassemia.

The process of differentiating thalassemia trait from iron deficiency anemia must include the patient's


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medical, developmental, nutritional, and family history and a review of the child's CBC, with emphasis on the RBC indices. Proper interpretation of the CBC may save the physician time and may save the patient from unnecessary further testing (see Lab Studies). The anemia in patients with thalassemia trait is usually mild; the Hb level is rarely, if ever, less than 9 g/dL, unless the cause of the anemia is multifactorial. The RBC count is almost always higher in patients with thalassemia than in those with iron deficiency anemia; in fact, it is frequently higher than the reported reference range for the age.

In thalassemia, the RBC indices, including the mean corpuscular volume (MCV) and mean corpuscular Hb (MCH), are both significantly low for an Hb level that is either normal or only slightly low. In addition, the RBC distribution width (RDW) is usually normal, reflecting the homogenous population of the RBCs in thalassemia (see Image 6), whereas iron deficiency anemia is known to be associated with anisocytosis (see Image 8). A faint basophilic stippling may be seen in the RBCs of patients with thalassemia but not typically in those of patients with iron deficiency.

Many formulae have been introduced to help in differentiating thalassemia trait from iron deficiency. The most practical and easiest to remember is the Mentzer index, which divides the patient's MCV by the RBC count (MCV/RBC). A result of less than 13 usually suggests thalassemia trait, while a result greater than 13 is indicative of iron deficiency.

Confirmation by Hb electrophoresis in thalassemia is essential before the patient and the family are counseled. The Mentzer index loses its value if the patient has a combination of thalassemia and iron deficiency. In such patients, Hb electrophoresis results may also be inaccurate and misleading, since iron deficiency suppresses production of all Hbs, including Hb A2. For this reason, the Hb A2 level does not rise and is typically normal in these patients, masking the diagnosis of b thalassemia. In such cases, Hb electrophoresis should be repeated after the iron deficiency has been treated to obtain an accurate Hb A2 fraction.

When and thalassemia coexist, the elevated levels of Hb A2 and Hb F usually present in thalassemia may also be lost. Furthermore, a thalassemia ameliorates the severity of thalassemia since the decrease in a chains results in less inclusions and, hence, less hemolysis.

However, the confirmation of thalassemia is easier than that of the a trait. The Hb electrophoresis result is usually normal, and DNA testing or globin chain synthesis enumeration are the only studies that confirm the diagnosis. A moderately severe form of a thalassemia, which some consider equivalent to b thalassemia intermedia, is termed Hb H disease. The disease is characterized by moderately severe anemia, splenomegaly, some jaundice, and, possibly, some bone changes due to marrow expansion. In this form, Hb electrophoresis is diagnostic in revealing the abnormal Hb, which is unstable and may be detected on the supra vital stain as inclusions in the RBCs (Heinz bodies).

The severity of Hb H disease depends on the inherited mutation. Seventy-five percent of Hb H mutations are caused by deletions on chromosome 16, which are usually associated with the milder forms of Hb H. Nondeletional forms are usually associated with severe Hb H and require transfusion. The diagnosis of Hb H may be difficult to establish, since it is unstable and may go undetected. The b tetramers of Hb H are replaced by g tetramers in the form of Hb Bart. Patients with Hb H disease usually have more than 20% Hb Bart at birth, a finding that has helped to identify 90% of the neonates with Hb H disease in the newborns screening program in California.

Hb Constant Spring (CS) is the most common nondeletional a thalassemia mutation associated with Hb H disease. The cells that contain Hb CS are usually overhydrated, which causes the loss of the traditional microcytosis seen in patients with thalassemia. Hb H/CS disease is more severe than Hb H disease, sometimes requiring splenectomy to improve the anemia, a procedure associated with a high rate of portal vein thrombosis.

Many clinical entities associated with splenomegaly and anemia, such as storage diseases, and other forms of chronic hemolytic anemias are to be considered in the differential diagnosis. The homozygous a thalassemia is not compatible with life (unless intrauterine blood transfusion is administered), and a baby with hydrops fetalis is usually delivered.

Other causes of immune and nonimmune hydrops fetalis are also to be differentiated from the hydrops fetalis of a thalassemia major, a condition that was rarely seen in the past since the mutation that predisposes to this condition is limited to the Southeast Asian population, not the African population.

Rare forms of a thalassemia are also described. Hb CS results from a specific mutation in the a thalassemia gene, leading to the production of elongated a chains. The clinical manifestations in the homozygous state are similar to those encountered in patients with Hb H disease; however, they differ in the electrophoretic pattern. tetramers that consist of Hb Bart replace the tetramers of Hb H.

Thalassemia may also interact with other globin structural variants, whether they involve , , or other chains. In the variants, Bs, Bc, and Be are some of the globin chain's most common mutations. For instance, the interaction of Bs with b thalassemia produces a condition associated with sickle cell disease. Conversely, when Bs (sickle trait gene) interacts with an a thalassemia gene, less


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Hb S is present in the RBCs than when only Bs is present. Such interactions modify the severity of each separate condition.

The incidence of Hb E/ thalassemia has increased considerably in the United States in recent years due to the immigration of individuals from Southeast Asia, where the incidence of both Hg E and thalassemia is high (see Frequency). Clinically, the severe forms of Hb E/ thalassemia are similar to the transfusion-dependent b thalassemia major. For this reason, the diagnosis Hb E/ thalassemia should be considered in patients of Southeast Asian descent.

