INTRODUCTION
Sickle cell disease (SCD) is a hereditary disorder characterized by the formation of abnormal, sickle-shaped erythrocytes. Affecting almost 300,000 newborns a year, it is a condition that is alarmingly spreading due to globalization. SCD is caused by a DNA base-pair alteration in the HbA gene which is one of a series of genes which produces protein subunits for hemoglobin. This mutation results in the mutation to HbS (Sickle hemoglobin) in both parental genomes, when HbS is presented in tandem with HbC or β-thalassemia, or others such as HbSD or HbSOarab (Kavanagh et al., 2022; Ware et al., 2017). SCD can be inherited in an autosomal recessive fashion from both parents (i.e., the child expresses homozygosity for HbS), or from one parent expressing an abnormal β-globin allele. This type of inheritance results in the child expressing compound heterozygosity for HbS and HbC/β-thalassemia (Piel et al., 2017).
This article will provide an in-depth review of SCD, outlining the epidemiology, pathophysiology, complications, and treatment options. A case study featuring a patient living with complications of SCD will be analyzed at the end.
EPIDEMIOLOGY
The HbS allele is believed to have been originally distributed in Sub-Saharan Africa, the Middle East, India, and the Mediterranean region. Today, the carrier rates range from 5% to greater than 40% in these areas (Houwing et al., 2019). This high carrier variation is showcased in the varied birth prevalence. In Africa, the birth prevalence is 1125 per 100 000 live births compared to 43.12 per 100 000 live births in Europe (Wastnedge et al., 2018). The high prevalence of carriers in Africa is believed to have resulted from selective advantage provided against Plasmodium falciparum (malaria-causing parasite) which is a monozygotic carrier of HbS (Kariuki & Williams, 2020). SCD provides an evolutionary advantage against malaria due to the altered shape and mechanisms of the red blood cells, rendering malaria parasites unable to effectively complete their life cycle. In mice models, the sickle hemoglobin also induces the expression of heme oxygenase-1, an enzyme that produces carbon monoxide as a byproduct, which in turn inhibits the progression of experimental cerebral malaria (Ferreira et al., 2011). The Americas and Northern Eurasia have very low to no presence of the HbS allele due to the lack of malaria cases in those areas (Rees et al., 2010).
SCD is a disease whose propagation is aided by globalization (Piel et al., 2017). Global migration has resulted in the introduction of SCD and Sickle Cell Trait (SCT) into populations from which it has been previously absent. Countries such as the United States, Brazil, and the United Kingdom have shown worryingly increasing trends in death rate and infection (Cox et al., 2020; Mburu & Odame, 2019; Morgan et al., 2019). Paired with developments in social care in low- and middle-income countries increasing the overall survival rate of SCD, the overall global burden of sickle cell disease is expected to increase (Piel et al., 2017). Overall, the birth incidence of SCD is estimated to be 300,000 per year (Campbell et al., 2019). Thus, with rising global incidence and the compounding effects of globalization for improved healthcare, the management and awareness of SCD emerges as critical priorities for public health initiatives worldwide.
PATHOPHYSIOLOGY
As referenced previously, SCD is typically caused by the homozygosity of the β-HbS allele located on the chromosome 11p15.5, resulting in HbA substituting into HbS. Specifically, it is caused by the single nucleotide substitution of thymine to adenine (GTG to GAG) within the β-globin gene (Gladwin et al., 2021). This mutation produces a repeating hydrophobic amino acid chain in hemoglobin such that, when deoxygenated, results in bonding between β-sheets of heme tetrameters, resulting in polymerization of hemoglobin molecules. This creates a nucleation site which quickly propagates intracellular polymerization of all hemoglobin present, disrupting the cellular architecture and removing the ability of the cell to hold oxygen. This disruption of architecture expresses itself in the “sickle” shaped erythrocytes for which the condition is named (Rees et al., 2010). There is a significant relationship between polymerization rate and concentration, and in addition, polymerization requires a double nucleation site to initiate. The requirement of a double-nucleation site explains why not all cells in a patient end up polymerizing to form a sickle cell (Eaton, 2020).
