Introduction
Sickle cell trait (SCT) is an inherited genetic condition characterized by the presence of one normal hemoglobin gene (A) and one sickle hemoglobin gene (S), resulting in the genotype AS. This is distinct from sickle cell disease (SCD), where individuals inherit two abnormal sickle genes (SS). While SCD is associated with significant morbidity and reduced lifespan due to chronic anemia and organ damage, SCT is generally considered a benign condition. Individuals with SCT typically do not experience the vaso-occlusive crises characteristic of SCD and often maintain a quality of life comparable to the general population.
However, despite its generally benign nature, sickle cell trait is not entirely without clinical implications. Under specific conditions, individuals with SCT can experience symptoms and complications. Recognizing the nuances of Sickle Cell Trait Diagnosis and management is crucial for healthcare professionals.
Since the inception of the Sickle Cell Anemia Act in 1972, screening for sickle cell trait and disease has become increasingly prevalent. Universal newborn screening programs are now standard practice across the United States. This continuing education activity aims to enhance healthcare professionals’ understanding of sickle cell trait, focusing on timely diagnosis, effective management strategies, and collaborative care approaches to optimize patient outcomes and minimize potential complications.
Objectives:
- Define the distinguishing characteristics of sickle cell trait and differentiate it from other hemoglobinopathies.
- Describe effective screening methods for sickle cell trait, considering family history and genetic predispositions.
- Clearly distinguish between sickle cell trait and sickle cell disease to ensure accurate diagnosis and appropriate patient counseling.
- Emphasize the importance of interprofessional collaboration in managing individuals with sickle cell trait to prevent complications and enhance their quality of life.
Etiology of Sickle Cell Trait
Sickle cell trait arises from a genetic mutation in the beta-globin chain, leading to the production of abnormal hemoglobin known as sickle hemoglobin (Hb S). This mutation involves a single point mutation where adenine (A) is replaced by thymine (T) at codon 6 of the beta-globin gene. This substitution results in the amino acid valine replacing glutamic acid in the hemoglobin protein. This alteration in the hemoglobin structure causes red blood cells to sickle, or take on a crescent shape, when exposed to low oxygen levels.
Individuals with sickle cell trait are heterozygous, inheriting the HbS gene from one parent and a normal hemoglobin gene (HbA) from the other. This genetic makeup distinguishes SCT from sickle cell disease, where individuals are homozygous for the HbS gene.
Epidemiology of Sickle Cell Trait
Sickle cell trait exhibits a higher prevalence in populations with African ancestry and those originating from tropical and subtropical regions where malaria is endemic. In the United States, approximately 9% of African Americans have sickle cell trait, compared to 0.2% of Caucasians. Globally, it is estimated that 300 million people live with sickle cell trait, with a significant proportion residing in sub-Saharan Africa. Regions with high malaria prevalence often show higher rates of SCT, with studies reporting rates as high as 25% in certain parts of Africa and 60% in Saudi Arabia.
Alt text: Graph showing the prevalence of sickle cell trait in African Americans, highlighting its significant presence within this population.
Migration patterns from high-prevalence regions, such as Africa and the Middle East, are contributing to an increased prevalence of both sickle cell trait and sickle cell disease in Western countries. This demographic shift underscores the importance of understanding and effectively managing sickle cell trait across diverse populations.
Pathophysiology of Sickle Cell Trait
Unlike sickle cell disease, sickle cell trait typically does not cause vaso-occlusive crises. However, under certain physiological stressors, individuals with SCT can experience sickling of red blood cells, mimicking some aspects of sickle cell disease. These conditions include:
- Hypoxia: Low oxygen levels, such as those encountered at high altitudes or during intense physical exertion.
- Dehydration: Reduced fluid volume in the body, leading to increased blood viscosity.
- Increased Sympathetic Outflow: Stress responses that can promote red blood cell sickling.
- Hypothermia and Hyperthermia: Extreme temperature fluctuations.
- Elevated 2,3-DPG Levels: Increased levels of 2,3-diphosphoglycerate, which reduces hemoglobin’s affinity for oxygen.
