Sickle Cell Disease

While many have heard of sickle cell anemia/disease, most do not know how prevalent this disease is in many countries, especially countries of color. Sickle cell diseases are one of the most common genetic disorders in the world. This mutation originated in African and Mediterranean areas because of the high likelihood of malaria. People in those area have approximately 100,000 annual births. Inusa et. al found that 80% of cases of sickle cell disease were from births occurring in Sub-Saharan African countries (2018).

In areas such as the United Kingdom there are only about 300 babies born annually with this disease (Inusa et al. 2018). People who have sickle cell disease (SCD) tend to have a normal outward appearance, and it is not until breaking down to a cellular level that many issues can be detected. SCD comes from the sickling or c-shaped mutation of red blood cells. Molecules of deoxygenated hemoglobin become polymerized, and this causes red blood cells to sickle in sickle cell patients.

Ordinarily, a round blood cell carries oxygen throughout the body (Charache et al. 1995).

When the red blood cells are in this sickle shape, it decreases oxygen levels throughout the body. This disease does have the potential to be life-threatening, especially when left undiagnosed. Those with SCD, specifically children, must manage their care or are at higher risk for morbidity. SCD was a way for the human body to adapt from contracting the malaria parasite. Though it is difficult, there is still a low probability that those with sickle cell can again contract malaria.

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Due to the sickle shape, the virus is unable to attach itself to the red blood cells. Malaria is a parasite that comes from a bite of a female mosquito and infects the body with Plasmodium.

If the parasite can enter the body, it goes into the bloodstream and heads towards the liver where it lays dormant. When it reaches the body, the parasite multiplies over about ten days. Once the Malaria parasite reproduces, the new parasites go into the bloodstream where they infect the red blood cells and attack the body. This is the process that makes SCD useful in certain cases of malaria, because the parasites are unable to attach to these red blood cells. The c shape prevents them from being able to latch onto the red blood cells and because of this, they are unable to live and soon will die.

Being that sickle cell disease is a genetic disorder, it can only be passed down from parent to offspring and not received later on in life. The disease mutation can be found on the hemoglobin-beta gene(HBB) that is located on the 11th chromosome. Normal red blood cells have hemoglobin-A, which creates normal blood cells that are round and smooth. This gives them the ability to easily travel through blood vessels and transport oxygen to the lungs and all parts of the body. What causes the hemoglobin change in a substitution in the 6th amino acid a nucleotide sequence. An A to T transversion in the sixth codon of the human 􏰂-globin gene is the molecular basis for sickle cell disease (Ryan et al. 1997). The mutation converts the glutamic acid codon from GAG to a GTG.

This creates the HbS gene that is shown in people with sickle cell. SCD is a homozygous S-gene recessive autosomal gene in which offsprings inherit a sickle hemoglobin gene (HbS) from both parents. Due to being recessive, a person can carry the sickle cell trait and potentially pass it down to their offspring if their partner is also a carrier or has the trait themselves. This would mean that one parent could have a normal hemoglobin trait (HbA) and one could be (HbS) and have a child who has sickle cell. Those who are carriers can live their entire lives being asymptomatic. However, some who are simply carriers can still have similar shared characteristics as those with the disease. One characteristic that the malaria parasite is unable to attach to those who are sickle cell carriers because the disease is homozygous and those with the trait are heterozygous. Sickle cell carriers or symptomatic patients are less likely to suffer from malaria (Shim et al. 2012). The sickled cells prevent the malaria parasite from being able to latch onto the red blood cells of those with either SCD or sickle cell trait.

Sickling of the red blood cells causes more problems than just not bringing enough oxygen throughout the body. Typical red blood cells are round so they can smoothly travel down blood vessels while bouncing off each other. When they are in the c-shape, they can latch onto each other, causing a block in the blood vessels. This blockage is referred to as a crisis and is extremely painful to those with SCD. It can last from hours to days depending on the severity and how long it takes for the clot to move. During the crisis, there is not much that can be done other than an attempt to manage the pain and put the person at as much ease as possible, typically by using some form of an opioid drug.

Managing the pain during this time can be extremely challenging as some blockages can feel unbearable. During this state, it is very likely that the pain can radiate. It may start in one location of the body, and then stop and move around throughout the body. Also, it can lead to other problems in the body such as heart problems. High doses of ESA and overcorrection of anemia has been shown in studies to be associated with a higher risk of cardiovascular problems (Derebail et al. 2014). Many times doctors must run other exams, monitoring heart ischemia during a sickling crisis to make sure a crisis does not cause other issues (Wagdy et al. 2018).

