Clinical Practice Guideline

for

Sickle Cell Disease/Trait

Developed for the

Aerospace Medical Association

by their constituent organization

American Society of Aerospace Medicine Specialists

 

Overview: Hemoglobin S results from the substitution of a valine for glutamic acid as the sixth amino acid of the beta globin chain, which produces a hemoglobin tetramer (alpha2/beta S2) that is poorly soluble when deoxygenated.3 The polymerization of deoxy hemoglobin (Hb) S is essential to vasoocclusive phenomena.3 However, polymerization alone does not account for the pathophysiology of sickle cell disease.  Changes in red cell membrane structure and function, disordered cell volume control and increased adherence to vascular endothelium also play an important role.3  Common varieties of sickle cell disease are inherited as homozygosity for beta S globin chain, called sickle cell anemia (Hb SS) or as compound heterozygosity of the beta S globin chain with another mutant beta globin:  sickle cell – beta 0 thalassemia (Hb S-β° thal), sickle cell-Hb C disease (Hb SC disease) and sickle cell – beta + thalassemia (Hb S-β+ thal).2  Disease manifestations are most severe in patients with sickle cell anemia, Hb SS.

 

Sickle cell anemia and Hb S-β° thal are characterized by a severe hemolytic anemia with intermittent painful vasoocclusive crises.  Other typical acute complications of sickle cell anemia include focal infarction of the spleen, kidneys, lungs, bone, retina, or brain, sudden extensive sequestration of blood in the spleen or liver, or overwhelming infection with encapsulated bacteria.  Hb S-β+ thal and Hb SC are characterized by rare crises and aseptic necrosis.  Sickling is said to occur when the PO2 falls below 60 mmHg, similar to the PO2 at standard cabin altitudes.6  Thus, sickle cell disease is clearly incompatible with a career in aviation. 

 

Sickle cell trait (SCT) (Hb AS) is a benign condition where 20-45% of hemoglobin is Hb S.  Normally human blood consists of 96-98% Hb A, 2-3% Hb A2, and <1% Hb F.  SCT is not associated with anemia, change in red blood cell survival, or life expectancy alteration.  Cases of red cell sickling in patients with SCT have been reported at altitudes as low as 9,000 feet; however, the majority of patients with SCT are unlikely to sickle below 21,000 feet.7 Though persons with SCT are generally regarded as clinically normal there has been rare association of sickle cell trait with acute medical issues.  The conditions include splenic infarction at high altitude with exercise or hypoxemia, hematuria secondary to renal papillary necrosis, fatal exertional heat illness with exercise, sudden idiopathic death with exercise, glaucoma or recurrent hyphema following a first episode of hyphema, hyposthenuria (an inability to fully concentrate urine), bacteriuria in women, bacteriuria or pyelonephritis associated with pregnancy, renal medullary carcinoma in young people (ages 11 to 39 years), early onset of end stage renal disease from autosomal dominant polycystic kidney disease, and priapism.5

 

Sickle cell disease/trait occurs often in sub-Saharan African populations and sporadically in those of Mediterranean, Middle Eastern or Indian descent.  Between 7 and 9% of African Americans have sickle cell trait (SCT).  It should be noted that the genetic defect that produces sickle cell occurs in Caucasians and that, in Europe, carriers are physically indistinguishable from the general population.  Due to this, screening in the military is not limited to black recruits.

 

Until 1982, the US military restricted individuals with sickle cell trait from entering flight training, aircrew duties, and even attendance to the US Air Force Academy due to the rare occurrences of sickle crises in stressed individuals with sickle cell trait.  In 1985, the Secretary of Defense ordered that “all military occupational restrictions on sickle cell trait be removed.”  Currently, each individual is tested for sickle cell disease/trait prior to accession to the US Armed Services.  A recruit will be allowed into the US Air Force with an Hb S level of up to 45%.  

 

The blood of sickle cell trait carriers is tested by hemoglobin electrophoresis for percentage of Hb S and to evaluate for other co-existing hemoglobinopathies.  The following table summaries electrophoretic patterns in common hemoglobinopathies.4

 

Condition

Hb A

Hb S

Hb C

Hb F

Hb A2

Normal

95-98*

0

0

<1

<3.5

Sickle cell trait

(HbAS)

50-60

35-45†

0

1-3

<3.5

Sickle-beta + thal

(Hb S-β+ thal)

5-30

65-90

0

2-10

>3.5

Sickle-beta 0 thal

(Hb S-β° thal)

0

80-92

0

2-15

>3.5

Sickle-Hb C disease

(Hb SC)

0

45-50

45-80

1-8

<3.5

Homozygous sickle cell disease (Hb SS)

0

85-90

0

2-15

<3.5

* Numbers indicate the percent of total hemoglobin for an untransfused adult patient.  Ranges are approximate and may vary depending upon the particular laboratory and method of determination.