- Released Inflammatory Cells: Inflammatory processes that can contribute to red blood cell adhesion and sickling.
When oxygen levels decrease, red blood cells in individuals with SCT can transform from their normal biconcave disc shape to a sickle shape. These sickled cells can adhere to blood vessel walls, leading to blockages in small blood vessels within muscles, kidneys, and other organs. This vascular obstruction can result in tissue ischemia and damage. Furthermore, inflammatory cells and platelets can interact with sickled red blood cells, exacerbating adhesion and contributing to vaso-occlusion. This process can affect various organs, potentially leading to complications. Repeated episodes of sickling and ischemia can lead to cumulative organ damage over time.
Histopathology of Sickle Cell Trait
Under normal, resting conditions, red blood cells from individuals with sickle cell trait appear normal and disc-shaped when examined microscopically. However, when these cells are subjected to oxidative stress or low oxygen conditions, they can transform into drepanocytes, or sickle-shaped cells. In cases of significant sickling, an increased reticulocyte count, indicating the bone marrow’s response to red blood cell destruction, may also be observed.
History and Physical Examination for Sickle Cell Trait Diagnosis
A comprehensive medical history and physical examination are crucial in evaluating individuals for sickle cell trait, especially in symptomatic cases. Family history is important, as a positive family history of sickle cell disease (HbSS) may increase suspicion for SCT in the patient.
While patients with sickle cell disease often present with broad clinical manifestations such as generalized pain and fatigue due to vaso-occlusive crises, hemolysis, and infections, individuals with sickle cell trait are typically asymptomatic. Most SCT patients remain asymptomatic with HbS levels below 35%. Their clinical presentation often mirrors that of individuals with normal hemoglobin genotypes.
When symptoms do occur in SCT patients, they may include:
- Hematuria: Blood in the urine, often painless.
- Exertional Rhabdomyolysis: Muscle breakdown during strenuous exercise, leading to muscle pain and weakness.
Factors like hot climates, dehydration, and high altitude environments can exacerbate these symptoms. It is important to note that symptoms of sickling can overlap with other conditions like heat stroke or cardiac arrhythmia. Therefore, a thorough clinical assessment, including detailed history and physical examination, is essential for accurate diagnosis.
Pain associated with SCT is often described as cramping, weakness, and a dull ache that develops within minutes of physical activity due to reduced blood flow to muscles. This contrasts with heat stroke, where pain presentation differs. Athletes with SCT exhibiting these symptoms should be treated as having a sickling exacerbation until other diagnoses are ruled out. Additional symptoms of sickling can include upper left quadrant abdominal or chest pain, chest tightness, and shortness of breath. Loss of consciousness or confusion is not typical in SCT-related events.
Physical examination findings in SCT patients may reveal:
- Muscle Weakness: Particularly in larger muscle groups (calves, quadriceps, hamstrings, glutes), although these muscles may appear normal in bulk compared to heat-exertion cramps.
- Dehydration: A common finding, especially in cases of exertional symptoms or sudden death associated with SCT.
The physical exam may also reveal findings consistent with comorbid conditions more prevalent in SCT patients, such as pulmonary embolism, deep venous thrombosis, or chronic kidney disease.
Evaluation and Sickle Cell Trait Diagnosis
Universal newborn screening programs in the United States include testing for sickle cell trait. Pregnant women in the US are also routinely offered genetic testing to identify fetuses with sickle cell disease.
The primary screening test for sickle cell trait is the sickling test. This simple test involves placing a drop of blood on a slide and preparing it for microscopic examination. If sickling is observed, hemoglobin electrophoresis is performed to confirm the diagnosis and quantify the different types of hemoglobin present.
Alt text: Illustration of hemoglobin electrophoresis, a key diagnostic tool for identifying hemoglobin variants in sickle cell trait diagnosis.
Hemoglobin electrophoresis separates and measures the percentages of different hemoglobin types in a blood sample. In individuals with sickle cell trait, electrophoresis typically reveals a mixture of normal hemoglobin A and hemoglobin S.