While being extremely painful, a crisis can lead to other complications. One of the greatest worries is cardiovascular issues caused by ischemia, such as low blood supply causing tissue death. If this happens a crisis can lead to life-threatening heart problems. A majority of children who experienced chest pain or ECG findings suggestive of myocardial infarction had myocardial perfusion, which can leave permanent damage (Wagdy et al. 2018). A crisis is painful and able to cause damage to the body and yet the only valid form of care that can be given during this time is pain management. This is highly concerning and is a big reason for the continued research with SCD(Wagdy et al. 2018).

The way sickle cell disease affects the body is continually undergoing research. With such high involvement in the body, impacting oxygen supply, it has the potential to alter someone’s life. This may include potentially cause decreased sleep ability such as obstructive sleep apnea syndrome (OSAS) to those with SCD. This makes it nearly impossible to know if sleep problems stem from OSAS or if the disease itself is actually what was impacting proper sleep. O’Donnell et al. looked into how having the SS or AS gene may affect sleep patterns. Researchers used Townes knockout-transgenic with sickle cell disease (SS) and sickle trait (AS) sickle cell mice that they made to be HbS homozygous and heterozygous, which they confirmed using Hb gel electrophoresis.

Townes was an exciting study because there is little that is known between the connection with sleep and sickle cell disease. It was hypothesized that because of the impact that it has on the body it must also play a role in something as important as proper sleep. Though this study, researchers placed four EEG electrodes onto the mice skulls to track sleep patterns, the amount of sleep they were getting, and the number of arousals during sleep. To conduct this experiment, they followed three critical elements of rest being awake, non-rapid eye movement (NREM), and rapid eye movement (REM). Doing this allowed them to distinguish between how much sleep each mice group was getting along with the quality of sleep as measured. It shows that SS mice showed significantly fewer arousals for each hour of sleep they received, despite spending less time in NREM sleep than AS mice. This was interesting because it would be most likely assumed that the mice with a sickle cell trait (AS) would have fewer arousals while sleeping because there NREM was deeper than those of sickle cell mice (SS) (O’Donnell et al. 2018).

When SS mice had a harder time falling back asleep after waking from NREM sleep which was assumed to be associated with the mice being in pain and was causing problems for the mice to fall back asleep. A reduction in NREM sleep time disrupted the ability of SS mice to fall back asleep (O’Donnell et al. 2018). The pain was assumed to be causing enough pain that it was causing substantial disruption of getting quality sleep (O’Donnell et al. 2018). A unique discovery was that Townes mice with SS genotype seemed to produce a distinctive phenotype that causes NREM sleep to be reduced which was paradoxical to the consolidation of sleep. It was noted that this might have been possible due to the anemia per se the Townes mice and may have contributed to the sleep phenotype that had been seen.

Overall this study was a great example of the continued unknown effects of SCD. Many of the SS mice were assumed to have pain while sleeping. This caused them trouble falling back asleep once woken from NREM which cannot be seen in AS mice. Though getting lower NREM sleep they still got equal REM sleep compared to the AS Townes mice. It was noted that they had fewer arousals compared to those of AS mice and were still able to sleep reasonably well. In conclusion, it was discovered that decreased NREM sleep with limited arousals when there is no OSAS, signals that there is an unknown sleep phenotype in the Townes mouse models that had SCD (O’Donnell et al. 2018).

Another important area of research study, was looking into potential gene therapies that can be used to help treat SCD. The human Beta A globin gene is what causes the mutation in those with SCD. Since it is nearly impossible to make a direct transgenic mouse model that has the exact features as an actual human SCD. Pawliuk et al. used A-T87Q- globin lentiviral vector in both the SAD and Berkeley SCD transgenic mouse models, to try and replicate the human disorder (2001). This study examined how bone marrow transplant can be effective gene therapy for chronic sickle cell patients. The gene therapy used was an erythroid-specific gathering of anti-sickling proteins that would make up more than half of hemoglobin and almost all of the red blood cells in the body. This helped to show the effects from sickle to anti-sickle cells. A big difference from SAD to BERK is that BERK has a major alteration in the hematological parameters, which is a result of SCD.

To properly propose a gene therapy useful to SCD, the adult red blood cells were forced to express human Beta-globin or hybrids after gene transfer to hematopoietic stem cells (Pawliuk et al. 2001). This was the beginning thought of how to create a sequence that would be able to combat the SCD cells. The locus control region, a long-range cis-regulatory element that enhances expression of linked genes at distal chromatin sites, was seen to have much potential in high globin gene expression, but before being able to use this, stabilization of murine oncoretroviral vectors that encompassed very few core elements of the LCR showed to be extremely difficult (Pawliuk et al. 2001). The goal is with a combination of chromosomal anti-sickling genes; this would be able to correct the main characteristics of SCD. Using this form of gene therapy is still experimental and needs further testing before it can become a viable option for those with SCD. It does, however, give a glimpse into a way the sickle can be ‘cured’ or removed from the body. The implantation of stem cells, cells that have yet to become a specific cell type, has excellent potential to create healthy red blood cells(Pawliuk et al. 2001).

