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Introduction   

Sickle cell disease (SCD) is a hereditary genetic disorder caused by a variant of the beta-globin gene (β-globin) called sickle hemoglobin (Hb S) that affects hemoglobin (Hb), the part in red blood cells responsible for transporting oxygen throughout the body [1] [11]. In a healthy individual, red blood cells are round and pliable, allowing them to move through the body’s small vasculature. However, in SCD, a genetic defect in the hemoglobin – the protein in red blood cells that carries oxygen – leads to the formation of rigid, sticky (clumped) cells shaped like a sickle, a C-shaped agricultural tool, or the letter C [1]. Their irregular shape obstructs blood flow in small vessels. This blockage can result in episodes of severe pain and heighten the risk of various serious health complications, including infections, acute chest syndrome, and stroke [1].  

Sickled cells can accumulate and expire in the spleen, leading to chronic anemia due to a reduction in healthy red blood cell count. The continual presence of sickled cells can cause damage to the spleen itself, increasing the risk of infections [2]. These malformed red blood cells have a shorter lifespan, leading to a persistent deficiency, known as anemia [2]. Average red blood cells have a lifespan of up to 120 days, sickle cells survive for a shorter period, between 10 to 20 days [2].  

In 1904, the reported first instance of sickle cell disease (SCD) in the United States involved Walter Clement Noel, a 20-year-old dental student from Grenada [3]. Noel, seeking treatment for anemia and a leg ulcer at Chicago Presbyterian Hospital, met Dr. James B. Herrick (1861-1954), a renowned cardiologist and medicine professor who was first to describe myocardial infarction in 1912 [3]. Dr. Herrick’s intern, Dr. Ernest E. Irons (1877-1959), conducted the first blood tests where he discovered the distinctive sickle-shaped red blood cells in Noel’s blood sample [3].  

In November 1910, Dr. Herrick published the first official case study of SCD in medical literature. His study, entitled “Peculiar Elongated and Sickle-Shaped Red Blood Corpuscles in a Case of Severe Anemia,” appeared in the Archives of Internal Medicine (Chicago) [3] [4].  

Even though Dr. James B. Herrick reported the first case of SCD in the United States, the condition has a long-standing presence in African and Mediterranean lineage [5]. African medical records from as early as the 1870s referred to the disease using the term “ogbanjes,” meaning “children who come and go,” reflecting the high infant mortality associated with the condition and in Ghana, one family’s history of the inherited disease dates to 1670 [5]. Vernon Mason coined the term “sickle cell anemia” in 1922 [6].  

There are two prevailing theories about the origin of the sickle cell disease (SCD) mutation: the multicentric model and the unicentric model coinciding with the adoption of agriculture ~4000–5000 years ago [7]. Recent evidence suggests that the HBB-βS variant, associated with sickle cell disease, originated from a singular source in the central-western region of Africa, near what is now known as Cameroon ~ 7300 years ago, although other sources propose a timeline extending ~ 22,000 years ago [8][9].  

A noteworthy aspect of the sickle cell trait is its protective advantage against Plasmodium falciparum malaria [10]. Research shows that the sickle cell trait confers a 60% reduction in overall mortality risk [10]. This protective effect is most pronounced in early childhood, particularly from 2 to 16 months of age in the period that precedes the development of clinical immunity in regions with high malaria transmission rates [10]. The protective effect of the sickle-cell trait in combating severe malaria has led to a widespread occurrence of the sickle-cell mutation (HBB-βS) across various regions in Africa [7].  

Patients with Sickle Cell Disease (SCD) often suffer from intense pain, starting from infancy through adulthood [27]. This pain leads to frequent hospitalizations and affects an individual’s quality of life [1][4]. Pain episodes are unpredictable and episodic, ranking among the most severe forms of pain experienced [28]. This pain results from the obstruction of microcirculation by sickled red blood cells (RBCs), leading to ischemia, swelling, tissue death, and potential organ damage [1]. Infants often show pain through irritability, while in older children and adults, the pain can occur anywhere in the body, triggered by factors like infections or environmental changes [1] [2]. Pain episodes can vary in duration and may evolve into chronic pain.

