for
THALASSEMIA
Developed for the
Aerospace Medical Association
by their constituent organization
American Society of Aerospace Medicine
Specialists
Overview: The thalassemias are hereditary
disorders characterized by reduction in the synthesis of globin chains (α or β). Reduced
globin chain synthesis causes reduced hemoglobin synthesis and eventually
produces a hypochromic microcytic anemia because of defective hemoglobinization
of red blood cells.4 Clinical
severity varies widely, depending on the degree to which the synthesis of the
affected globin is impaired, altered synthesis of other globin chains, and
coinheritance of other abnormal globin alleles.1
Thalassemia
is among the most common genetic disorders worldwide; 4.83% of the world’s population
carries globin variants, affecting nearly 200 million people worldwide including
1.67% of the population who are heterozygous for α-thalassemia and β-thalassemia.7 About
15% of American blacks are silent carriers for α-thalassemia; α-thalassemia
trait (minor) occurs in 3% of American blacks and in 1 to 15 of
persons of Mediterranean origin. β-Thalassemia has a 10 to 15% incidence in
individuals from the Mediterranean and
The α-like
globin genes (α,ζ)
are encoded on chromosome 16; the β-like genes (β,g,d,ε) are encoded on chromosome 11.
The ζ and ε genes encode
embryonic globins.1 Thalassemia is inherited in an
autosomal recessive pattern. Normal
adult hemoglobin is primarily hemoglobin A, which represents approximately 98%
of circulating hemoglobin. Hemoglobin A
is formed from a tetramer - two α chains and two β chains α2β2.
The tetramer of α2d2
forms hemoglobin A2, which normally comprises 1-2% of adult
hemoglobin. The tetramer a2g2 forms hemoglobin F, which is the major hemoglobin of
fetal life but which comprises less than 1% of normal adult hemoglobin (see
table 1).2
Table
1: Distribution of the different types
of hemoglobin (Hb) in a normal adult.
|
HbA |
HbA2 |
HbF |
HbH |
Hb Barts |
|
a2β2 (98%) |
a2d2 (1-2%) |
a2g2 (<1%) |
β4 |
g4 |
a-Thalassemia:
a-Thalassemia
results from deletion of one or more of the four genes responsible for a-globin synthesis. Four-gene deletions results in fatal hydrops fetalis with 90-95% Hb Barts (g4). Three-gene
deletions results in hemoglobin H (HbH). A two-gene deletion is trait and one-gene
deletion is a "silent" carrier state.1
Table 2: a-Thalassemia
types.1
Condition |
HbA
(%) |
HbH
(β4) (%) |
Hb
Level (g/dL) |
MCV |
|
|
97 |
0 |
15 |
90 |
|
Silent
thalassemia: -a/aa |
98-100 |
0 |
15 |
90 |
|
Thalassemia
trait: -a/-a, homozygous a-thal-2* or --/aa, heterozygous a-thal-1* |
85-95 |
Rare
red blood cell inclusions |
12-13 |
70-80 |
|
HbH disease: --/-a, heterozygous a-thal-1/a-thal-2 |
70-95 |
5-30 |
6-10 |
60-70 |
|
Hydrops fetalis --/--,
homozygous a-thal-1 |
0 |
5-10# |
Fatal
in utero or at birth |
|
*
When both aalleles on one chromosome are deleted,
the locus is called a-thal-1;
when only a single a
allele on one chromosome is deleted, the locus is called a-thal-2.
# 90-95% of the hemoglobin is hemoglobin Barts
(tetramers of a
chains).
Persons with a-thalassemia
trait may exhibit mild hypochromia and microcytosis usually without anemia. HbA2 and HbF
levels are normal. HbH
disease resembles β-thalassemia intermedia, with the added complication
that the HbH molecule behaves like a
moderately unstable hemoglobin, resulting in moderately severe hemolytic anemia but
milder ineffective erythropoiesis. Survival into mid-adult life without
transfusions is common.1 Another more virulent alpha chain
defect (four gamma chains-Hb Bart’s) causes the
deadly hydrops fetalis.
β-Thalassemia. β-Thalassemia
is caused by any of more than 200 point mutations in β-globin chain
synthesis and very rarely deletions.12
Table 3: β-Thalassemia
types.4
|
Condition |
β-Globin Genes |
HbA (%) |
HbA2 (%) |
HbF (%) |
|
|
Homozygous
β |
97-99 |
1-3 |
<1 |
|
β-Thalassemia
minor (trait) |
Heterozygous
β0 Heterozygous
β+ |
80-95 80-95 |
4-8 4-8 |
1-5 1-5 |
|
β-Thalassemia
intermedia |
Homozygous
β+ (mild) |
0-30 |
0-10 |
6-100 |
|
β-Thalassemia
major |
Homozygous
β+ |
0-10 |
4-10 |
90-96 |
|
β-Thalassemia
major |
Homozygous
β0 |
0 |
4-10 |
90-96 |
β0: Absent β globin
chain synthesis.
β+: Reduced β
globin chain synthesis.
