Hemoglobinopathies

Dr.Izzeddin Eqtait ,
MD
 Altered structure, function, or production.

 Usually inherited.

▶ Range in severity from asymptomatic laboratory abnormalities to death in

utero.

▶ Different hemoglobins are produced during embryonic, fetal, and adult

life.
 Hemoglobin
▶ HbA1 (α2 β2)‐ major adult ( 1st appear at 1 month of age )
▶ HbA2 (α2δ2)‐minor
▶ HbF (α2γ2) – fetal
Properties of adult Hb
 RBC can alter shape ( deformability )
 Can bind upto 4, O2 molecule
▶ 2α chains ( 141 amino acids) & 2β chains (146 amino acids).
▶ Unpaired globin precipitates, forming inclusions that damage the cell.
▶ Bind O2 efficiently & retain at high O2 tension (alveolus).
▶ Release at low O2 tension(tissue).
Bohrs Effect
Properties of fetal Hb
 It has α2γ2 chains

 It has high O2 affinity

 As a consequence, fetal hemoglobin can bind oxygen more efficiently than

can adult hemoglobin. This small difference in oxygen affinity mediates the
transfer of oxygen from the mother to the fetus

 Within the fetus, the myoglobin of the fetal muscles has an even higher affinity
for oxygen, so oxygen molecules pass from fetal hemoglobin for storage and use
in the fetal muscles

 In the placenta there is net flow of O2 from mother to fetus

 Classification of hemoglobinopathies
1) Structural hemoglobinopathies— hemoglobins with altered amino acid
sequences eg HbS
2) Thalassemias—defective biosynthesis of globin chains
3) Thalassemic hemoglobin variants—structurally abnormal Hb
associated with
co‐inherited thalassemic phenotype
4) Hereditary persistence of fetal hemoglobin
5) Acquired hemoglobinopathies
A. Methemoglobin
B. Sulfhemoglobin
C. Carboxyhemoglobin
 Sicke cell disease
▶ Mutation in β globin gene that changes sixth amino acid from glutamic acid to
valine
▶ Sickle cell anemia is HbSS – when both β globin have sickle cell mutation
▶ Sickle cell disease refers to pt of sickle cell anemia , HbS,compound
heterozygote where one chain have SC mutation and other is HbC, β-
thalassemia , HbD, HbO.
▶ In normal RBC Hb molecule do not interact with each other ,whereas in SC
mutation Hb molecule are now interact with each other forming a rigid
molecule in deoxygenated state that gives its chachecteristic appearance
“sickeled shaped”
▶ Lung is the only organ capable of reversing the polymer so any disease of lung
can compromise the degree of reversibility
▶ SC RBC are less deformable and more prone for hemolysis.
Sickle cell trait (Hb A and Hb S).
• Less than half the Hb in each red cell is Hb S
• Occasional renal papillary necrosis
• Inability to concentrate the urine (older individuals)
• Red cells do not sickle unless oxygen saturation is <40% (rarely
reached in venous blood)
• Painful crises and splenic infarction have been reported in severe
hypoxia, such as in unpressurised aircraft, or under anaesthesia
• Sickling is more severe where Hb S is present with another β
globin chain abnormality, such as Hb S and Hb C (Hb SC) or Hb S
and Hb D (Hb SD)
Sickle cell anaemia (homozygous Hb S).
• Anaemia (Hb 6.0–10.0 g/dL): symptoms milder than expected as
Hb S has reduced oxygen affinity (i.e. gives up oxygen to tissues
more easily)
• Sickled cells may be present in blood film: sickling occurs at
oxygen tensions found in venous blood; cyclical sickling episodes
• Reticulocytes: raised to 10–20%
• Red cells contain ≥80% Hb S (rest is Hb F)
• Variable haemolysis
• Hand and foot syndrome (dactylitis)
• Intermittent episodes, or crises, characterised by bone pain,
worsening anaemia, or pulmonary or neurological disease
• Chronic leg ulcers
• Gallstones
▶ Sickling occurs most commonly in post capillary venules
▶ SCD is also an inflammatory disease ( increase TLC and cytokines)
▶ Factors increasing sickling are
a) Hypoxia
b) Low PH
c) Fever
d) Infection
e) Excess exercise
f) Anxiety , Dehydration
g) Exposure to cold
h) Swimming for prolonged hours
 Clinical feature
 Fever & Bacteremia – because of splenic infarction by 6 mo of age , risk of
encapsulated organism infection like S.pneumoniae , H.influenzae type b,
N.meningitides.
 Aplastic Crisis –Human parvovirus B19 infection causing profound
reticulocytopenia
 Splenic Sequestration – As a result of trapping of blood in spleen
causing
• Rapid enlargement of spleen causing left sided abdominal pain
• Profound anemia
Sequestration may be triggered by Fever, Bacteremia, or viral
infection
Treatment- Isotonic fluid , Blood transfusion
Blood transfusion is to be given by 5ml/kg because of the risk of hyperviscosity
syndrome and Autotranfusion
 Dactylitis or Hand Foot Syndrome –Either symmetrical or unilateral painful
swelling of hands, and / or feet