SCD is often expressed symptomatically through a diverse range of disease developments. One of the most common is the vaso-occlusive crisis (VOC) which constitute the major morbidity in SCD. VOC occurs due to sickled RBCs expressing adhesiveness to vascular endothelium which may cause them to eventually block vessels, especially capillaries. The resulting ischemia manifests itself with varying degrees of, often severe, pain (Uwaezuoke et al., 2018). Repeated VOCs may eventually lead to tissue and/or organ damage. Similarly, the affinity of sickle cells to adhere to endothelial cells often leads to strokes in patients, including young children and adults. SCD patients under 14 years old have a 7.4% incidence rate of stroke which increases to 11% for those under 20 years old (Pinto et al., 2019).
However, adherence to the endothelium as a result of VOC is not the sole interaction that can occur between sickled RBCs and the blood vessels’ endothelial lining. The hemolysis of RBCs releases Hb, which acts as a reducing agent to hydrogen peroxide and nitric oxide. These interactions (respectively known as the Fenton Reaction and uncoupled endothelial NO synthase) release hydroxide, nitrates, and methemoglobin which cause oxidative stress to the endothelial lining of blood vessels. This can potentially lead to sterile inflammation which can cascade into a VOC (Sundd et al., 2019).
SYMPTOMOLOGY & COMPLICATIONS
Acute anemia is another acute development of SCD. Acute anemia is typically the result of either an aplastic crisis or a hemolytic crisis. Either as a sequalae to or independent of acute anemia, splenic and/or hepatic sequestration can also occur. Acute spleen/hepatic sequestration are considered medical emergencies and are typically characterized by rapid swelling of the respective organ. The inflammation of the spleen leads to an immunocompromising effect. Typically, all patients with SCD are considered immunocompromised (Pinto et al., 2019) as a result of permanent spleen dysfunction.
Acute chest syndrome (ACS) is a vaso-occlusive crisis of the pulmonary vasculature, marked by an increase in inflammatory and endothelial indicators, a shadow on chest x-rays, and/or featuring one or more of the following symptoms: fever, cough, sputum production, tachypnoea, and dyspnoea. It is most common in adults and is usually preceded by thrombocytopenia. ACS is a medical emergency, as without rapid treatment, can lead to multiorgan failure (Martí-Carvajal et al., 2019).
SCD also features a variety of long-term complications that negatively affect health. Examples include but are not limited to retinopathy, kidney disease, gallstones, avascular necrosis, and iron overload (Pinto et al., 2019). In pediatric patients, for example, further complications of SCD include a 36-times greater risk of Streptococcus pneumoniae infection and 13-times greater risk of Hemophilus influenza type B (Mburu & Odame, 2019).
TREATMENT OPTIONS
Since the discovery of SCD in 1910, there have only been a handful of drug therapies and procedures approved by the United States Food and Drug Administration (FDA). Historically, the objective of these therapeutics was to alleviate pain and increase the quality of life for patients, but recent advances in treatments have explored the pathogenesis of the disorder (Gardner, 2018; Kapoor et al., 2018), specifically the induction of fetal hemoglobin or genome editing (Salinas Cisneros & Thein, 2020). We will discuss the different modalities available for each of the pathogenetic mechanisms of SCD, drawing inspiration from Cisneros & Thein’s (2020) framework.
Sickle Hemoglobin (HbS) Polymerization PreventioN
Although there are countless drugs in clinical trials, there are currently only two FDA-approved medications that target hemoglobin S polymerization (the formation of polymer chains from individual monomers): hydroxyurea (also known as hydroxycarbamide) and voxelotor. Hydroxyurea has a long history as the first FDA-approved drug, serving as the default treatment for over 30 years (Gardner, 2018; Kavanagh et al., 2022). As a ribonucleotide reductase inhibitor, it primarily increases the amount of fetal hemoglobin (HbF) in the bloodstream, which then prevents intracellular HbS polymerization and thus reduces blood cell sickling (Gardner, 2018; Kapoor et al., 2018; Kavanagh et al., 2022). Further, it also decreases cell rigidity by increasing the presence of nitric oxide which is a powerful vasodilator, slowing the production of leukocytes and subsequent vaso-occlusion (Kavanagh et al., 2022). Hydroxyurea also reduces the expression of adhesion molecules on blood cells (Gardner, 2018). The efficacy of hydroxyurea has led it to become the standard treatment of SCD, with the FDA extending their approval of the drug to children in 2017 (Kapoor et al., 2018). Voxelotor (also known as GBT-440), is a molecule that, when bound to a HbS molecule (specifically the N-terminus of the alpha subunit), increases the oxygen affinity and stabilizes the oxygenated state of the hemoglobin (Gardner, 2018; Kapoor et al., 2018; Kavanagh et al., 2022). This action in turn prevents polymerization of the molecule and decreases the occurrence of cell sickling and hemolysis (Kavanagh et al., 2022).