In addition to diagnostic testing for SCT itself, clinicians should also consider evaluations for associated comorbid conditions, such as chronic kidney disease, especially given the increased incidence in SCT patients. For individuals with SCT and signs of kidney disease, annual renal function testing, including creatinine, urinalysis, and blood pressure measurements, is recommended. Due to the increased risk of renal medullary carcinoma in SCT patients, renal and urinary tract ultrasound imaging and CT scans with contrast should be considered if hematuria is present.
Treatment and Management of Sickle Cell Trait
Management Approach
Asymptomatic individuals with sickle cell trait do not require specific treatment. Management focuses on:
- Reversing Conditions Causing Sickling: Addressing factors that can trigger sickling episodes, such as dehydration and hypoxia.
- Managing Comorbid Conditions: Treating any medical conditions associated with SCT, such as chronic kidney disease or renal complications.
- Recognizing and Managing Complications: Promptly addressing complications associated with SCT, including papillary necrosis, microvascular disease, and deep vein thrombosis, as they arise.
Preventative Management
Preventative strategies are crucial for individuals with sickle cell trait, particularly those at higher risk of complications:
- Acclimation Programs: Recommended for athletes with SCT participating in activities at moderate or high altitudes.
- Hydration Maintenance: Emphasizing adequate fluid intake to prevent dehydration, especially during physical exertion and in hot climates.
- Avoidance of Hypoxia and Hyperthermia: Taking precautions to avoid situations that can lead to low oxygen levels or extreme body temperatures.
- Yearly Clinical Assessment: Recommended for children with SCT, including monitoring iron, folic acid, and vitamin D levels.
Management in Pregnant Women with Sickle Cell Trait
Specific guidelines apply to pregnant women with SCT:
- Routine Urine Cultures: Recommended every trimester to screen for asymptomatic cystitis due to increased risk of pyelonephritis.
- Aggressive Pyelonephritis Treatment: Prompt and aggressive treatment is crucial if pyelonephritis is suspected.
- Folic Acid and Iron Supplementation: Recommended throughout pregnancy and breastfeeding to address potential anemia.
- Hemoglobinopathy Testing: Some experts recommend hemoglobinopathy testing for women planning pregnancy or pregnant women with anemia, microcytosis, family history of hemoglobinopathy, or from regions endemic for sickle cell disease and thalassemia.
Differential Diagnosis
The differential diagnosis for sickle cell trait includes other hemoglobinopathies and conditions with similar symptoms:
- Sickle Cell Disease (HbSS, HbSC, HbS beta-thalassemia): These conditions involve more severe clinical presentations and vaso-occlusive crises.
- Beta-thalassemia Major: A severe form of thalassemia characterized by severe anemia.
- Beta-thalassemia Minor: A milder form of thalassemia, which, like SCT, is a hemoglobinopathy trait.
Distinguishing SCT from these conditions relies on hemoglobin electrophoresis and clinical evaluation.
Prognosis of Sickle Cell Trait
Despite the association of sickle cell trait with certain complications, the overall prognosis for individuals with SCT is excellent. Studies have shown that life expectancy for people with sickle cell trait is comparable to that of the general population. While sickle cell disease is associated with increased in-hospital mortality, sickle cell trait generally does not carry this increased risk.
Complications Associated with Sickle Cell Trait
Although generally benign, sickle cell trait is associated with a predisposition to certain medical and clinical complications. These include:
- Papillary Necrosis: Damage to the renal papillae, often leading to hematuria.
- Splenic Infarction: Blockage of blood flow to the spleen, potentially causing pain and requiring intervention.
- Renal Medullary Carcinoma: A rare but aggressive kidney cancer more common in individuals with SCT.
- Chronic Kidney Disease: Increased risk of developing chronic kidney disease and albuminuria.
- Sudden Death Due to Exertion: Although rare, a higher risk of exertional sudden death, particularly in athletes and military personnel under intense physical stress.
- Exertional Rhabdomyolysis: Muscle breakdown during exercise, leading to myoglobinuria and potential kidney damage.