Destructive changes and periosteal reaction

 Acute vasoocclusive pain- can occur in any part of the body but most often
occurs in the Chest, Abdomen, or Extremities
▶ These painful episodes are often abrupt and cause disruption of daily life
activities
▶ Because blood flow is disrupted in the microvasculature by sickled cells,
resulting in tissue ischemia
▶ Treatment- NSAIDs, Acetamenophen, Hydrocodone
 Osteomyelitis- Both Salmonella spp. and S. aureus cause osteomyelitis in
children with sickle cell anemia, which is often in the diaphysis of long bones (in
contrast to children without sickle cell anemia where osteomyelitis is in the
metaphyseal region of the bone).
 Avascular necrosis- Causes of both acute and chronic pain
 Most common site is femoral head , other site is humeral head and mandible
 Manage by opioids
 Blood transfusion is not effective in abating acute or chronic pain
 Priapism- It is defined as an unwanted painful erection of the penis.
 Priapism occurs in 2 patterns
a) Prolonged- lasting for more than 4 hr
b) Stuttering-with brief episodes that resolve spontaneously but may occur in
clusters and herald a prolonged event
▶ Most episodes occur between 3 a.m. and 9 a.m.
▶ Recurrent prolonged episodes of priapism are associated with impotence.
▶ Acutely, supportive therapy, such as a hot shower, short aerobic exercise, or
pain medication, is commonly used by patients at home
▶ Prolonged episode lasting >4 hr should be treated by aspiration of blood from
the corpora cavernosa followed by irrigation with dilute epinephrine to
produce immediate and sustained detumescence
▶ Simple blood transfusion and exchange transfusion has been proposed for the
acute treatment of priapism
 Neurologic complications- Ranging from acute ischemic stroke with focal
neurologic deficit to clinically silent abnormalities
▶ Other neurologic complications include headaches, seizures, cerebral venous
thrombosis and posterior reversible encephalopathy syndrome (PRES)
▶ For patients presenting with acute focal neurologic deficit oxygen
administration to keep oxygen saturations >96% and simple blood transfusion
within1 hr of presentation with a goal of increasing the hemoglobin to a
maximum of 10 g/dL is warranted.
▶ Transcranial Doppler ultrasonography (TCD) assessment of the blood
velocity in the terminal portion of the internal carotid and the proximal
portion of the middle cerebral artery.
▶ Children with sickle cell anemia with an elevated time-averaged mean
maximum (TAMM) blood-flow velocity >200 cm/sec are at increased risk for a
cerebrovascular event.
 Lung disease-ACS refers to a life-threatening pulmonary complication of
sickle cell disease defined as a new radiodensity on chest radiography plus
any 2 of the following: fever, respiratory distress, hypoxia, cough, or
chest pain
 ACS may progress rapidly from a simple infiltrate to extensive infiltrates and
a pleural effusion
▶ Continued pulse oximetry and frequent clinical exams are required, and
repeat chest x-rays are indicated for progressive hypoxia, dyspnea,
tachypnea, and other signs of respiratory distress
▶ Cause of ACS
a) Infection -most common pathogens are S. pneumoniae, Mycoplasma
pneumoniae,and Chlamydia sp
b) Fat Emboli-arising from infarcted bone marrow
▶ Management is by Opioids and use of an incentive spirometer at 10-12
breaths every 2 hr can significantly reduce the frequency of subsequent
acute chest pain episodes
▶ Since there is clinical overlap between pneumonia and ACS all episodes
are treated with IV Antibiotics
▶ Blood transfusion therapy using either simple or exchange transfusion is the
only method to abort a rapidly progressing episode of ACS