Β-Thalassemia,
homozygous disease is not compatible with a long life. β-Thalassemia
major, with either absent or reduced beta chain production, results in a
significant amount of HbF (a2g2). This tetramer
is unstable, readily breaks down, and results in severe microcytic, hypochromic
anemia. It is associated with massive
enlargement of the liver and spleen, due to excessive red-cell destruction and
extramedullary erythpoiesis. Thinning of
cortex due to bone marrow expansion also leads to pathological fractures.3
Transfusion therapy is necessary to sustain life.5 The
clinical phenotype of patients designated as having thalassemia
intermedia is more severe than the usual
asymptomatic thalassemia trait but milder than
transfusion-dependent thalassemia major. It encompasses a wide range of disorders from
transfusion-dependent with growth and development retardation to asymptomatic
with Hb 10-12 g/dl.12 β-Thalassemia minor (i.e., thalassemia trait)
usually presents as profound microcytosis and hypochromia with target cells,
but only minimal or mild anemia. The
mean corpuscular volume is rarely >75 fL; the
hematocrit is rarely <30 to 33. Hemoglobin electrophoresis classically reveals
an elevated HbA2 (4-8 ), but some forms are associated with
normal HbA2 and/or elevated HbF. Individuals with β-thalassemia trait
should be warned that their blood picture resembles iron deficiency and can be
misdiagnosed.1
Aeromedical Concerns: The homozygous forms are severe and
sufficiently compromise the oxygen-carrying capacity of the individual such that
flying is contraindicated. The
homozygous β-thalassemias in thalassemia major and intermedia are
incompatible with long life and require frequent blood transfusions; therefore they
are unsuitable for flight duties. On the
other hand, the heterozygous β-thalassemias generally do not impair normal
life and are compatible with aircrew duties; the only potential concern is a
mild, microcytic, hypochromic anemia. Likewise,
heterozygous a-thalassemias,
such as silent thalassemia and a-thalassemia trait, rarely produce
more than a mild anemia and are compatible with flying duties. As a matter of fact, most individuals with
thalassemia minor require no medication and live normal lives, suffering no ill
effects or restrictions.6 Homozygous a-thalassemia Hb
Barts mostly results in
spontaneous abortion and Hb H usually presents
with severe anemia and requires frequent blood transfusions, hence all of these
conditions are incompatible for flight duties.
Aeromedical Disposition (military): Thalassemia is disqualifying for military
flying. A waiver for a- and β-thalassemia minor/trait
is likely as long as the anemia is minimal with hematocrit >32 and patient
is symptom free. Indefinite waiver could also be possible if stable hematocrit
> 38 for males and >36 for females and asymptomatic.8
However, waiver guidance for
heterozygous thalassemia associated with other hemoglobinopathies cannot be
generalized and thus waiver status is considered on a case by case basis. Patients who have required splenectomy because
of their thalassemia are permanently disqualified from military flying.11
The
aeromedical summary for initial waiver should include the following:
A. History – ethnicity, family history for
“anemia,” symptoms such as fatigue, shortness of breath, dizziness,
palpitations (include negatives), and activity
level.
B. Physical – skin, mucous membranes, heart,
lung, abdomen, extremities
C. CBC with reticulocyte
count.
D. Iron studies (serum iron, total iron binding
capacity (TIBC), and serum ferritin).
E. Hemoglobin electrophoresis.
F. Hemoglobin A2 quantification in cases of
beta-thalassemia trait.9
F. Blood smear result.
G. Hematology consult.
Aeromedical Disposition (Civilian): There is no specific guidance for
waiver considerations with Federal Aviation Administration (FAA), however,
disease of the blood or blood-forming tissues that could adversely affect
performance of airman duties should submit a current status report and all
pertinent medical reports to FAA for considerations.10
However, in civil aviation, an anemia
with a Hgb < 10 or a hematocrit <
30% is disqualifying for flying.
Waiver Experiences (Military): Review
of the United States Air Force Waiver database from 2001 through mid-February
2008 showed 47 cases of thalassemia. All
the thalassemia cases were heterozygous and minor /trait (eight specifically
identified as a-thalassemia
and 25 specifically identified as β-thalassemia). Of the 47 cases, only three were
disqualified, and two were associated with other diagnoses such as stroke and
intervertebral herniation, hence almost 98% have received waivers. Of note, 20 cases were granted an indefinite
waiver.8
|
ICD-9-CM for thalassemia |
|
|
282.4 |
Thalassemia |
|
282.7 |
Other
hemoglobinopathies |
|
282.8 |
Other
specified hereditary hemolytic anemias |
|
282.9 |
Hereditary
hemolytic anemia, unspecified |
V.
References.
1. Benz EJ.
Chpater 91 – Hemoglobinopathies. In Kasper DL,
2. DeHart RL.
Chapter 21. Selected medical
and surgical conditions of aeromedical concern. In DeHart RL, Davis JR, eds. Fundamentals
of Aerospace Medicine, 3rd ed.
3. Giangrande
PLF. Chapter 43 - Haematology.
In Rainford DJ, Gradwell
DP, eds. Ernsting’s Aviation Medicine, 4th Ed. Hodder Education: 2006; 657-8.
4. Linker CA. Chapter13 - Blood disorders. In McPhee SJ, Papadakis MA, Tierney LM, eds. Current
Medical Diagnosis & Treatment, 47th ed.
5.
6. Rayman RB, Hastings JD, Kruyer,
WB, Levy RA, Pickard JS. Chapter 2:
Internal medicine - anemia. Clinical Aviation Medicine, 4th
Ed. Professional Publishing
Group, Ltd; 2006: 32-5.
7. Rund D, Rachmilewitz E. Beta-thalassemia. N Engl
J Med. Sep 15 2005; 353(11): 1135-1146.
8. United States Air Force, Aircrew Medical
Waiver Guide: Thalassemia, revised March 2008
9.
10.
11.
12. Weatherall DJ. Chapter 46 - Disorders of globin synthesis:
the thalassemias. In Lichtman
MA, Kipps TJ, Kaushansky K,
Beutler E, et al, eds. Williams
Hematology,7th
ed.
July 22, 2008