Sickle cell disease was first described by James B Herrick in 1910. It was almost 4 decades later that Linus Pauling and his colleagues concluded that sickle cell disease was caused by a genetic disorder. It is one of the well known molecular disorders. It is called molecular because it is caused by a single protein mutation. Sickle cell causes lifetime debilitation from chronic anemia, organ damage leading to poor quality of life, and early mortality. It is a major public health issue. Since the Sickle Cell Anemia Act established in 1972, there has been more screening for sickle cell trait and disease. For instance, each state in the United States now offers newborn screening prior to discharge from the hospital.
There are different forms of sickle cell disease. They include Hb SS, Hb SC, Hb S beta thalassemia etc. All of these hemoglobin types cause a vaso-occlusive crisis. HbSS is the most common and severe type. HB SC occurs because patients inherit Hb S from one parent and Hb C from the other. Hb C is caused by a switch from glutamic acid to lysine. Hb S beta thalassemia is very rare. It occurs when an individual inherits beta thalassemia hemoglobin from one parent and HbS from the other parent. Vaso-occlusive crisis does not occur just because of sickling hemoglobin. It occurs because of multiple events, including deformed red blood cells, increased red blood cell fragility, and increased cation permeability and stickiness.
Sickle cell trait is benign because patients do not get vaso-occlusive crisis; they have a better quality of life and mortality is the same as the rest of the general population. Due to the benign nature of sickle cell trait, it generally does not have any clinical implications. However, there have been reports of adverse conditions that occur due to patient's trait status. Therefore, sickle cell trait may not be completely benign and these patients should be managed aggressively whenever they develop some of these complications. This article discusses sickle cell trait etiology, epidemiology, histopathology, complications, and why more attention should be given to this condition.
Sickle cell trait is caused by abnormal hemoglobin called sickle hemoglobin or Hb S. Sickle hemoglobin is as a result of a point mutation in the beta globin chain. This point mutation replaces A with T at codon 6 of beta hemoglobin chain. This causes the switch from glutamic acid to valine amino acid. The valine-type hemoglobin causes red cells to sickle when exposed to a low oxygen threshold. Patient with sickle cell trait inherits HbS from one parent and HbA from the other parent making them heterozygous.
Sickle cell trait is more prevalent in people who are of African-descent and also whose ancestors come from tropical and sub-tropical regions where malaria is endemic.The prevalence rates of sickle cell trait in the United States is 9% among African American which is about 3 million people, and 0.2% among Caucasians. Worldwide, it is estimated that there are 300 million people with sickle cell trait and one-third of this number are in sub-Saharan Africa.The prevalence of sickle cell trait is higher in areas where malaria is endemic. Gibson and colleague mentions that the prevalence is as high as 25% in some part of Africa and 60% in Saudi Arabia. Because of the high migration of people from areas of high prevalence like Africa, Middle East, the prevalence of both sickle cell trait and disease will increase in the western part of the world.
Sickle cell trait does not cause a vaso-occlusive crisis, unlike that of sickle cell disease. However, patients with sickle cell trait could have the same presentation as sickle cell anemia if they are exposed to conditions that favor sickling. Conditions include severe hypoxia, dehydration, increase in sympathetic outflow, hypothermia/hyperthermia, high 2,3-DPG levels and release of inflammatory cells. The HbS will result in the clogging of tiny capillary vessels most especially in the bones by sickled red blood cells. Apart from the sickling of the cells, other cells interact to cause more adhesion of the red blood cells including inflammatory cells, and platelets. This could occur in multiple organs in the body including the chest, heart, lungs, abdomen, kidneys, and extremities. Due to the repeated attacks, organ damage may happen due to constant ischemia.
In those with sickle cell trait, red blood cells,at rest, are normal appearing when viewed under the microscope. However, when these cells are under oxidative stress, the red blood cells appear as drepanocytes also known as sickle cells. There may also be increased reticulocytes counts if severe sicking occurs.
History and Physical
Sickle cell disease patients have broad clinical manifestations due to vaso-occlusive crisis and hemolysis. These patients present with generalized pain. Exacerbation could be due to some form of infection so a patient could also present with an upper-respiratory infection, urinary tract infection, or pneumonia.
Unlike sickle cell disease, sickle cell trait patients do not have crises. They are for the most part asymptomatic. Their presentation is similar to patients with normal hemoglobin.They could have a family history positive for HbSS.
Sickle cell trait patients may have hematuria and rhabdomyolysis.
Unlike other developing and some developed world countries, parents in the United States are offered genetic testing when the female is pregnant. Also, there is a requirement for newborn screening in all 50 states for the sickle cell trait before a baby is discharged from the hospital. To evaluate this disease, the sickling test can be used as a primary screening procedure. A drop of blood is placed on a slide and then prepared to be inspected under the microscope. If sickling is observed, hemoglobin electrophoresis is used to confirm the diagnosis. The hemoglobin electrophoresis gives a percentage of each hemoglobin types that are present in a sample. In sickle cell trait, patients have a mixture of both the normal hemoglobin A and hemoglobin S.
Treatment / Management
Sickle cell trait patients usually do not require any treatment. Treatment is only indicated if a patient present with medical conditions including the ones that have been associated with the trait. It is important for clinicians to recognize the complications associated with sickle cell trait so that prompt management can be started once patients present with symptoms.
For instance, if a sickle cell trait patient presents with hematuria, it is important to rule out papillary necrosis and these patients should get conservative management.