 Renal Disease and Enuresis-Seven sickle cell disease nephropathies have

been identified:
(1) Gross hematuria
(2) Papillary necrosis
(3) Nephrotic syndrome
(4) Renal infarction
(5) Hyposthenuria
(6) Pyelonephritis
(7) Renal medullary carcinoma
▶ Presence of nocturnal enuresis occurring in children with sickle cell anemia is
troublesome to affected children and their parents. The overall prevalence of
enuresis is 33%
▶ Cognitive and Psychological Complications-One of main reason behind the
low high school graduation rate is that approximately a third of children with
sickle cell anemia have had a cerebral infarct—either silent cerebral infarcts
or overt strokes.
 Diagnosis
▶ Thin layer/isoelectric focusing and high-performance liquid chromatography
(HPLC) is most commonly used in newborn screening

▶ A confirmatory step is recommended, with all patients who have initial

abnormal screens being retested during the first clinical visit and after 6 mo
of age to determine the final hemoglobin phenotype
▶ The hemoglobin with the greatest quantity is reported first, followed by
other
hemoglobins in order of decreasing quantity.
 THERAPEUTIC CONSIDERATIONS
1) Hydroxyurea- a myelosuppressive agent, is the only drug proven effective in
reducing the frequency of painful episodes
▶ Hydroxyurea alone is inferior to transfusion therapy for secondary stroke
prevention in patients who do not have contraindications to ongoing
transfusions
▶ The starting dose of hydroxyurea is 15-20 mg/kg given once daily, with an
incremental dosage increase every 8 wk of 5 mg/kg, and if no toxicities occur,
up to a maximum of 35 mg/kg per dose.
▶ Achievement of the therapeutic effect of hydroxyurea can require several
months
2) Hematopoietic Stem Cell Transplantation-The only cure for sickle cell
anemia is transplantation with human leukocyte antigen (HLA)–matched
hematopoietic stem cells from a sibling or unrelated donor.
▶ The most common indications for transplant are recurrent ACS, stroke and
abnormal TCD

3) Red blood cell transfusions-are frequently used in the management of

children with sickle cell anemia, both in the treatment of acute complications
such as ACS, aplastic crisis, splenic sequestration, and acute stroke, and to
prevent surgery-related ACS
▶ Patients with sickle cell disease are at increased risk of developing
alloantibodies to less-common red cell surface antigens after receiving even a
single transfusion.
▶ Therefore in addition to standard cross-matching for major blood group
antigens (A, B, O, RhD), more extended matching should be performd for C-,
E-, and Kell-antigen
▶ There are 3 methods of blood transfusion therapy that are used
a) Automated erythrocytapheresis,
b) Manual exchange transfusion
c) Simple transfusion.