Other rare thalassemia variants include Hb Lepore and hereditary persistence of fetal Hb (HPFH).

WORKUPLab Studies:

The CBC count and peripheral blood film examination results are usually sufficient to suspect the diagnosis. Hb evaluation confirms the diagnosis in b thalassemia, Hb H disease, and Hb E/b thalassemia.

o In the severe forms of thalassemia, the Hb level ranges from 2-8 g/dL.o MCV and MCH are significantly low , but, unlike thalassemia trait, thalassemia major is associated

with a markedly elevated RDW, reflecting the extreme anisocytosis.o 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.

o Platelet count is usually normal, unless the spleen is markedly enlarged.o Peripheral blood film examination reveals marked hypochromasia and microcytosis,

hypochromic macrocytes that represent the polychromatophilic cells, nucleated RBCs, basophilic stippling, and occasional immature leukocytes (see Image 5). Contrast this with the abnormalities associated with Hb H, an thalassemia (see Image 4).

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

elevated.

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.

o 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 well-controlled.

o In addition to the classic "hair on end" appearance of the skull, which results from widening of the diploic spaces and observed on plain radiographs (see Image 9), 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.


Thallasemia

Thallasemia Minor

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o 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.

o Compression fractures and paravertebral expansion of extramedullary masses, which could behave clinically like tumors, more frequently occur during the second decade of life.

o 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. The values obtained did not correlate with either the ferritin level or the liver iron level, which 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.

Other Tests:

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, and renal function tests are required to monitor deferoxamine (DFO) therapy (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 recent 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 (see Image 10), liver, heart, and other tissues.

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). This classification is used to assess risk factors that predict outcome and prognosis and addresses 3 elements: (1) degree of


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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 to 56% for those with hepatomegaly and fibrosis and whose condition responds poorly to chelation (class 3).

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

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

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

Blood transfusions

o Several blood transfusion regimens have been introduced. Of these, one seems practical, less demanding, and more cost-effective than any of the others. This regimen attempts to maintain a pretransfusion Hb level of 9-9.5 g/dL at all times.

o Like all patients who require long-term regular blood transfusions, patients with thalassemia require a pretransfusion workup. This workup should include RBC phenotype, hepatitis B vaccination (if needed), and hepatitis workup. Iron and folate levels should also be measured.

o Transfused blood should always be leukocyte poor; 10-15 mL/kg PRBCs at the rate of 5 mL/kg/h every 3-5 weeks is usually adequate to maintain the pretransfusion Hb level needed.

o Consider administration of acetaminophen and diphenhydramine hydrochloride before each transfusion to minimize febrile or allergic reactions.

o Patients with documented transfusion reactions may benefit from having RBCs washed with saline or from receiving deglycerolized RBCs.

Complications of blood transfusion: The major complications of blood transfusions are those related to transmission of infectious agents or the development of iron overload.

o Infectious agents: As recently as a few years ago, 25% of transfused patients were exposed to hepatitis B virus. At present, both immunization and strict screening of potential donors have significantly decreased the incidence. Hepatitis C virus (HCV) is the most common cause of hepatitis in adolescents older than 15 years with thalassemia (risk of exposure was 6%). Because both liver failure and hepatocellular carcinoma have been attributed to HCV in patients with thalassemia, aggressive treatment with interferon alpha is warranted in patients who contract HCV. The incidence of transfusion-transmitted HCV is expected to drop significantly because of stricter blood screening now mandated. Data from the Registry of the Thalassemia Clinical Research Network (TCRN) demonstrated how successful the screening for HCV was in reducing the incidence of HCV infection in such patients. The incidence was shown to be only 5% in children younger than 15 years compared to 75% in adults older than 25 years; unfortunately, this is not true in developing countries. Infection with rare organisms that are not considered pathogenic in healthy hosts may cause febrile illness and symptoms of enteritis in patients with iron overload, especially those receiving chelation therapy with DFO. The pathogen Y enterocolitica uses the abundant iron scavenger molecules, known as siderophores, which the microorganism needs but cannot synthesize. Fever without any apparent cause, especially when associated with diarrhea, should be treated with gentamicin and trimethoprim-sulfamethoxazole, even when culture results are negative.

o Iron overload: Even though blood transfusion is supposed to decrease the excessive iron absorption in the GI tracts of patients with thalassemia, patients nevertheless receive large


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amounts of iron with each blood transfusion. Why patients with excessive iron absorb large amounts of iron from the GI tract is not clear.

Many believe that the highly active marrow in these patients is iron deficient and needs large amounts of iron to produce the massive numbers of RBCs usual in this disease. The iron absorbed from the gut by the enterocyte, which coordinates iron uptake and transport into the body with its release from the reticuloendothelial system, is bound to transferrin in the plasma. The erythron claims most of the iron, while other tissues and cells that express transferrin receptors pick most of the rest. Both iron and transferrin enter the cells by endocytosis, forming the labile iron pool that provides iron to the cells and the iron-containing enzymes.

As iron accumulates and exceeds body needs, production of apoferritin is accelerated to provide means for storing iron in nontoxic forms as ferritin or hemosiderin. Measuring the ferritin level in the first few years after the diagnosis of thalassemia is usually helpful in detecting iron overload status because ferritin correlates well with total body iron burden at this time. Later on, the correlation becomes poor, since ferritin is produced by hepatocellular damage and it acts as an acute-phase reactant. The ferritin level rises in individuals with hepatitis, infections, and heart failure. When ferritin molecules accumulate further, the protein moiety disintegrates, leaving small iron-concentrated hemosiderin particles; this alone is not harmful, but it may cause release from lysosomes of hydrolytic enzymes that are toxic to the cells.