Differential diagnosis of sickle cell trait include different types of sickle cell disease, beta thalassemia major, beta thallasemia minor
Although sickle cell trait has been associated with many complications like papillary necrosis, asymptomatic bacteriuria, splenic infarction, and exercise-induced death, the prognosis of patients with sickle cell trait is promising. Tsaras G and colleagues mentioned in their article that despite the associated complications of sickle cell trait, the average life expectancy of people with sickle cell trait is the same as the general population.
Although sickle cell trait is seen as benign, patients with these traits have a propensity for medical and clinical complications. It is associated with hematuria due to renal papillary necrosis, splenic infarction, renal medullary carcinoma, chronic kidney disease, sudden death due to exertion, and asymptomatic bacteriuria in females.
Papillary necrosis is one of the complications that has been reported in several case studies. In the case study presented by Li EJ and Carroll VG, they mentioned that there are hematologic parameters that allow sickle cell trait patients to have this complication. Sickle cell trait patient with an average HbS level of 34% or higher are more likely to get papillary necrosis compared to those who have HbS of 20%. Necrosis is caused by the presence of sickling hemoglobin in small capillaries or vasa recta of the kidney which could cause microthrombi formation and then infarction. Patients with papillary necrosis usually present with gross hematuria and abdominal pain. The management is conservative including IV fluids, bed rest and pain management. The prognosis is usually very good because only a single papillary is mostly affected and there is enough viable tissue.
The pathogenesis causing splenic infarction is similar to other complications. Like other complications, it occurs when the patient is exposed to low oxygen environment in high altitudes, dehydration, increased acidity, and viscosity. Unlike the other complications, it also occurs even when the patient is at rest at low altitudes. Several case reports of a young sickle cell trait patient presenting with multiple infarctions in the spleen have been reported.
Renal medullary carcinoma is also another complication associated with sickle cell trait. It is usually an aggressive tumor at the time of presentation with possible metastasis on diagnosis. A case report was published by Goenaga-Vasquez Y and his colleagues on a 9-year-old boy who presented with diffuse abdominal pain and was found to have renal medullary carcinoma with metastasis to the cervical, mediastinal and retroperitoneal lymph node.
Sickle cell trait has also been associated with increased chronic kidney disease in African American males. Studies have shown that the presence of SCT was associated with a decline in GFR, and the development of albuminuria compared to those without the trait. According to Niket and his colleagues, GFR decreased at a rate of 0.254 mL/min/1.73 m per year (95% CI, 0.089 to 0.418) in sickle cell trait individuals compared to the noncarriers. The reason for this is because of chronic reversible sickling induced by hypoxia in the renal medullae, leading to constant ischemia and microinfarction of the renal tubules. Ischemia of the renal medulla and tubules causes the release of vasoactive elements. These elements contribute to hyperfiltration leading to sclerosis and proteinuria.
Sudden death due to exertion has been associated with athletes, police, and military recruits. According to Harmon KG and colleagues, there was a 37 times higher risk of exertional death in Division I football players with sickle cell trait in their database study. As a result of this complication found in athletes, a mandatory policy of NCAA sickle cell screening program was proposed. Tarini BA et al estimated that over 2000 athletes can be identified with this screening program. These identified individuals can be prevented from having a sudden death if proper intervention is made.
Studies have also shown that sickle cell is associated with exertional rhabdomyolysis. Rhabdomyolysis is the break down of skeletal muscle cells during physical exertion causing myoglobinuria. There is a 54% higher rate or rhabdomyolysis during physical exertion in the presence of sickle cell trait.  It is said to be the cause of the sudden death of a 19 -year-old college athlete during intense football training. The death of this college freshman led to the screening policy implemented by the NCAA.
Deterrence and Patient Education
About 9% of the African Amerian population have sickle cell trait. Unfortunately, only 16% of individuals of childbearing age with sickle cell trait have knowledge of their status. Most of these individuals were identified as having the trait during newborn screening. However, after that, they are unlikely to be screened for the trait, which reduces their chances of knowing their status. Also, lack of knowledge and language barriers could be reasons deterring individuals from not having knowledge about their status. In a study by Creary S and colleagues, they found that before educating caregivers about sickle cell trait, only 38.1% had knowledge of sickle cell at baseline. However, after educating caregivers about sickle cell trait, 90.3% achieved better knowledge.
Enhancing Healthcare Team Outcomes
An estimated 3 million African Americans have the sickle cell trait in the United States and 300 million worldwide. More attention needs to be paid to individuals with Sickle cell trait and efforts should be made to reduce the percentage of this trait because it does not seem to be completely benign. Individuals with sickle cell trait have been shown to develop sickling of the hemoglobin leading to organ damage when exposed to hypoxia, high altitude, dehydration, excessive exercise etc. They also have the chance of transferring sickle cell trait and disease to their offsprings. Efforts should be made toward reducing this cycle. Genetic counseling has proven to reduce the percentage of trait and disease. Genetic counseling should be offered to adolescents at risk of transferring sickle cell disease to offspring. This will educate them about their status and enable them to make knowledgable choices when choosing a life partner. In the endemic region of the world, efforts should be made to offer genetic counseling to individuals. In a study done by Memish DA and colleague, they found that premarital screening in Saudi Arabia markedly reduced the number of individuals with sickle cell trait marrying another sickle cell trait individual. This is why it is important to implement sickle cell screening, not just of newborns, but also adolescents because they are the ones that will produce the next generation of offspring. If individuals know their sickle cell trait status, there will be less chance of transferring the trait or disease to the next generation. Physicians and other health care professionals should educate the high-risk groups and encourage screening at least one time during adolescence if the individual does not know their sickle cell trait status. By doing this, health care professionals would help to reduce the percentage of sickle cell trait and disease.