† Percent Hb S can be as low as 21 percent in patients with sickle cell trait in conjunction with alpha thalassemia.

 

Aeromedical Concerns: Individuals with sickle cell disease have a severe risk of splenic infarct and other vasoocclusive episodes involving the abdomen, lungs or nervous system when exposed to hypoxia, infection, dehydration or exposure to cold.  Sickle cell trait except for rare occasions is not associated with increased aeromedical risk.

 

Medical Workup: The initial laboratory test to screen for sickle cell disease/trait is a Sickledex™; if positive then hemoglobin electrophoresis is required.  Hb AS, with Hb S up to 45 % is acceptable for flying duties.

 

 The aeromedical evaluation should include the following:

A.  A thorough history for any symptomatic vasoocclusive episodes, negatives included

B.  Complete blood count

C.  Hemoglobin electrophoresis

D.  Hematology consult

 

Aeromedical Disposition (military):

 

Condition

Waiver Required

Waiver Potential

Waiver Authority

Asymptomatic sickle cell trait (Hb S ≤45%)

No

N/A*

Symptomatic sickle cell trait

Yes

No

AFMOA/MAJCOM†

Hb SS, Hb SC, Hb S +thal, Hb S 0thal

Yes

No

AFMOA/MAJCOM†

* Test results must be sent (PEPP) to certification authority annotated on initial flying class (I, II, III) physical

† FC I/IA – AETC; FC II – AFMOA; FC III - MAJCOM

 

Aeromedical Disposition (civilian):  Sickle cell disease is not one of the specifically disqualifying conditions.  Airmen with sickle cell disease are eligible for all classes of FAA certificates.  These are handled under the category of special issuance.  Applicants are required to document the severity, stability, and any sequelae of their disease to the FAA for evaluation.  If deemed acceptable they will receive a special issuance.  Sickle cell trait is not tested for and is not disqualifying for any class of FAA certificate.

 

Waiver Experience (military): A large military waiver database through January 2007 revealed 32 waiver submissions for the diagnosis of SCT for FC I/IA (4), FC II (7) and FC III (21).  Waivers were granted in 29 of the 32 cases.  Hemoglobin S levels of up to 44% as documented in the database have been waivered as long as there is no history of anemia or other sequelae.  Of the three disqualified cases, one was a combination sickle cell trait/α-thalassemia with anemia; the other two had other disqualifying medical conditions (hepatitis C and H-3 hearing with hearing aids).  No aviators were disqualified for a sole diagnosis of sickle cell trait.

 

Waiver Experience (civilian):  The FAA has had very few applicants with sickle cell disease, and therefore waiver experience is limited, but would be considered as described above.

 

References:

 

1.  Benz EJ.  Chap 91:  Hemoglobinopathies.  In:  Harrison’s Principles of Internal Medicine.  16th ed.  Eds:  Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL.  McGraw-Hill Companies, Inc.; 2005.

 

2.  Embury SH.  Chapter 171: Sickle cell anemia and associated hemoglobinopathies.  In Cecil’s Textbook of Medicine.  EdsGoldman L, Ausielllo D.  Saunders, Philiadelphia.  2004.

 

3.  Embury SH, Vichinsky EP.  Variant sickle cell syndromes.  UpToDate.  Online version 15.1.  November 22, 2006.

 

4.  Embury SH, Vichinsky EP, Mahoney Jr DH.  Diagnosis of sickle cell syndromes.  UpToDate.  Online version 14.3.  September 12, 2005.

 

5.  Long ID.  Sickle cell trait and aviation.  Aviat Space Environ Med.  1982 Oct; 53(10):  1021-9.

 

6.  McKenzie JM.  Evaluation of the hazards of sickle trait in aviation.  Aviat Space Environ Med.  1977 Aug; 48(8):  753-62.

 

7.  Rayman RB. Sickle cell trait and the aviator.  Aviat Space Environ Med.  1979 Nov; 50(11):  1170-2.

 

8.  Rayman RB, Hastings JD, Kruyer, WB, Levy RA, Pickard JS.  Hemoglobinopathies.  In Clinical Aviation Medicine, 4th ed.  Professional Publishing Group, LTD; New York.  2006

 

9.  Saunthararajah Y, Vichinsky EP, Embury SH.  Chapter 37: Sickle cell disease.  In Hematology: Basic Principles and Practice, 4th ed.  Eds:  Hoffman R, Benz EJ, et al.  Elsevier, Philadelphia.  2005.

 

10.  Voge VM, Rosado NE, Contiguglia JJ.  Sickle cell anemia trait in the military aircrew population: a report from the Military Aviation Safety Subcommittee of the Aviation Safety Committee, AsMA.  Aviat Space Environ Med.  1991 Nov; 62(11):  1099-102.

 

 

2/15/08