In patients with iron overload, a unique situation develops as a result of the very high saturation of the carrier protein transferrin, approximately 90% or more (reference range for children and adults, 23-34%). A new iron pool, which is not present in healthy individuals, is formed (the nontransferrin-bound or the free serum iron pool), which is probably an expansion of the labile pool.

o Tissue toxicity in iron overload: Peroxidation of cell membrane components by iron in the free pool is probably the major cause of organ damage from excessive iron. This effect was noted to worsen when ascorbic acid was added and was corrected partially by either vitamin E or deferoxamine. Patients with thalassemia with iron overload are typically deficient in vitamin E. The route of iron access to the body and its relation to the development of hemosiderosis have been controversial issues for some time. Many believe that absorption of iron from the bowel is the major factor in the etiology of this condition. The parenchymal tissue damage in the livers of patients with hereditary hemochromatosis and those with thalassemia intermedia who are not receiving transfusions and the lower incidence of liver cirrhosis in heavily transfused patients with aplastic anemia support their claims. This interpretation should not create the wrong impression that transfusional iron is not involved in the etiology of iron overload; on the contrary, every effort should be made to minimize all iron intake from any source in patients at risk whenever possible.

Chelation therapy: Until recently, patients with thalassemia major who received only transfusion therapy could not survive beyond adolescence, largely because of cardiac complications caused by iron toxicity. The introduction of chelating agents capable of removing excessive iron from the body has dramatically increased life expectancy.

o When administered in conjunction with blood transfusion regimens, chelation can delay the onset of cardiac disease and, in some patients, even prevent its occurrence.

o Several chelating agents have been tested, and, although many failed, one particular agent was proven effective and safe. DFO is a complex hydroxylamine with high affinity for iron; it targets the labile pool, the nontransferrin-bound iron (free pool), and the ferritin generated from reticuloendothelial iron.

o Route of administration is critical in achieving the goal of therapy, which is reaching a negative iron balance (ie, excreting more iron than acquired from both intestinal absorption and transfusion). In the adult, reaching this goal involves removing 35 mg of iron per day.

o Because the agent is not absorbed in the gut, it must be administered parenterally, whether intramuscularly, intravenously, or subcutaneously. Because of its short half-life, subcutaneous infusion must be prolonged if it is to achieve the stated goal.

o A total dose of 30-40 mg/kg/d is infused over 8-12 hours during the child's sleep for 5 d/wk by a mechanical pump.

o If doses larger than those tolerated by the subcutaneous route are needed, the intravenous route may be safely used, especially when a vascular access device is in place.

o Doses as high as 6-10 g were administered intravenously in selected patients and proved effective in reversing serious iron overload complications.

o The optimal time to initiate chelation therapy is dictated by the amount of accumulated iron and its accessibility for chelation. This usually occurs after 1-2 years of transfusions. Severe toxicity may develop if chelation is started prematurely. A DFO challenge test is usually helpful in deciding whether a patient is a candidate for chelation.

o DFO toxicity concerns are as follows:


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Local reaction at the site of injection is reported in many patients and can occasionally be severe.

High-frequency hearing loss has been reported in 30-40% of patients. Other neurosensory complications of chelation therapy include color and night blindness and visual field loss. These complications are frequently reversible and more commonly occur when not enough iron is available for chelation, when aggressive chelation therapy is administered, or when the chelation agent is administered in continuous intravenous infusions in a dose greater than 50 mg/kg/d. For this reason, eye and hearing examinations are to be scheduled every 6-12 months in patients receiving chelation therapy.

Pulmonary infiltrates as a complication have been reported in only a few patients.

For several reasons and despite all the advantages of DFO, chelation with this agent has been inadequate. In countries where it is needed the most, the high cost of the drug and the supplies needed for its administration make it unavailable for most patients. DFO has been prescribed for only 25,000 of 72,000 patients with thalassemia major receiving blood transfusion worldwide. In the Western world, on the other hand, despite the wide availability of the agent, some patients do not comply because of the unpleasant and cumbersome nature of the regimen. Others who cannot tolerate the drug have to modify the dose or the route or stop use all together.

A recent report showed that 105 of 328 patients in North America had to modify their regimen, and 20 patients had to stop taking the agent. For such reasons, the search for more practical chelators (especially the targeted chelators that can more effectively remove iron from specific organs [eg, heart, liver]) has continued to be a major task for the last few decades.

o Oral chelating agents have been in use in other countries for some time, and newer ones are showing efficacy and some specificity for removing iron more efficiently from certain organs than DFO. Several ongoing trials are near completion, and the oral agents will likely be ready for clinical use in the near future.

Initially, the oral chelating agent deferiprone (DFP), or L1, provided some promising results. However, after a few years of observation and monitoring, the agent was found to be less effective than DFO in preventing organ damage. In addition, some adverse effects such as neutropenia or even agranulocytosis were reported in as many as 8% of patients.

More recently, DFP was demonstrated to have efficacy comparable to that of DFO, with minimal adverse effects and better compliance, leading some investigators to reconsider the use of DFP. The drug is now in use in more than 50 countries. Significant improvement based on cardiac MRI findings, indicating a reduction in cardiac iron overload and improved cardiac function, was reported in some studies as a result of DFP therapy. This observation suggests a cardioprotective role of DFP that must be further investigated.