VASO-OCCLUSION
Similar to Sickle Hemoglobin Polymerization, the FDA has currently approved two drugs to address sickle cell induced vaso-occlusion: L-glutamine and crizanlizumab.
L-glutamine is a naturally occurring essential amino acid which is required for the synthesis of pyridines in nucleotides and is essential if there is oxidative stress exposure (Cox et al., 2020). The availability of glutamine is paramount in SCD, where the ratio of nicotinamide adenine dinucleotide redox is lower than in normal red blood cells. It should be noted that L-glutamine is not effective when administered to treat hemolysis or anemia and as such should be paired with a drug that can target these symptoms accordingly.
Crizanlizumab is a humanized monoclonal antibody which attaches to P-selectin, a membrane protein which facilitates interactions between of endothelial cells with white blood cells and platelets. Upon binding, crizanlizumab blocks the interactions of P-selectin with P-selectin glycoprotein ligand 1, the facilitator of interactions between leukocytes and other blood cells (Ataga et al., 2017). The interaction between these two proteins are responsible for the adhesion which causes vaso-occlusion, thus making crizanlizumab an ideal drug for treatment and prevention. Like L-glutamine, this drug does not address other symptoms of SCD so should be used with other medications such as hydroxyurea for a comprehensive treatment if necessary.
EXPERIMENTAL TREATMENTS
Many experimental treatments with gene therapy and stem cell transplant are being studied closely in hopes of treating patients with a more curative approach. Gene therapies involve re-coding the specific genomic sequences that express HbF. The first method is by implementing additional nucleotides for the gene region that code for HbF: For example, scientists recently discovered that three single nucleotide polymorphisms (SNPs) in the BCL11A and HBB gene regions result in higher HbF expression (Gardner, 2018). Alternatively, it is also possible to increase HbF by decreasing the expression of genes that suppress HbF production, such as MYB or BCL11A (Gardner, 2018). Other gene modification interventions, such as gene correction with CRISPR/Cas9 therapies, are also under consideration.
Hematopoietic stem cell transplant (HSCT) is also a rising field and is considered the only curative treatment against SCD (Kariuki & Williams, 2020). Although multiple clinical trials display encouraging results, the ultimate challenges with HSCT are finding donors and the uncertainty of the intervention’s effectiveness. Not only are donors scarce in availability and the matching criteria strict, but to date, transplants have only been performed on patients who “have the worst disease severity” (Gardner, 2018; Kavanagh et al., 2022). Overall, it is clear that most if not all of these treatments remain in the early stages of research and development.
DISCUSSION AND CASE ANALYSIS: THE CASE OF PATIENT X
For our case study, we will follow the case of Patient X. Patient X is a 14-year-old female presenting with symptoms of jaundice in the eyes, dyspnea (shortness of breath), and fatigue. Her medical history was unremarkable, with the exception of a hospitalization at age ~8 for fever and severe pain and immobilization in her left leg, along with a diagnosis for asthma 3 years prior. Her aunt on the father’s side of the family is asthmatic but there were no shared symptoms among any family members. A physical examination revealed reduced respiratory expansion, a dull percussion note observed in right middle lobe in addition to coarse crackles on auscultation (examination with a stethoscope). Her splenic tip was palpable and there was evidence of hepatitis (inflammation of her liver), along with minor tenderness in her abdomen. Her palms were pale, and she suffered from dactylitis (severe swelling of the fingers and toes).
On physical investigation, blood labs show reduced RBC, hemoglobin, platelet, and hematocrit count, paired with an elevated white blood cell and reticulocyte count. She possessed no HbA but expressed mainly HbF and HbS. A peripheral smear showed sickle-shaped cells. Liver tests showed elevated alanine aminotransferase and bilirubin, indicating potential liver and kidney damage. Most alarmingly, however, a urine and blood culture revealed bacteriuria (bacterial presence in urine) and bacteremia (bacterial presence in blood).