Sickle Cell Case Study

Patient Information

• Patient: Jason Keel (pseudonym)
• Age: 9 years
• Sex: Male
• Race: African American
• Past medical history: Notable for asthma, no prior hospitalizations.
• Family history: Both patents with the mutated hemoglobin S gene (HbS)

Presenting Complaint

Patient presents to the emergency department with severe pain in his lower back and legs, which he rates as 9/10 in intensity. The pain started the previous night.

History of Present Illness (HPI)

• The pain is sharp and persistent, not relieved by over-the-counter pain medications (Tylenol).
• No recent injuries, trauma or excessive physical activities could explain the pain.
• The patient also reports feeling fatigued and short of breath.
• No reports of fever, chest pain, or other systemic symptoms.

Physical Examination

• Vitals: BP 120/75 mmHg, Heart Rate 98 bpm, Respiratory Rate 22 breaths/min, Temp 98.6°F, Oxygen Saturation 95% on room air.
• General: Appears in moderate distress due to pain.
• Cardiovascular: Regular rhythm, no murmurs.
• Respiratory: Clear to auscultation bilaterally.
• Abdominal: Soft, non-tender.
• Musculoskeletal: Pain on palpation of the lumbar spine and long bones of the legs. No swelling or redness.
• Skin: Jaundice noted.

Diagnostic Workup

• Complete Blood Count (CBC): Shows anemia with a hemoglobin level of 7 g/dL.
• Peripheral Smear: Presence of sickle cells.
• Hemoglobin Electrophoresis: Confirms HbSS genotype.
• Chest X-ray: Clear, no signs of acute chest syndrome.
• Pain Assessment: Severe pain not controlled by NSAIDs.

Diagnosis

Sickle Cell vaso occlusive crisis.

Treatment Plan

• Pain Management: IV opioids for pain control.
• Hydration: IV fluids to support hydration.
• Oxygen Therapy: Supplemental oxygen to support saturation above 95%.
• Monitoring: Regular monitoring of vital signs and hemoglobin levels.
• Education: Educate the patient and family about sickle cell disease management, including the importance of staying hydrated, avoiding temperature extremes, and seeking prompt medical care for future crises.

Follow-up

• Regular follow-up with a hematologist.
• Discussion about hydroxyurea therapy for chronic management.
• Genetic counseling for the patient and family.
• Vaccinations and prophylactic antibiotics to prevent infections.

Case Study Discussion

This case highlights a classic presentation of a vaso occlusive crisis (blood vessel occlusion) in a patient with sickle cell disease. Initial patient management focuses on symptomatic management and addressing the immediate crisis [14]. Long-term considerations include managing anemia, preventing infections, and addressing any organ damage due to the disease [14].

To have a child with sickle cell disease (SCD), both parents must carry a faulty gene related to the disorder. SCD is an inherited autosomal recessive pattern. This means that each parent must have one copy of the mutated gene (hemoglobin S gene) and pass it on to their child [12]. When both parents carry one hemoglobin S gene, there is a 25% chance with each pregnancy that the child will inherit two hemoglobin S genes, resulting in sickle cell disease [12]. If a child inherits only one sickle cell gene (hemoglobin S) from one parent and a normal hemoglobin gene (hemoglobin A) from the other parent, the child will have the sickle cell trait [12]. People with the sickle cell trait most often do not have the disease, but they are carriers of the sickle cell gene and can pass it on to their children [13]. The sickle cell trait (SCT) is present in about 1 in every 13 Black or African American newborns [13]. Over 100,000 individuals in the United States live with Sickle Cell Disease (SCD) [13]. The incidence of SCD is about 1 in every 365 births among Black or African American individuals [13]. In the Hispanic American population, SCD occurs at a rate of 1 in every 16,300 births [13].

Children with Sickle Cell Anemia (SCA) often receive a diagnosis during childhood secondary to extensive newborn screening programs in developed nations that can detect the condition in its neonatal stage [58]. By 2007, the United States had implemented nationwide screening for SCA in all states, using methods like high-performance liquid chromatography and isoelectric focusing [29].