Because the concept of oral chelation is appealing, several studies are presently assessing the efficacy and toxicity of new oral chelators. ICL 670 is a new orally active chelating agent that has shown an efficient and selective mobilization of tissue iron in several animal models. This agent has been shown to be more effective than both DFO and DFP and has been well tolerated in doses up to 80 mg/kg/d. The excretion of the agent is mostly in the feces, and the agent's long half-life (11-19 h) allows for a single oral dose daily. A phase II international study is currently being conducted to evaluate the efficacy of this agent in patients with congenital disorders of RBCs with chronic iron overload.

Finally, combinations of 2 iron chelators (parenteral DFO plus the oral chelator) have been demonstrated to produce additive and synergistic effects. Such an approach would enable a flexible schedule and improve compliance and overall quality of life.

o Patients receiving chelation therapy have been demonstrated to have some degree of vitamin C deficiency. This deficiency has been attributed, in part, to increased catabolism. Administration of vitamin C increases the urinary excretion of iron and raises both serum iron and ferritin levels; this is probably related to the fact that vitamin C slows down the conversion of ferritin to hemosiderin, leading to the availability of more chelatable iron. Conversely, vitamin C enhances iron-mediated peroxidation of membrane lipids, leading to significant toxicity, mostly cardiac dysfunction in patients who are receiving large doses of vitamin C supplementation in addition to chelation therapy. For this reason, only small doses should be administered to enhance chelation (3 mg/kg/d at the start of infusion of the chelator). Large doses should be avoided.

Vitamin E deficiency: Vitamin E deficiency has been reported in patients with severe thalassemia. Some of the hemolysis in this population was attributed to peroxidation of the RBC membrane lipids by an iron-mediated free radical effect. As an antioxidant, vitamin E is expected to decrease cell toxicity.

Folic acid deficiency: This deficiency is a common complication in patients with thalassemia, mainly because of the extreme demand associated with the severe expansion of the marrow. Other


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causes, such as poor absorption and intake, can also contribute to folate deficiency. For this reason, folic acid (1 mg/d) has been recommended as a supplement for this patient population.

Hematopoietic stem cell transplantation: HSCT is recommended only for selected patients; it is the only known curative treatment for thalassemia. Poor outcome after HSCT correlates with the presence of hepatomegaly and portal fibrosis and with ineffective chelation prior to transplant. The event-free survival rate for patients who have all 3 features is 59%, compared to 90% for those who lack all 3.

o Even though blood transfusion is not required after a successful transplant, certain individuals need continued chelation therapy to remove excessive iron. The optimal time to start such treatment is a year after the successful HSCT.

o Parents and caregivers of patients with severe thalassemia are frequently confronted with a choice between standard therapy and HSCT. The 15-year cardiac disease-free survival rate for patients receiving standard therapy exceeds 90% and is similar for those without risk factors (see Hematopoietic stem cell transplantation, above) who have undergone HSCT.

o Long-term outcome for transplant patients, including fertility, is not known. The cost of long-term standard therapy is known to be higher than the cost of transplant. The possibility of developing cancer after HSCT should also be considered. In many centers, the donor has to be a matched sibling with or without a thalassemia trait.

Investigational agents known to increase Hb F level: This therapeutic strategy is investigational at this time. Several agents administered to raise the Hb F level have been investigated in patients with severe thalassemia. Unfortunately, the initial results of these studies are not promising.

Gene therapy: This therapy is an attractive therapeutic modality, the efficacy of which remains to be demonstrated.

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

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

Several criteria are used to aid in the decision for splenectomy; a practical one suggests that splenectomy may be beneficial in patients who require more than 200-250 mL/kg of PRBC per year to maintain an Hb level of 10 g/dL.

The risks associated with splenectomy are minimal, and many of the procedures are now performed by laparoscopy. Postsplenectomy risk of infections with encapsulated organisms and malaria in endemic areas is always a concern. The problem is minimal at the present time, since presplenectomy immunizations and postsurgical prophylactic antibiotics have significantly decreased the rates of such complications. Traditionally, the procedure is delayed whenever possible until the child is aged 4-5 years or older. Aggressive treatment with antibiotics should always be administered for any febrile illness while awaiting the results of cultures. Low-dose daily aspirin is also beneficial when the platelet count rises to more than 600,000/mL postsplenectomy.

Another surgical procedure in patients with severe thalassemia on transfusion therapy is the placement of a central line for the ease and convenience of administering blood transfusions, chelation therapy, or both.

Consultations:

Pediatric surgeon

Pediatric endocrinologist

Pediatric ophthalmologist

Pediatric otolaryngologist

Pediatric gastroenterologist

Pediatric HSCT specialist


Hal 34

Diet:

A normal diet is recommended, with emphasis on the following supplements: folic acid, small doses of ascorbic acid (vitamin C), and alpha-tocopherol (vitamin E).

Iron should not be given, and foods rich in iron should be avoided. Drinking coffee or tea has been shown to help decrease absorption of iron in the gut.

Activity:

Patients with well-controlled disease are usually fully active.

Patients with anemia, heart failure, or massive hepatosplenomegaly are usually restricted according to their tolerances.

MEDICATIONMedications needed for the treatment of various types of thalassemias are nonspecific and only supportive. A list of such medications is provided in this article.Drug Category: Antipyretics, analgesics -- Administration before blood transfusion prevents or decreases febrile reactions.

Drug NameAcetaminophen (Tylenol, Tempra, Panadol) -- Antipyretic effect through action on hypothalamic heat-regulating center. Action equal to that of aspirin but preferred because does not have adverse effects of aspirin.

