HAEMOGLOBINOPATH

Y:

Marshell Tendean MD, DPCP

Department of Internal Medicine
UKRIDA Jakarta

OBJECTIVE :

Natural history of hemoglobin synthesis

Classification of Major Hemoglobinopahty
Sickle cells disease
Classification of Thalasemia
Approach to diagnosis in patient with Thalasemia
Treatment for patient with Thalasemia

HISTORY OF HUMAN
HEMOGLOBIN
Embryo hemoglobin
Zeta, epsilon, alpha, and
gamma chains attain
significant levels and in
various combinations form:
Hb Gower I (22), Hb
Gower II (22), Hb
Portland (22), and fetal
hemoglobin (HbF) (22
136-G and 22 136-A)
6 months
postpartum, only
small amounts of HbF
(<2%) Delta chains
remains at a low level
throughout adult life
(<3%).
Schroeder WA. Proc Natl Acad Sci U S A
1968;60(2):537544

HISTORY OF HUMAN
HEMOGLOBIN

Adult :
Hb A (96%) 2 pairs of globin chain consist of alfa and beta (22)
Hb A2 (2.5%) 2 pairs of globin chain consist of alfa and delta (22)

Fetus :
HBF 2 pairs of globin chain consist of alfa and gama (22)

HUMAN HEMOGLOBIN

Component of normal hemoglobin :

The genes for the chains chains are duplicated
(/, /)
The chains are encoded by a single gene locus (/).

Production of abnormal hemoglobin :

Abnormal hemoglobin in fetus :
chains is reflected by the presence of excess chains,
which form 4 tetramers

Abnormal hemoglobin in adult :

Excess chains form 4 tetra- mers, called hemoglobin H (HbH)

HEMO-GLOBINOPATY :

Diseases related to hemoglobinopathy :

1.

Structural hemoglobinopathy :
1.

Sickle cell syndrome :

HbS
Double heterozigot HbS with variance

2.

Hemoglobin with changes in oxygen afinity : Hb Yakima

3.

Unstable hemoglobinopathy : Hb koln

2.

Thalasemia

3.

Thalasemic hemoglobin variant

4.

Persisten hereditary hemoglobin : HbF persistent

5.

Acquired hemoglobinopathy : methemoglobin

Synthesis
disorders

SICKLE CELL ANANEMIA :

CLINICAL
MANIFESTATION :
Pain due to vasooclusive disease and infarction
Anemia
Aplastic crisis (Co-infecion with parvo B-19 virus)
Infection with encapsulated organism (pneumonia and
osteomylitis)
Avascular necrosis
Renal involvement (isostenuria)
Cholelthiasis
Priapism
Pulmonary hypertension

MANAGEMENT

The goals of treatment in SCD are symptom control and

management of disease complications
Management of vaso-occlusive crisis
Management of chronic pain syndromes
Management of chronic hemolytic anemia
Prevention and treatment of infections
Management of the complications and the various organ damage
syndromes associated with the disease
Prevention of stroke
Detection and treatment of pulmonary hypertension

PHARMACOTHERAPY

Antimetabolites: Hydroxyurea
Opioid analgesics (eg, oxycodone/ASA, methadone,
morphine sulfate, oxycodone/APAP, fentanyl, nalbuphine,
codeine, APAP/codeine)
Nonsteroidal analgesics (eg, ketorolac, ASA, APAP,
ibuprofen)
Antibiotics (eg, cefuroxime, amoxicillin/clavulanate,
penicillin VK, ceftriaxone, azithromycin, cefaclor)
Vaccines (eg, PCV7, PPV23, meningococcal, influenza,
recommended scheduled childhood/adult vaccinations)
Vitamins (eg, folic acid)

Thalasemia :
A syndrome caused by hemoglobin mutation at the globin
gene which caused synthesis disorders

FEATURES OF THALASEMIA

Chromosome 11

Chromosome 16

Lysine to Glutamine Subs at

B chain

& thalasemia due to partial or absolute deficiency of chain and

chain. Hb Lepore
Thomas G
.NEngljmed.371;14

GENOTIPE-PHENOTYPE
FEATURES -THALASEMIA

Frederic B. Piel. N Engl J Med

2014;371:1908-16

THE THALASEMIA
SYNDROME

GENOTYPE / PHENOTYPE
FEATURES OF BETA THALASEMIA

Deborah Rund. N Engl J Med 2005;353:1135-46.