- Increased COVID-19 Mortality: Studies suggest a possible association with increased mortality in COVID-19 infection.
Papillary Necrosis
Papillary necrosis, a recognized complication of SCT, is linked to the sickling of red blood cells in the small capillaries of the kidney’s vasa recta. This sickling can lead to microthrombi formation and infarction. Patients typically present with gross hematuria and abdominal pain. Management is generally conservative, involving IV fluids, bed rest, and pain control. The prognosis is usually favorable as often only a single papilla is affected.
Splenic Infarction
Splenic infarction in SCT occurs due to similar pathophysiological mechanisms as other complications, often triggered by low oxygen environments, dehydration, increased acidity, and blood viscosity. Splenic infarction can occur even at low altitudes, and the risk increases with higher altitudes. Elevated bilirubin or LDH levels may indicate significant splenic complications. Splenectomy is infrequently required.
Renal Medullary Carcinoma
Renal medullary carcinoma is a rare but serious complication associated with sickle cell trait. It is often diagnosed at an advanced stage with metastasis. Patients may present with abdominal pain.
Chronic Kidney Disease
Sickle cell trait is linked to an increased risk of chronic kidney disease, particularly in African American males. Studies indicate a correlation between SCT and a decline in glomerular filtration rate (GFR) and the development of albuminuria. Chronic reversible sickling in the renal medulla, induced by hypoxia, contributes to ischemia, microinfarction, and subsequent hyperfiltration, sclerosis, and proteinuria.
Sudden Death
Sudden death associated with exertion is a concern, particularly in athletes and military recruits with SCT. Studies have shown a significantly higher risk of exertional death in athletes with SCT. This risk has led to mandatory sickle cell screening programs for athletes to identify at-risk individuals and implement preventative measures.
Exertional Rhabdomyolysis
Exertional rhabdomyolysis, the breakdown of skeletal muscle cells during physical exertion, is more common in individuals with sickle cell trait. This condition can lead to myoglobinuria and potential renal complications.
COVID-19
Emerging research suggests a potential link between sickle cell trait and adverse COVID-19 outcomes, including increased mortality.
Deterrence and Patient Education
Approximately 9% of African Americans have sickle cell trait, but only a small percentage are aware of their status. Lack of awareness and language barriers can hinder knowledge of SCT status. Patient education is crucial to improve understanding of sickle cell trait and its implications. Studies have demonstrated that targeted education significantly improves caregivers’ knowledge about SCT. Healthcare professionals should provide comprehensive education and genetic counseling to individuals with SCT and their families.
Enhancing Healthcare Team Outcomes
Given the significant number of individuals with sickle cell trait globally, increased attention and proactive management strategies are warranted. While SCT is often considered benign, it is not entirely without risks. Individuals with SCT can experience hemoglobin sickling and organ damage under specific conditions. They can also pass on sickle cell genes to their offspring.
Genetic counseling plays a vital role in reducing the transmission of sickle cell traits and diseases. Offering genetic counseling to adolescents at risk, particularly in endemic regions, empowers them to make informed decisions about family planning. Premarital screening programs have proven effective in reducing the likelihood of individuals with sickle cell trait partnering with another carrier.
Healthcare professionals should prioritize educating high-risk populations about sickle cell trait and encourage screening, especially during adolescence, if status is unknown. By promoting awareness and screening, healthcare teams can contribute to reducing the prevalence of sickle cell traits and diseases in future generations.
Review Questions
(Note: Review questions are present in the original article for continuing education purposes, but are not included here as per instructions.)
References
(Note: References are directly copied from the original article to maintain accuracy and are crucial for EEAT.)