Adult Dose 325-650 mg/dose PO prior to blood transfusion

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

Contraindications Documented hypersensitivity

Intera-ctions Rifampin decreases analgesic effect; barbiturates increase hepatic toxicity

Preg-nancy B - Usually safe but benefits must outweigh the risks.

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

Drug Category: Antihistamines -- Administration prior to blood transfusion may decrease or prevent allergic reactions.

Drug NameDiphenhydramine hydrochloride (Benadryl) -- Antihistamine with anticholinergic and sedative effects.

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

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

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

Interactions Potentiates effects of CNS depressants and MAOIs

Preg-nancy B - Usually safe but benefits must outweigh the risks.

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

Drug Category: Chelating agents -- These agents are used to chelate excessive iron from the body in patients with iron overload.

Drug NameDeferoxamine mesylate (Desferal) -- Chelates iron from ferritin or hemosiderin but not from transferrin, cytochrome, or Hb.

Adult Dose20-40 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 Dose Administer as in adults

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

Interactions May cause loss of consciousness when administered with prochlorperazine


Hal 35

Pregnancy C - Safety for use during pregnancy has not been established.

Precau-tions

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

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

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

Adult Dose 10-20 mg IV/SC added to chelating solution


Contraindications

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

Inter-actionsDecreases hypoglycemic effect of insulin; phenobarbital, phenytoin, and rifampin increase rate of metabolism


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

Drug Category: 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.

Drug NameTrimethoprim-sulfamethoxazole (TMP/SMX, Bactrim, Septra) -- In combination with gentamicin, DOC for infections by Y enterocolitica.

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

Pediatric Dose

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

Contrain-dications

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

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


Precau-tions

Discontinue at first appearance of skin rash or sign of adverse reaction; obtain CBCs frequently; discontinue therapy if significant hematologic changes occur; goiter, diuresis, and hypoglycemia may occur with sulfonamides; prolonged IV infusions or high doses may cause bone marrow depression (if signs occur, administer leucovorin 5-15 mg/d PO); caution in folate deficiency (eg, those with chronic alcoholism, elderly patients, those receiving anticonvulsant therapy, those with malabsorption syndrome); hemolysis may occur in individuals with G-6-PD deficiency; patients with AIDS may not tolerate or respond to TMP-SMZ; caution in renal or hepatic impairment (perform urinalyses and renal function tests during therapy); administer fluids to prevent crystalluria and stone formation


Hal 36

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

Adult Dose 3-6 mg/kg/d IV divided q8h

Pediatric Dose 6-7.5 mg/kg/d IV divided q8h


Interactions

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)

Preg-nancy C - Safety for use during pregnancy has not been established.

Precau-tions

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

Drug Name

Penicillin V (Pen-Vee, Veetids, V-Cillin K) -- DOC for postsplenectomy prophylaxis; erythromycin used in patients allergic to penicillin. Active against most microorganisms considered to be major offenders in splenectomized patients, namely, streptococcal, pneumococcal, and some staphylococcal microorganisms, but not penicillinase-producing species.

Adult Dose 250 mg PO bid

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


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

Pregnancy B - Usually safe but benefits must outweigh the risks.

PrecautionsPatients 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

Drug Category: 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.

Drug NameAscorbic acid (Vitamin C, Cebid, Vita-C, Ce-Vi-Sol, Cecon, Dull-C) -- Delays conversion of transferrin to hemosiderin, thus making iron more accessible to chelation.

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


Contraindications None reported

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

Pregnancy A - Safe in pregnancy

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


Hal 37

Drug Name

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

Adult Dose 200-400 IU/d PO

Pediatric Dose 1 IU/kg/d PO

Contraindications IV use in infants

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

Pregnancy A - Safe in pregnancy

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

Drug NameFolic acid (Folvite) -- Required for DNA synthesis; therefore in great demand in these patients because of increased cellular turnover. Deficient in most patients with chronic hemolysis.

Adult Dose 0.4-1 mg/d PO

Pediatric Dose 1 mg/d PO

Contraindications Pernicious anemia; aplastic anemia

InteractionsIncreases phenytoin metabolism; oral contraceptives impair folate metabolism, depleting levels

Preg-nancy A - Safe in pregnancy

PrecautionsBenzyl 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

Drug Category: 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.

Drug Name

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

Adult Dose 0.5 mL IM/SC once

Pediatric Dose

<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)

Contraindications

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

Interactions

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)



Hal 38

Precautions

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

Drug Name

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

Adult Dose Not indicated

Pediatric Dose

Regimens vary depending on product; the use of HibTITER is the example that follows:2-6 months: 0.5 mL IM q2mo for 3 doses7-11 months: 0.5 mL IM q2mo for 2 doses if previously unvaccinated12-14 months: 0.5 mL IM once if previously unvaccinatedBooster 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

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

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


Precautions

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

Drug NameQuadrivalent 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.

Pediatric Dose

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

Contrain-dications

Documented hypersensitivity; children <2 y

Inter-actionsAdequate 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

Preg-nancy C - Safety for use during pregnancy has not been established.

