Clinical Practice Guideline

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 Southeast Asia and 0.8% in American blacks.1

 

The α-like globin genes (α) 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 (%)

HbH4) (%)

Hb Level (g/dL)

MCV

Normal

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

(%)

Normal

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, Fauci AS, Longo DL, et al, eds.  Harrison's Principles of Internal Medicine, 16th ed.  The McGraw-Hill Companies, Inc; 2005.

 

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. Philadelphia: Lippincott Williams & Wilkins; 2002; 448.

 

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.  New York:  Lange Medical Books/McGraw-Hill, Medical Publishing Division; 2008.

 

5.  Muncie HL.  Thalassemia.  In Domino FJ, ed.  The 5-Minute Clinical Consult, 16th E.  Philadelphia:  Lippincott Williams &Wilkins; 2008.

 

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.  United States Army.  Aeromedical Policy Letters, Anemias/Congenital (including sickle cell trait and Thalassemia trait), revised Mar. 2006

 

10.  United States Federal Aviation Administration. Guide for Aviation Medical Examiners.  Washington, DC, US Dept. of Transportation,  Federal Aviation Administration, update April 1, 2008.

 

11.  United States Navy.  Aeromedical Reference and Waiver Guide. Thalassemia, update March 2007

 

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.  New York:  The McGraw-Hill Companies, Inc.; 2006.

 

 

July 22, 2008