1.Mitchell BL. Sickle Cell Trait and Sudden Death. Sports Med Open. 2018 May 23;4(1):19. [PMC free article: PMC5966366] [PubMed: 29796715]
2.Naik RP, Haywood C. Sickle cell trait diagnosis: clinical and social implications. Hematology Am Soc Hematol Educ Program. 2015;2015(1):160-7. [PMC free article: PMC4697437] [PubMed: 26637716]
3.Thoreson CK, O’Connor MY, Ricks M, Chung ST, Sumner AE. Sickle Cell Trait from a Metabolic, Renal, and Vascular Perspective: Linking History, Knowledge, and Health. J Racial Ethn Health Disparities. 2015 Sep;2(3):330-5. [PMC free article: PMC4548979] [PubMed: 26322267]
4.Gibson JS, Rees DC. How benign is sickle cell trait? EBioMedicine. 2016 Sep;11:21-22. [PMC free article: PMC5049987] [PubMed: 27580691]
5.El Ariss AB, Younes M, Matar J, Berjaoui Z. Prevalence of Sickle Cell Trait in the Southern Suburb of Beirut, Lebanon. Mediterr J Hematol Infect Dis. 2016;8(1):e2016015. [PMC free article: PMC4771139] [PubMed: 26977274]
6.Rogers ZR. A Pediatrician’s Quick Guide to Sickle Cell Trait. Pediatr Rev. 2023 Apr 01;44(4):240-242. [PubMed: 37002355]
7.Vargas-Hernández DA, Uscategui-Ruiz AC, Prada-Rueda AJ, Romero-Sánchez C. Sickle Cell Trait, Clinical Manifestations and Outcomes: A Cross-Sectional Study in Colombia: Increasing Rate of Symptomatic Subjects Living in High Altitude. Mediterr J Hematol Infect Dis. 2023;15(1):e2023015. [PMC free article: PMC10000961] [PubMed: 36908870]
8.Nelson DA, Deuster PA, Carter R, Hill OT, Wolcott VL, Kurina LM. Sickle Cell Trait, Rhabdomyolysis, and Mortality among U.S. Army Soldiers. N Engl J Med. 2016 Aug 04;375(5):435-42. [PMC free article: PMC5026312] [PubMed: 27518662]
9.Ebert EP, Escobar JD, Costello AA, Webber BJ. Association of Sickle Cell Trait on Career and Operational Outcomes in the United States Air Force. Mil Med. 2023 Jan 04;188(1-2):e214-e219. [PubMed: 34117774]
10.Naik RP, Smith-Whitley K, Hassell KL, Umeh NI, de Montalembert M, Sahota P, Haywood C, Jenkins J, Lloyd-Puryear MA, Joiner CH, Bonham VL, Kato GJ. Clinical Outcomes Associated With Sickle Cell Trait: A Systematic Review. Ann Intern Med. 2018 Nov 06;169(9):619-627. [PMC free article: PMC6487193] [PubMed: 30383109]
11.Hajjaj OI, Cserti-Gazdewich C, Dumevska L, Hanna M, Lau W, Lieberman L., Canadian Obstetrical Pediatric Transfusion Network. Reconsidering sickle cell trait testing of red blood cell units allocated to children with sickle cell disease. Transfusion. 2023 Mar;63(3):507-514. [PubMed: 36519666]
12.Pinto VM, De Franceschi L, Gianesin B, Gigante A, Graziadei G, Lombardini L, Palazzi G, Quota A, Russo R, Sainati L, Venturelli D, Forni GL, Origa R. Management of the Sickle Cell Trait: An Opinion by Expert Panel Members. J Clin Med. 2023 May 12;12(10) [PMC free article: PMC10219090] [PubMed: 37240547]
13.Tsaras G, Owusu-Ansah A, Boateng FO, Amoateng-Adjepong Y. Complications associated with sickle cell trait: a brief narrative review. Am J Med. 2009 Jun;122(6):507-12. [PubMed: 19393983]
14.Mohamed Jiffry MZ, Hassan R, Davis A, Scharf S, Walgamage T, Ahmed-Khan MA, Dandwani M. Sickle Cell Anemia Associated With Increased In-Hospital Mortality in Post-Cardiac Arrest Patients. Cureus. 2023 Apr;15(4):e37987. [PMC free article: PMC10202522] [PubMed: 37223169]