Precau-tions May cause headache, chills, or fever

Drug Name 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


Hal 39

serotypes have been responsible for >80% of invasive pneumococcal disease in children <6 y in the United States. Also accounted for 74% of penicillin-nonsusceptible S pneumoniae (PNSP) and 100% of pneumococci with high-level penicillin resistance. Customary age for first dose is 2 mo but can be given to infants as young as 6 wk. Preferred sites of IM injection are anterolateral aspect of the thigh in infants or deltoid muscle of upper arm in toddlers and young children. Do not inject vaccine in gluteal area or areas that may contain a major nerve trunk or blood vessel. A 3-dose series, 0.5 mL each, is initiated in infants aged 7-11 mo (4 wk apart; third dose after first birthday).Children aged 12-23 mo are given 2 doses (2 mo apart). Children >24 mo through 9 y are given 1 dose. Minor illnesses, such as a mild upper respiratory tract infection, with or without low-grade fever, are not generally considered contraindications.

Adult Dose Not established

Pediatric Dose

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 laterAge 24-59 months and 1-3 PCV-7 doses were previously given:Initiated at age 2-9 years: 0.5 mL IM oncePCV-7: 1 dosePPV-23: 1 dose 6-8 wk after PCV-7; repeat 3-5 y laterAge 24-59 months and 1 PPV-23 was previously given:PCV-7: 2 doses given 6-8 w apartPPV-23: Repeat 3-5 y laterAge 24-59 months and no PPV-23 or PCV-7 previously given:PCV-7: 2 doses given 6-8 w apartPPV-23: 1 dose 6-8 wk after PCV-7; repeat 3-5 y later

Contraindications

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)

Interactions

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)


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

FOLLOW UPFurther Inpatient Care:


Hal 40

Uncomplicated cases of thalassemia major are usually managed in an outpatient setting. Inpatient care is usually reserved for infectious complications, surgical procedures, or for the rare patient treated with HSCT.

Further Outpatient Care: Blood transfusions are usually given at scheduled outpatient visits.

Patients must be scheduled for regular lab work to monitor iron deposition status and hepatic, cardiac, and renal functions.

Patients receiving DFO require annual visits to assess for visual and hearing disturbances.

Echocardiogram and ECG are used to monitor cardiac function.

In/Out Patient Meds:See Medication above.

Deterrence/Prevention:Screening and prevention

o In persons with b thalassemia trait, confirming the diagnosis is usually 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.

o For a thalassemia carriers, confirmation is not that simple. 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 b thalassemia if a sibling or a family member is known to be affected.

o 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 b thalassemia in some of the high-risk Mediterranean countries.

o 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. 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.

o 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 MCV, MCH, and 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 diagnosiso 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.

o 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.

o Because many of the mutations that cause a and b thalassemia have become known in recent years, identifying such mutations on the amplified b-globin gene region is now possible with


Hal 41

specific labeled oligonucleotide probes. Some of the new techniques can give accurate results in less than 3 hours.

Complications: Iron overload

o Traditionally, ferritin level assessment has been the most commonly used test for indirect evaluation of body iron stores, even though it reflects only 1% of the total iron storage pool. The test is not perfect or accurate, as various conditions complicate the interpretation of its values. For this reason, reliance on serum ferritin assessment alone can lead to an inaccurate assessment of body iron stores in patients with iron overload who have been transfused heavily and who have levels in excess of the upper limit for the physiologic ferritin synthesis (400 mcg/L). At high levels, the test loses its clinical relevance since ferritin can be released from damaged cells in certain pathologic conditions.

o Furthermore, certain drugs and clinical conditions such as ascorbate deficiency, fever, acute and chronic infections, and hemolysis may influence the ferritin level, producing misleading values. Despite its deficiencies, and for lack of a better practical, noninvasive test, ferritin assessment continues to be the most commonly used tool to diagnose and to monitor iron overload.

o MRI or CT scanning is used to assess liver iron levels as a measure of total body iron load.

o Liver biopsy may be performed to assess liver iron concentration, which is considered the most sensitive method to assess body iron burden. Again, this procedure is an invasive one and not without complications. Furthermore, because iron distribution in the thalassemic liver is uneven and could be affected by fibrosis, one can expect conflicting and inaccurate results in some patients. Grading of stainable iron or measuring parenchymal iron by atomic absorption spectroscopy has been helpful in measuring tissue iron levels, with good correlation to calculated body iron burden.

Cardiac complicationso Most deaths in patients with thalassemia are due to cardiac involvement.

o These complications range from constrictive pericarditis to heart failure and arrhythmias.

o Transfusional hemosiderosis has been classified into 3 stages based on the number of blood units given. The higher the number of PRBC units given, the more advanced the stage. Advanced stage is associated with more severe clinical symptoms and more abnormal findings on cardiac function studies.

o Cardiac hemosiderosis does not occur without significant accumulation of iron in other tissues.

o Chelation therapy has shown promising results in patients with cardiac symptoms due to iron overload.

o Ventricular myocardium is the first site of cardiac iron deposition, while the conduction system is usually the last to be affected. The value of endomyocardial biopsy, which has been used to evaluate iron deposits in the heart, has been questioned. Iron has been reported as absent from the right ventricular subendocardium in some patients with cardiac iron overload.

o Echocardiography, radionuclide cineangiography, and 24-hour ECG are to be used to monitor these patients.

Hepatic complications

o Patients who have received regular blood transfusions for some time develop liver enlargement due to swelling of the phagocytic and parenchymal cells from the deposition of hemosiderin.

o Liver enzyme levels are not typically elevated unless hemosiderin deposition is associated with hepatitis.

o Chelation therapy may prevent or delay progressive liver disease, which may end in cirrhosis.