4) Excessive Iron Stores-Develop after 100 mL/kg of red cell transfusion

or about 10 transfusions.
▶ Ferritin measurements have significant limitations in their ability to estimate
iron stores
▶ MRI of the liver has proven to the most effective and common approach for
assessment of iron stores.
▶ Iron chelators used are Deferoxamine, Deferasirox, Deferiprone
5) ANTICIPATORY GUIDANCE
a. Spleen Palpation-Splenomegaly is a common complication of sickle cell
anemia and splenic sequestration can be life-threatening
b. Prophylactic Penicillin-Children with sickle cell anemia should receive
prophylactic oral penicillin until at least 5 yr of age
c. Immunizations- Pneumococcal and meningococcal vaccinations.
d. Transcranial Doppler Ultrasound
e. Retinopathy
f. Echocardiography
Treatment of major complications of sickle cell
disease.
• Hand and foot syndrome: hydration; paracetamol
• Painful crises: hydration; analgesia (including graded intravenous
analgesics); oxygen (check arterial blood gases); blood cultures;
antibiotics
• Pulmonary infiltrates: especially with deterioration in arterial
gases, falling platelet count and/or Hb concentration suggesting
lung syndrome requires urgent exchange blood transfusion to
reduce Hb S level together with oxygenation
• Splenic sequestration crisis: transfusion; splenectomy to prevent
recurrence
• Neurological symptoms: immediate exchange transfusion
followed by long‐term transfusion
• Prevention of crises: ongoing trials of cytotoxic agent hydroxyurea
show that it raises Hb F level and ameliorates frequency and
severity of crises; long‐term effects unknown
 Thalassemia

▶ The thalassemias are a group of congenital anemias that have in common

deficient synthesis of one or more of the globin subunits of the normal human
hemoglobins (Hbs).

▶ Cooley & Lee in 1925 first described thalassemia as a clinical entity

 β- Thalessemia syndromes
▶ Result from a decrease in β globin chains with a relative excess
of α globin chains.
 β0 thalassemia mutation- no β globin chain production
 β+ thalassemia mutation- decreased amount of normal β globin production

▶ β Thalessemia major: β- refers to the severe β thalassemia patient who

requires early transfusion therapy and often is homozygous for β0 mutations.
▶ β Thalessemia intermedia: patient with a less-severe clinical phenotype,
usually does not require transfusion therapy in childhood. Many have at least 1
β+ thalassemia mutation
▶ β Thalassemia Carriers: people with a single β-globin mutation are generally
asymptomatic, except for microcytosis and mild anemia.
β thalassaemia trait (heterozygous carrier).
• Mild hypochromic microcytic anaemia
• Hb 9.0–11.0 g/dL
• Mean cell volume 5.0–7.0 g/dL
• Mean corpuscular Hb 20–22 pg
• No clinical features, patients asymptomatic
• Occasional symptomatic anaemia in pregnancy
• Often diagnosed on routine blood count
• Raised Hb A2 level
β thalassaemia major (homozygous β thalassaemia).
• Severe anaemia
• Blood film
• Pronounced variation in red cell size and shape
• Pale (hypochromic) red cells
• Target cells
• Basophilic stippling
• Nucleated red cells
• Moderately raised reticulocyte count
• Infants are well at birth but develop anaemia in first few months
of life when switch occurs from γ to β globin chains
• Progressive splenomegaly; iron loading; susceptibility to infection
β-thalessemia
 α Thalessemia Syndromes

▶ There is an absence or reduction in α-globin production. Normal individuals

have 4 α-globin genes. The more genes affected, the more severe the
disease.

 α0-mutation indicates no α-chains produced from that gene.

 α+ mutation produces a decreased amount of α-globin chain.
α- thalessemias
The α thalassaemias.
−α/αα, one α gene deleted
• Asymptomatic
• Majority show reduced mean cell volume (MCV) and mean
corpuscular Hb (MCH)
−α/−α or αα/− −, two α genes deleted
• Hb is normal or slightly reduced
• Reduced MCV and MCH
• No symptoms
− −/−α, three α genes deleted, Hb H disease
• Chronic haemolytic anaemia
• Reduced α chain production with formation of β4 tetramers (β4 is
termed Hb H)
• Hb H is unstable and precipitates in older red cells
• Hb is 7.0–11.0 g/dL, although may be lower
• Reduced MCV and MCH
• Clinical features: jaundice, hepatosplenomegaly, leg ulcers,
gallstones, folate deficiency
• A more severe form of Hb H disease results from the inheritance
of the genotype αNDα/– –; ND stands for non‐deletion and
represents a variety of different mutations that inactivate rather
than delete the α globin gene
− −/− −, four α genes deleted, Hb Bart’s hydrops
• No α chains produced
• Mainly γ, forms tetramers (γ4, termed Hb Bart’s)
• Intrauterine death or stillborn at 25–40 weeks or dies soon after
birth αα/αα represents two α globin genes inherited from each
parent. Changes due to α thalassaemia are present from birth,
unlike in β thalassaemia
 Epidemiology
▶ There are >200 different mutations resulting in absent or decreased globin
production.