CLINICAL APPROACH IN PATIENT WITH THALASEMIA

Clinical features of anemia +

splenomegaly + mongoloid appearance +
* complications (endocrinopathy)
Microcytosis and feature of
hypoproliverative anemia
MCV < 70 fl
children
Rule out Iron Deficiency
MCV<
80fl
Adult
Normal RDW (Red
anemia.
cell distribution
Iron store study
width)
Feritin + serum iron +
Peripheral blood
TIBC
smears :
Serum
- Target
cell *
Electrophoresis :
Figure 1. The presence of Target
Elevation of Hb A2
cell
Elevation of HbH
(arrow sign)
Other Ancilary
Thomas G. N Engl J Med 2014;371:1324Procedures.*
31

Radiographic Examinations :
Anteroposterior (AP) of both hands
Lateral skull
AP and lateral of thoracolumbar spine
AP of abdomen for gallstones
AP of chest for cardiomegaly, congestive heart failure, and
extramedullary hematopoiesis
Magnetic resonance imaging (MRI).
Computed tomography (CT) scanning may be required to further
evaluate faciomaxillary changes and the pelvis resulting from
extramedullary hematopoiesis

Figure 2. A. Hair on end appearance in thalasemia and

widening of calvaria
B. Osteopenia as a sign of Extramedulary
erythropoesis

ELECTROPHORESIS PATTERN
IN THALASEMIA-ALFA

ELECTROPHORESIS PATTERN
IN THALASEMIA-BETA

COMPLICATIONS OF
THALASEMIA

Manifests as 4
main
symptoms :

Complications of
anemia
Complications of
inefective
erythropoesis
Complications of
Hemosiderosis
Complications of
hypercoagulability
(Phosphatydileserine
expression)

THERAPEUTIC MEASURES

Blood transfusion :

Recommended to achieve target 9 to 10

g/dL
Neocytes (new blood cell) and washed,
filtered and frozen are recommended
monthly

Olivieri N. Baillieres Clin Haematol 1998;11(1):147

162.

Prevention of Hemosiderosis :
Hemosiderosis known as the major cause mortality
and morbidity Non transferin bound iron.
1 unit PRC contatins 250 mg iron.
Iron may store in the skin, endocrine organs,liver,
spleen and heart.
Therapy with iron chelating agent are
recommended in first three years of life.

IRON CHELATING AGENT :

Therapy

Recommendation

Deferasirox
(Exjade)

Initial dose at 20 mg/kgBW/day in patients with

regular transfussion
30 mg/kgBW/day in patients with severe
overload
10-15 mg/kgBW/day in patients with mild cases

DFO (Desferal)

< 50-60 mg/kgBW/day in adult

Deferiprone
(Ferriprox)

75mg/kgBB/day
Can be given in combination with DFO if DFO
alone is not effective

Ferritin levels below 2500 mg/mL are associated with improved

survival.
It is important to try to maintain serum ferritin levels below 1500
Hoffbrand.AVBlood
2003;102(1):1724.
mg/mL.

THERAPY WITH SPECIAL

MEASURE :

Augmentation of Fetal hemoglobin :

Preventing or reversing the switch from fetal to
adult hemoglobin would provide efficacious therapy
for thalassemia and various other
hemoglobinopathies.
Several therapeutic agents such as erythropoietin,
hydroxyurea, cytarabine, and butyrate analogs have
produced an increase in HbF synthesis in the
thalassemic patients by stimulating the HbFproducing progenitor cell population

BONE MARROW
TRANSPLANTATION IN
THALASEMIA

The only curative treatment

From 1000 bone marrow transplants.
Disease-free survival of 80% to 90% was
achieved in patients who had adequate iron
chelation and did not suffer from liver
failure or hepatomegaly.
In patients without these good prognostic
features, disease-free survival rates
dropped to 50%
Argiolu Bone Transplant 1997;19(Suppl 2):65.

SPLEENECTOMY IN
THALASEMIC PATIENTS :

Annual blood requirements exceed represents

consumption of more than 200220 ml of red cells
(assuming haematocrit of transfused cells is
75%)/kg/year
Splenic enlargement is accompanied by symptoms
such as left upper quadrant pain or early satiety.
Leucopenia or thrombocytopenia due to
hypersplenism causes clinical problems (e.g.
recurrent bacterial infection or bleeding).

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