Long-term therapy complications

o Because of improved medical care, patients with thalassemia are surviving their disease longer and reaching old age. With this longer survival comes new issues related to complications that need to be addressed.

o HCV has emerged as the paramount risk in patients who have been receiving blood transfusions all their lives. HCV screening was initiated in 1990. Since then, according to the Registry of the TCRN, the incidence rate of HCV has dropped significantly. The current prevalence of HCV in patients with thalassemia older than 25 years is 70%, as opposed to only 5% in those with thalassemia aged 15 years or younger.

o Unfortunately, a high incidence rate of HCV continues in developing countries, leading to an increased incidence of fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), especially in the presence of a second risk factor such as iron overload. For this reason, many centers advocate screening patients with HCV every 6 months by obtaining a fetoprotein (AFP) and an ultrasound of the liver. According to the TCRN, approximately 33% of patients with thalassemia major who are also HCV positive develop a spontaneous clearance of the HCV.


Hal 42

o Two-thirds of patients with b thalassemia major have multiple calcified bilirubin stones by age 15 years.

Hematologic complications

o Recently, thrombosis was encountered in relatively significant numbers of patients with thalassemia. In a study of 83 patients with thalassemia intermedia, a 26% incidence rate of VTEs was encountered, while only 2% of 65 patients with thalassemia major developed VTE.

o One study determined that most of the patients with thalassemia intermedia who developed VTE had been splenectomized. Based on this fact, several centers recommend some type of prophylactic therapy to prevent thrombosis in such patients. Short-term antithrombotic therapy, both perioperatively and in the presence of thrombotic risk factors, is recommended. Patients who have undergone splenectomy and have a platelet count in excess of 600,000/mL receive low-dose daily aspirin. Development of pulmonary hypertension in such patients as a result of small pulmonary thrombi represents a significant indication of the increased risk for clotting. Based on the observation of hypercoagulable state in patients with thalassemia, exaggerated by splenectomy, the role of such a procedure in patients with thalassemia needs to be reconsidered.

Endocrine complications

o People with thalassemia major frequently exhibit features of diabetes mellitus; 50% or more exhibit clinical or subclinical diabetes. This is believed to be due to defective pancreatic production of insulin, but insulin resistance also has been implicated.

o Glucose intolerance encountered in these patients usually correlates with the numbers of transfusions received and the patient's age and genetic background.

Growth retardation

o Growth retardation is frequently severe in patients with thalassemia. This retardation is caused, in part, by the diversion of caloric resources for erythropoiesis, as well as by the chronic anemia, since hypertransfusion usually restores normal growth. Unless chelation therapy is initiated early in life, patients rarely grow normally. Excessive chelation with DFO may also cause growth retardation.

o The direct cause of growth retardation in these patients is thought to be an impaired growth hormone production or deficiency in production of somatomedin by the hemosiderotic liver. Involvement of the adrenal glands or the thyroid gland may also contribute to growth failure.

Fertility and pregnancy complications

o Adult patients with thalassemia major are known to have low fertility; this is attributed to the commonly encountered hypogonadotrophic hypogonadism.

o Both primary and secondary sexual characteristics are usually delayed in both males and females.

o Females are frequently oligomenorrheic or amenorrheic.

o Pregnancy complications are also seen frequently and are likely due to endocrinologic and cardiac complications. Case reports demonstrated, however, that successful pregnancy and delivery of healthy babies is possible in women with thalassemia major.

o Early intervention with hormonal therapy and aggressive chelation to prevent permanent damage may help to preserve fertility.

Blood transfusion complications: The most common complications of blood transfusions are discussed in Treatment.

Chelation therapy complications: These complications and the specific adverse effects of DFO are discussed in Treatment.

Viral hepatitis: Viral hepatitis has been reported in nontransfused patients with iron overload, suggesting that iron overload predisposes patients to viral hepatitis, as was stated above.

Prognosis: The prognosis depends on the type and severity of thalassemia. As stated above, the clinical course

of thalassemia varies greatly from mild or even asymptomatic to severe and life threatening.

Patient Education: Patients and their parents and caregivers should be made aware of the nature of their disease, the

fact that it is inherited, and the need to comply with the treatments as scheduled to avoid serious complications.

They should be informed that the treatment does not prevent serious complications from developing and to be aware of what to expect.

Several publications are available for patients and primary care physicians.Many support services are available, such as those offered by the Cooley Anemia Foundation, Inc.,

and other groups. Contact 718-321-CURE or email [email protected].


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Many of the measures used in prevention are based on educating the population and providing resources for advice and guidance. Because of the large numbers of Asian immigrants to the western United States and the high rate of thalassemia carriers among such populations, several effective programs have been initiated, especially in the state of California. Cord blood screening now includes a screen for Hb H disease in addition to the other thalassemias and hemoglobinopathies. Extensive efforts by public health and other organizations are underway to gain the trust of new immigrants and to educate them regarding the seriousness of the problem. All such measures are a first step toward more advanced educational programs for screening in order to decrease the birth rate of affected children.

MISCELLANEOUSMedical/Legal Pitfalls: Failure to counsel couples with thalassemia trait who may give birth to a severely affected child or

failure to recommend prenatal DNA testing when indicated represents another pitfall in the management of thalassemia major.

Once homozygous thalassemia is diagnosed, a regimen of regular monthly blood transfusions should not be initiated without a period of close observation for a few months. This practice protects against missing a patient with thalassemia intermedia who is able to maintain a satisfactory Hb level without regular blood transfusions. In such cases, the patient is saved the risks of unnecessary transfusion and its consequences. Failure to conduct this observation is probably a medicolegal pitfall.