▶ Although most arerare, the20 most common abnormal allelesconstitute

80% of the known thalassemias worldwide

▶ 3% of the world’s population carries alleles for β-thalassemia

▶ In Southeast Asia 5-10% of the population carry alleles for α-thalassemia.

 Pathophysiology: β thalessemias

▶ Two related features contribute to the sequelae of β-thalassemia major:

 inadequate β-globin chain production
 α-globin chains are in excess to non–α-globin chains, and α globin
tetramers (α4) are formed and appear as red cell inclusions.

▶ Free α-globin chain inclusions precipitate in red cell precursors, damage the
red cell membrane, shorten red cell survival leading to anemia and increased
erythroid production.
▶ Because the β0-thalassemia patient cannot make HbA, the α-chains combine
with γ-chains, resulting in HbF (α2γ2) being the dominant hemoglobin.
▶ δ-Chain synthesis is not usually affected, therefore patients have a relative
or absolute increase in HbA2 production (α2δ2).
 Pathophysiology: α thalessemias
▶ Reduced copy numbers of α-globin genes produce successively more
severe effects.
 Most people have four copies of the α-globin gene (αα/αα).
 People with three copies (αα/α-) are healthy; those with two (whether the
phase is α-/α- or αα/--) suffer mild α-thalassemia.
 Those with only one gene (α-/--) have severe disease, while lack of all four α
genes (--/--) causes lethal hydrops fetalis.

▶ Excess of β- and γ-globin chains are produced. They form Bart haemoglobin
(γ4) in fetal life and HbH (β4) after birth. These tetramers are non-functional
with very high oxygen affinity.
 Homozygous β-thalassemia
(Thalassemia major, Cooley anemia)
 CLINICAL FEATURES
▶ Depending on the mutation and degree of fetal hemoglobin
production, transfusions in β-thalassemia major are necessary
beginning in the 2nd mo to 2nd yr of life, but rarely later.
▶ The classic presentation of children with severe disease
includes:
 Thalassemic facies (maxilla hyperplasia, flat nasal
bridge, frontal bossing)
 Pathologic bone fractures
 Marked hepatosplenomegaly, hypersplenism and cachexia
▶ Chronic anemia even without transfusion exposure leads to
increase in iron absorption from G.I tract and secondary
hemosiderosis.
 Homozygous β-thalassemia
(Thalassemia major, Cooley anemia)
 CLINICAL FEATURES cont…

▶ Each mL of packed red cells contains 1 mg of iron. Physiologically, there is no

mechanism to eliminate excess body iron.
▶ Iron is initially deposited in the liver. Liver hemosiderosis after 1 yr of
chronic transfusion therapy and is followed by iron deposition in the
endocrine system.
▶ Endocrine manifestations: hypothyroidism, hypogonadotrophic gonadism,
growth hormone deficiency, hypoparathyroidism, and diabetes mellitus.
▶ After 10 yr of transfusion, cardiac dysfunction secondary to hemosiderosis
begins and is a major cause of mortality.
 Homozygous β-thalassemia
(Thalassemia major, Cooley anemia)
 Laboratory Findings

▶ There is anemia after the newborn period. Microcytosis (MCV), hypochromia

(MCH), and targeting characterize the red cells. Nucleated red cells, marked
anisopoikilocytosis, and a relative reticulocytopenia are typically seen.
▶ The unconjugated serum bilirubin level is usually elevated.
▶ Elevated serum ferritin and transferrin saturation.
▶ Bone marrow hyperplasia can be seen on radiographs.
▶ Newborn screening techniques such as hemoglobin electrophoresis is not
definitive. DNA diagnosis of the β-thalassemia mutation can also be done.
Ineffective erythropoiesis in a 3 yr old patient who has β-
thalassemia major and has not received a transfusion.