One of the most significant issues when dealing with sickle cell is those who are not knowledgeable about their disease and proper treatment plans. In America alone there is a significantly low number of people who know their diagnosis (Creary et al. 2017). This is a country where medical care and knowledge is relatively high; whereas other countries such as Nigeria, a country where SCD is extremely prevalent, has few resources that can screen for this disorder. Due to this, there has been an increase in disease screening to try and help stress the importance of early diagnosis. Infant screening for hemoglobinopathy has been used frequently in recent decades (Creary et al. 2017). One of the greatest treatment plans that can be offered is first and foremost knowing that someone has the disease. With knowledge, countries such as the US and the UK, who are more economically developed, have designated SCD as a public health issue. The quality of care is improving, and and there has been a significantly lower rate of mortalities in lower patients (Creary et. al 2017). With this, steps can be taken to properly manage the person’s disease (Inusa et al. 2018). Without this knowledge there is little that can be done to help reduce pain or understanding of what is happening to the body.

Being a genetic disease, sickle cell cannot be fully cured due to the need of having to change the cellular level of a person with this disorder. The best form of care comes from proper caregiving. Many patients with this disorder are prescribed opioids when in a crisis as an attempt to help manage their pain. A vast majority of patients reported opioid use. Opioids, medicines that helps to decrease pain, can be extremely beneficial when used by patients during a crisis. Having a crisis is one of the most painful parts of having SCD; it causes the body to feel like it is ripping apart. This leaves patients in agony for hours to days, and for those who are uneducated about their condition they have no idea what is happening to them.

There is nothing that can be done to stop or prevent a crisis from occurring. Since it cannot be avoided the only course of action that one can take for it is trying to use powerful drugs. This is unlikely to stop the pain completely but can attempt to minimize the effects. With numerous other diseases, opioid usage has been linked to addictions. However, it has been shown that sickle cell disease the opioid addiction has not been as prevalent of a problem as with other diseases. There is no evidence that sickle cell patients are more likely to suffer from an opioid use disorder (Lanzkron et al. 2018). These patients have learned how to use these drugs to help manage their pain while taking proper care of themselves.

Beyond the treatment of crises, a big way to manage SCD is with preliminary care. Many new studies have shown that hydroxyurea has helped patients with chronic sickle cell disease by reducing their number of crises while also being a great way to manage the disease. Hydroxyurea is the first clinically acceptable drug that has been shown to deter painful crises in adults with sickle cell anemia (Charache et al. 1995). Hydroxyurea differs from opioids because it does not have any effect during a crisis (Charache et al. 1995). Its goal is to help decrease the number of crises and provide a long-term health treatment (Charache et al. 1995). Patients who have not had great success with hydroxyurea may be encouraged to use blood transfusion therapy. When doing this, blood is taken out of the body, and new blood is transfused in.

Though more extreme, this method helps remove the sickled cells and insert normal red blood cells back into the body. This decreases the number of crisis seen in patients but does not offer a permanent solution(Hilliard et al. 2018). Chronic transfusion therapy may create a clinical risk of iron overload for patients that do not adhere to iron chelation and have a history of poor adherence to hydroxyurea. It also has the potential to be harmful to SCD patients long term. This treatment should be reserved for only extreme cases. A more permanent but not guaranteed way to help eliminate SCD is a bone marrow transplant. This attempts to completely replace the mutated genes and place in normal ones. However, this is not always successful and can result in the reappearance of the mutated genes(Charache et al. 1995).

Sickle cell disease has shown to be a prevalent disease all over the world. Whether in Africa or the United Kingdom, this disease takes its toll. Many underestimate the number of people who face this disorder and how challenging it can be on the body. This mutation makes it so that decreased oxygen levels are always traveling the body. This leads to a number of disorders, daily challenges, and extreme health risks. Though being such a massive problem to the body, it is still an underestimated complication that not all are aware of and not much education is given on in areas with low medical health coverage. The first step in decreasing mortality is knowledge; without this, it is nearly impossible to understand or treat this disorder. Sickle cell disease has been shown to be an extremely challenging illness for people to manage.

One of the most prominent being that no set cure can be offered at this time. There are plenty of theoretical treatment options, but none have been shown to have an overwhelming success rate in the elimination of this disease. It is essential to continue to bring awareness about this disease to the public along with continually looking into how it affects the body beyond just the sickling of cells. Until this occurs sickle cell disease will continue to be one of the world’s leading genetic disorders.