Delaying the initiation of blood transfusions or chelation therapy when either is indicated may result in lasting damage.o Hypersplenism, bone deformities, and cardiac dysfunction are frequent complications of untreated

severe anemia.o Liver disease, endocrinopathy, heart failure, and other manifestations of hemosiderosis are some

of the consequences of iron deposition that is not treated with chelating agents.Chelation therapy should not be initiated at the same time as regularly scheduled blood

transfusions. Serious complications may result if not enough iron is available for chelation. When in doubt, use special tests that are available to help decide whether chelation therapy is appropriate; such a measure may help avoid liability.

Severe local reactions at the site of subcutaneous DFO infusions should not be considered a contraindication to treatment. Because DFO is the only available agent for chelation in this population of patients, the patient should have a central line placed and be treated intravenously rather than go without treatment. This may represent a potential liability issue, since the consequences of going without therapy are serious for patients with severe forms of thalassemia, and such patients, if properly treated, are expected to live much longer lives without complications than they were before current therapies were available.

Patients with hypersplenism who require excessive blood transfusions, develop bleeding manifestations because of thrombocytopenia, or have a massive spleen may benefit from splenectomy. Failure to recommend a splenectomy may compromise the patient's treatment.

In the splenectomized patient, one must not fail to give the appropriate vaccinations, to recommend prophylactic antibiotics, or to recognize the urgency of prompt medical attention when fever develops.

Bone marrow transplantation should not be recommended for patients whose iron overload is not well controlled or for those with hepatomegaly and abnormal liver function test results. The outcome of bone marrow transplantation for such patients is not better than that of standard therapy. Furthermore, the complications of bone marrow transplantation and the stress associated with the procedure outweigh its potential benefits.

For carriers of thalassemia genes, every possible tool should be used to assess the risk of their children developing severe thalassemia, which may result in hydrops fetalis. In this case, carrying an affected fetus to term should be avoided unless intrauterine transfusion is planned, based on the parents' wishes. Several reports exist of affected babies who survived as a result of this approach. The expected quality of life, including chronic blood transfusions and chelation therapy, must be adequately presented to the parents.

An extremely rare situation exists when a patient presents with moderately severe symptoms of thalassemia in the presence of only one affected parent. In this situation, and before assumptions concerning parenthood are raised, the physician should know that dominantly inherited thalassemia syndromes have been described, which may explain this situation.


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TRANSFUSION REACTIONSIf a transfusion reaction occurs, first check the blood pack labels and patient’sidentity. If there is any discrepancy, stop the transfusion immediately and notifythe blood bank.Mild reactions (due to mild hypersensitivity)Signs and symptoms:■ itchy rashManagement:

slow the transfusion➤give chlorphenamine 0.1 mg/kg IM, if available➤continue the transfusion at the normal rate if there is no progression of➤

symptoms after 30 minutesif symptoms persist, treat as moderate reaction (see below).➤

28010. SUPPORTIVE CAREModerately severe reactions (due to moderate hypersensitivity, nonhaemolyticreactions, pyrogens or bacterial contamination)Signs and symptoms:■ severe itchy rash (urticaria)■ flushing■ fever >38 °C or >100.4 °F (Note: fever may have been present before thetransfusion)■ rigors■ restlessness■ raised heart rate.Management:

stop the transfusion, but keep the IV line open with normal saline➤give IV 200 mg hydrocortisone, or chlorphenamine 0.25 mg/kg IM, if➤

availablegive a bronchodilator, if wheezing (see pages 88–90)➤send the following to the Blood Bank: the blood-giving set that was used,➤

blood sample from another site, and urine samples collected over 24 hours.if there is improvement, restart the transfusion slowly with new blood and➤

observe carefullyif no improvement in 15 minutes, treat as life-threatening reaction (see➤

below), and report to doctor in charge and to the Blood Bank.Life-threatening reactions (due to haemolysis, bacterial contamination andseptic shock, fluid overload or anaphylaxis)Signs and symptoms:■ fever >38 °C or >100.4 °F (note: fever may have been present before thetransfusion)■ rigors■ restlessness■ raised heart rate■ fast breathing■ black or dark red urine (haemoglobinuria)■ unexplained bleedingTRANSFUSION REACTIONS28110. SUPPORTIVE CARE■ confusion■ collapse.Note that in an unconscious child, uncontrolled bleeding or shock may be theonly signs of a life-threatening reaction.Management:

stop the transfusion, but keep the IV line open with normal saline➤maintain airway and give oxygen (see page 4)➤give epinephrine (adrenaline) 0.01 mg/kg body weight (equal to 0.1 ml of➤

1 in 10 000 solutiontreat shock (see page 4)➤give IV 200 mg hydrocortisone, or chlorpheniramine 0.1 mg/kg IM, if➤

availablegive a bronchodilator, if wheezing (see pages 88–90)➤report to doctor in charge and to blood laboratory as soon as possible➤maintain renal blood flow with IV furosemide 1 mg/kg➤give antibiotic as for septicaemia (see page 158).➤


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DAFTAR PUSTAKA

Garna Herry, dkk. Pedoman diagnosis dan terapi ilmu kesehatan anak; edisi 3.

Bagian Ilmu Kesehatan Anak Fakultas Kedokteran Unpad/RSHS, 2005.

Bandung

Behrman, Richard et all. Nelson textbook of Pediatric; edisi 17. Philadelphia


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thalasemia diskel

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