• A, Massive widening of the diploic spaces of the skull as

seen on MRI.
• B, Radiographic appearance of the trabeculae as seen on
plain radiograph.
• C, Obliteration of the maxillary sinuses
with hematopoietic tissue as seen on CT scan.
 Management and treatment of
thalassemia
 Transfusion Therapy

▶ Of patients with homozygous β0-thalassemia,15-20% may have a clinical

course that is phenotypically consistent with thalassemia intermedia.
▶ In contrast, 25% of patients with homozygous β+-thalassemia, may become
transfusion-
dependent thalassemia major.

▶ Patients should receive red cells depleted of leukocytes and matched for, at least, D, C, c, E,
e, and Kell antigens.
▶ Cytomegalovirus-negative units are indicated in stem cell transplantation candidates.
▶ Transfusions generally given at intervals of 3-4 wk, goal is to maintain a pretransfusion HB
level of 9.5-10.5 g/dL.
▶ Monitor for transfusion-associated infections (hepatitis A, B, C, HIV), alloimmunization,
annual blood transfusion requirements, and transfusion reactions.
 Management and treatment of
thalassemia
 Iron Overload Monitoring

▶ Serial serum ferritin levels are a useful screening technique in assessing iron
balance trends.
▶ Ferritin may not accurately predict quantitative iron stores.
▶ Quantitative liver iron can be measured by liver biopsy.
▶ Quantitative liver iron by approved MRI technology is the best noninvasive
indicator of total-body iron stores.
▶ Quantitative cardiac iron, determined by T2 MRI cardiac software, should be
obtained after 7 yr of transfusion therapy.
 Management and treatment of
thalassemia
 Chelation therapy
▶ Significant iron overload occurs after 1 yr of transfusion therapy and correlates with
serum ferritin >1,000 ng/mL and/or a liver iron of >2,500 μg/g dry weight.
▶ There are 3 available iron chelators:
▶ Deferoxamine: It requires s.c, or i.v, (half-life <30 min) necessitating administration
of at least 8 hr daily, 5-7 days/wk. Initially started at 20 mg/kg and can be increased
to 60 mg/kg in heavily iron-overloaded patients.
▶ Deferasirox: Given orally. Requires once-a-day administration of a dispersible tablet
in water (half life >16hr). Initial dose is 20 mg/kg with gradual escalation to 30
mg/kg.
▶ Deferiprone: Oral iron chelator. Has a half-life of 3 hr and requires 25 mg/kg 3 times
a day. May be more effective than other chelators in reducing cardiac hemosiderosis.
▶ Combination therapy with two chelators may be needed in some patients.
 Management and treatment of
thalassemia
 Hydroxyurea

▶ Hydroxyurea, a DNA antimetabolite, increases stress erythropoiesis, which

results in increased HbF production.
▶ It has been most successfully used in sickle cell disease and in some patients
with β thalassemia intermedia. Studies in β-thalassemia major are limited.
▶ In general, there appears to be a mean increase in haemoglobin of 1 g (range:
0.1-2.5 g).
▶ The initial starting dose for thalassemia intermedia is 10 mg/kg.
 Management and treatment of
thalassemia
 Hematopoietic Stem Cell Transplantation

▶ All children who have an HLA-matched sibling should be offered the option of
bone marrow transplantation.
▶ Most success has been in children younger than 15 yr of age without excessive
iron stores and hepatomegaly who undergo sibling HLA-matched allogeneic
transplantation.
▶ In general, myeloablative conditioning regimens are required in order to
prevent graft rejection and thalassemia recurrence.
 Management and treatment of
thalassemia