15.Li EJ, Carroll VG. Sickle cell trait and renal papillary necrosis. Clin Pediatr (Phila). 2014 Sep;53(10):1013-5. [PubMed: 24807983]
16.Yanamandra U, Das R, Malhotra P, Varma S. A Case of Autosplenectomy in Sickle Cell Trait Following an Exposure to High Altitude. Wilderness Environ Med. 2018 Mar;29(1):85-89. [PubMed: 29331296]
17.Goenaga-Vázquez Y, Colón G, Barrios N, Correa M. Renal medullary carcinoma: a nearly fatal malignancy specifically affecting patients with a so-called benign condition. CEN Case Rep. 2018 May;7(1):121-126. [PMC free article: PMC5886939] [PubMed: 29396817]
18.Naik RP, Derebail VK, Grams ME, Franceschini N, Auer PL, Peloso GM, Young BA, Lettre G, Peralta CA, Katz R, Hyacinth HI, Quarells RC, Grove ML, Bick AG, Fontanillas P, Rich SS, Smith JD, Boerwinkle E, Rosamond WD, Ito K, Lanzkron S, Coresh J, Correa A, Sarto GE, Key NS, Jacobs DR, Kathiresan S, Bibbins-Domingo K, Kshirsagar AV, Wilson JG, Reiner AP. Association of sickle cell trait with chronic kidney disease and albuminuria in African Americans. JAMA. 2014 Nov 26;312(20):2115-25. [PMC free article: PMC4356116] [PubMed: 25393378]
19.Harmon KG, Drezner JA, Klossner D, Asif IM. Sickle cell trait associated with a RR of death of 37 times in National Collegiate Athletic Association football athletes: a database with 2 million athlete-years as the denominator. Br J Sports Med. 2012 Apr;46(5):325-30. [PubMed: 22442191]
20.Tarini BA, Brooks MA, Bundy DG. A policy impact analysis of the mandatory NCAA sickle cell trait screening program. Health Serv Res. 2012 Feb;47(1 Pt 2):446-61. [PMC free article: PMC3288389] [PubMed: 22150647]
21.Slomski A. Sickle Cell Trait Associated With Kidney Failure and COVID-19 Death. JAMA. 2022 Aug 02;328(5):415. [PubMed: 35916859]
22.Christian J, Lanzkron S, Naik RP. COVID-19 outcomes in sickle cell disease and sickle cell trait. Best Pract Res Clin Haematol. 2022 Sep;35(3):101382. [PMC free article: PMC9450487] [PubMed: 36494153]
23.Creary S, Adan I, Stanek J, O’Brien SH, Chisolm DJ, Jeffries T, Zajo K, Varga E. Sickle cell trait knowledge and health literacy in caregivers who receive in-person sickle cell trait education. Mol Genet Genomic Med. 2017 Nov;5(6):692-699. [PMC free article: PMC5702560] [PubMed: 29178654]
24.Beeman CM, Abrams MA, Zajo K, Stanek J, Martinez-Mendez A, Creary SE. Closing knowledge gaps among parents of children with sickle cell trait. Pediatr Blood Cancer. 2023 Jul;70(7):e30384. [PubMed: 37102416]
25.Gilpin-Macfoy F, Perilla MJ, Koehly LM. Variability in sickle cell knowledge by sickle cell status. J Genet Couns. 2023 Aug;32(4):916-925. [PubMed: 36994658]
26.Memish ZA, Saeedi MY. Six-year outcome of the national premarital screening and genetic counseling program for sickle cell disease and β-thalassemia in Saudi Arabia. Ann Saudi Med. 2011 May-Jun;31(3):229-35. [PMC free article: PMC3119961] [PubMed: 21623050]
Disclosures:
(Note: Disclosures are directly copied from the original article.)
Disclosure: Damilola Ashorobi declares no relevant financial relationships with ineligible companies.
Disclosure: Adam Ramsey declares no relevant financial relationships with ineligible companies.
Disclosure: Robert Killeen declares no relevant financial relationships with ineligible companies.
Disclosure: Ruchi Bhatt declares no relevant financial relationships with ineligible companies.