These results indicated that she was suffering from a pneumonia infection in conjunction to a hemolytic anemia secondary to SCD. Her hemolytic anemia was likely triggered by metabolic stress from the pneumonia infection. Critically, her bacteremia, if allowed to progress, could result in sepsis. As indicated by elevated alanine aminotransferase, her spleen inflammation and liver damage could suggest the initial stages of spleen and hepatic sequestration (trapping of sickled red blood cells).
Overall, her condition is quite severe and could lead to permanent damage if untreated. Hemolytic anemia is the most severe symptom and must be addressed before pneumonia and other long-term SCD treatment options are considered. The only known immediate treatment that suits this situation is blood transfusion. The patient had no history of previous blood transfusion resulting in hemolysis, and as a result, this should be safe and effective with minimal risk hyperhemolytic syndrome or iron overload. RBC exchange transfusions will also have the effect of introducing normal HbA into her blood, helping increase oxygen delivery while reducing the risk of further severe anemia, sequestration, or any other major complications such as ACS or stroke. Her blood type is currently unknown but should be identified prior to administering a blood transfusion to prevent alloimmunization (Abboud, 2020).
It is our recommendation that hydroxyurea be administered both as a treatment and prophylactically. Hydroxyurea has been shown to decrease the number and severity of attacks. However, its overall long term effects are unknown, and as a result, it may not be acceptable to prescribe a long-term course of this treatment (Platt, 2008). Voxelotor may be a potentially more useful long-term treatment option as it prevents cell sickling and hemolysis by stabilizing the oxidized state of hemoglobin. The initial prescribed dose of hydroxyurea should be 10-15 mg/kg/day with a dose escalation of 5 mg/kg for every 4-6 weeks until a positive clinical effect is observed (Agrawal et al., 2014).
The blood culture reveals that the highest occurring non-common floral bacteria is gram-positive Streptococcus pneumoniae, which explains the patient’s reported respiratory complications. The antibiotic sensitivity results yielded three viable treatment options among fourteen tested antibiotics: Cefepime, Ceftazidime, and Meropenem. In addition to being rated as “sensitive,” all three antibiotics had a minimum inhibitory concentration of 4.0 μmol/L, the lowest in the tests. However, the sensitivity test reveals that Cefazolin, belonging to the same drug class as Cefepime and Ceftazidime, is classified as resistant. As a result, it is recommended that cephalosporins are to be avoided in the treatment and as such Meropenem has been selected to treat the patient’s pneumonia. It is our recommendation that the patient be held for observation for a short period of days (<1 week) in order to ensure proper recovery of organ systems and to monitor for development of potential risks such as acute chest syndrome, of pneumonia infection is a possible trigger (Kavanagh et al., 2022).
Of course, stabilizing the patient’s SCD symptoms is the long-term treatment goal. As previously discussed, hydroxyurea or voxelotor are viable treatments for preventing and reducing the severity of attacks in the longer term. If the patient consents, experimental treatments may be used, such as CRISPR or stem cell-based treatments. CRISPR is a less invasive experimental treatment, but its side effects are unknown, and its long-term viability is still under research. Stem cell transplants may still be effective as the patient is young. However, as stated previously, the intervention’s effectiveness is under question, and such treatment would only be reserved if the patient's condition escalates with no treatment.
CONCLUSION
SCD results from mutations in the codon for hemoglobin. Specifically, a nucleotide substitution of thymine to adenine (GTG to GAG) resulting in hemoglobin that has the ability to polymerize and develop a “sickle” shape. A variety of treatment options were investigated, however, blood transfusions and FDA-approved drugs remain the most common therapies indicated for SCD. Yet, it must be noted that many of the treatments are only specific to an individual case. Hence the case study only using specific treatments, especially with management of some acute symptoms. We aimed to walk through the decisions made through the case on the selection of medication for case management and summarize information about the cause, epidemiology, and complications of SCD. In further research, a more comprehensive review on all factors that affect treatment should be considered, and a broader variety of current and historical medications considered. In addition, further research is required to further develop novel interventions, such as gene therapy and stem cell transplantation.
ACKNOWLEDGEMENTS
The authors would like to thank The Surgical Journal and YPStem Youth Medical Conference for the opportunity to perform a literature review and case analysis. We would also like to thank the editors and managing team at the Canadian Science Fair Journal for the opportunity to publish and their guidance during the peer-review process.
Conflicts of interest
We declare that there are no conflicts of interest.
Funding
This review article did not obtain funding or require ethics approval as no human participants were involved.
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