 Splenectomy

▶ Splenectomy may be required in thalassemia patients who develop

hypersplenism. These patients have a falling steady state haemoglobin and/or
a rising transfusion requirement.
▶ Splenectomised children have risk of infections, venous thrombosis, pulmonary
hypertension, leg ulcers, and silent cerebral infarction.
▶ All patients should be fully immunized against encapsulated bacteria and
should be on long-term penicillin prophylaxis with appropriate instructions
regarding fever management.
Preventative Monitoring of Thalassemia
Patients
 Cardiac
▶ Serial echocardiograms should be monitored to evaluate cardiac function and
pulmonary artery pressure.
▶ Pulmonary hypertension frequently occurs in non-transfused
thalassemia
patients and may be an indication for transfusion therapy.
▶ After 8 yr of chronic transfusion therapy, cardiac T2* MRI imaging studies are
recommended.
▶ Patients with cardiac hemosiderosis and decreasing cardiac ejection
fraction require intensive combination chelation therapy.
Preventative Monitoring of Thalassemia
Patients
 Endocrine
▶ Iron deposition in the pituitary and endocrine organs can result in multiple
endocrinopathies, including hypothyroidism, GH deficiency, delayed puberty,
and hypoparathyroidism, diabetes mellitus, osteoporosis, and adrenal
insufficiency.
▶ Monitoring starts by 5 yr of age, or after at least 3 yr of chronic transfusions.
▶ All children require monitoring of their height, weight, and
sitting height semi-annually.
▶ Nutritional assessments are required. Most patients need vitamin D, calcium,
vitamin B, vitamin C, and zinc replacement.
▶ Fertility is a growing concern amongpatients and should be
assessed routinely.
Preventative Monitoring of Thalassemia
Patients
 Psychosocial Support

▶ Thalassemia imposes major disruptionin thefamily unit and significant

obstacles to normal development.
▶ Culturally sensitive anticipatory counselling is necessary.
▶ Consultation to address financial and social issues is needed.
 α-Thalassemia syndromes

 The deletion of 1 α-globin gene allele (silent trait) is not identifiable

hematologically.

 The deletion of 2 α-globin gene alleles results in α-thalassemia trait. The α-

globin alleles can be lost in a trans-(−α/−α) or cis- (α,α/--) configuration.
▶ α-Thalassemia trait manifest as a microcytic anemia that can be mistaken for
iron-deficiency anemia. The haemoglobin analysis is normal, except during
the newborn period, when Hb Bart is commonly <8% but >3%.
▶ The simplest approach to distinguish between iron deficiency and α-
thalassemia trait is with a good dietary history. A brief course of iron
supplementation along with monitoring of erythrocyte parameters might
confirm the diagnosis of iron deficiency.
 α-Thalassemia syndromes
 The deletion of 3 α-globin gene alleles leads to the diagnosis of HbH disease.
▶ The simplest manner of diagnosing HbH disease is during the newborn period,
when excess in γ-tetramers are present and Hb Bart is commonly >25%.
▶ Later in childhood, there is an excess of β-globin chain tetramers that results
in HbH(β4).
▶ A definitive diagnosis of HbH disease requires DNA analysis with
supporting evidence.
▶ Patients with HbH disease have a marked microcytosis, anemia,
mild
splenomegaly, and, occasionally, scleral icterus or cholelithiasis.
▶ Chronic transfusion is not commonly required for therapy because the range
of hemoglobin is 7-11 g/dL, with MCV 51-73 fL but intermittent transfusions
for worsening anemia may be needed.
 α-Thalassemia syndromes
 The deletion of all 4 α-globin gene alleles causes profound anemia during
fetal life, resulting in hydrops fetalis.
▶ The ζ-globin gene must be present for fetal survival. There are no normal
hemoglobins present at birth (primarily Hb Bart, with Hb Gower 1, Gower 2,
and Portland).
▶ If the fetus survives, immediate exchange transfusion is indicated.
▶ At-risk couples for hydrops fetalis should be identified and offered molecular
diagnosis on fetal tissue obtained early in pregnancy. Later in pregnancy,
intrauterine transfusion can improve fetal survival, but chronic transfusion
therapy or bone marrow transplantation for survivors will be required.
Before iron chelation After iron
D/D based on red cell indices
-thal trait IDA

▶ Hb N/  
▶ RBC  
count
▶ MCV  
▶ MCH  
▶ MCHC N 
▶ RDW N 
Thalassemia
major
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