Pathophysiology

The pathophysiology of sickle cell disease (SCD) involves a complex interplay of various processes. Sickle cell disease is a genetic condition affecting hemoglobin production, caused by a specific genetic mutation in the β-globin gene [1]. This mutation results in the formation of an abnormal hemoglobin, known as hemoglobin S (HbS), which is the underlying cause of the disease’s symptoms and complications [15]. This mutation produces abnormal hemoglobin S (HbS), which polymerizes when deoxygenated, causing red blood cells to become misshapen and leading to their premature destruction [16]. This process triggers a chain of events including microvascular vaso-occlusion, ischemia-reperfusion injury, and oxidative stress, resulting in chronic inflammation [16][17]. Increased adhesion of blood cells to vascular endothelium and reduced blood flow contribute to this pathology [18]. In addition, hemolysis, or the breaking down of red blood cells, releases cell-free hemoglobin into the bloodstream, which depletes nitric oxide and worsening endothelial dysfunction [19].

Frequent and unpredictable vaso-occlusive episodes are a defining characteristic of sickle cell disease [20]. A vaso-occlusive crisis arises when sickled red blood cells block the small blood vessels, leading to tissue damage and intense pain due to insufficient blood and oxygen flow to the affected organs [1]. This process involves complex interactions between impaired blood flow, erythrocyte adhesiveness, and blood clotting activation [20]. Factors like blood viscosity, erythrocyte deformability, and exposure of adhesion molecules on erythrocytes, including those from immature reticulocytes, play a significant role [20] [21]. Endothelial dysfunction and inflammation further worsen these issues by increasing cell adhesion and promoting activation of blood cells [21].

In tissues with high oxygen demand, the deoxygenation of intraerythrocytic hemoglobin S (HbS) exposes the hydrophobic groups present on the HbS tetramers (polymer). This results in hydrophobic interactions between the HbS tetramers (polymer) leading to polymerization [22]. These polymers form fibers, increasing cellular rigidity and distorting erythrocyte membranes, resulting in sickling, cellular stress, and hemolysis [22]. The concentration of HbS and fetal hemoglobin (HbF) influences the level of polymerization [22] [23]. Advances in understanding HbS polymerization have led to the development of various therapeutic strategies targeting various stages of sickle cell disease pathobiology [21] [22].

Etiology

Sickle cell disease (SCD) is a prevalent genetic disorder caused by a specific mutation in the gene responsible for the beta subunit of hemoglobin [4]. Sickle cell anemia (SCA), also known as HbSS disease, is the most severe form of sickle cell disease (SCD). It occurs when an individual inherits two sickle cell alleles (S), one from each parent, making them homozygous for the mutation [4][12]. This genetic configuration results in the specific manifestation of the disease known as HbSS [4].

The misshapen, sickle-shaped red blood cell characteristic of sickle cell anemia (SCA) are inefficient in transporting oxygen and cause blockages in capillaries [4] [12]. This obstruction restricts blood flow to vital organs, including the brain and heart, leading to intense pain due to vaso-occlusion [4]. The majority of symptoms stem from a single nucleotide mutation [25]. SCA stands out as a critical disease caused by a unique change in one of the three billion nucleotides making up the human genome [25].

SCD disease affects multiple organs, caused by a genetic mutation that leads to the replacement of glutamic acid with valine at the sixth position of the beta chain of hemoglobin [4] [25]. Sickle cell disease (SCD) follows an autosomal recessive inheritance pattern. It is a common genetic disorder among African Americans, where its prevalence is about 1 in 500 [24]. About 1 in 12 African Americans carries the mutation for Sickle Cell Disease (SCD), and over 300,000 infants are born with sickle cell anemia (SCA) each year [24].

In sickle-hemoglobin C disease (HbSC), a form of sickle cell disease (SCD), individuals inherit a sickle cell allele (S) from one parent and an abnormal hemoglobin allele (C) from the other [26]. This variant of SCD tends to be less severe compared to others [4][24].

In sickle-β-thalassemia disease, which includes HbS/β+-thalassemia and HbS/β°-thalassemia, an individual inherits a sickle cell allele (S) from one parent and a β-thalassemia allele from the other. The severity of this type of sickle cell disease varies: HbS/β°-thalassemia often results in a severe form, while HbS/β+-thalassemia leads to a milder condition [4] [13].

Sickle cell trait (SCT), also known as HbAS, results from heterozygosity where one parent contributes a normal allele (A) and the other a sickle cell allele (S). Individuals with SCT often do not show symptoms of sickle cell anemia (SCA) and lead normal lives, but they can pass the trait to their children. Screening processes such as newborn screenings, childbirth or blood donations often find individuals with Sickle cell trait (SCT) [4][13].

Patients with the HbSS phenotype of Sickle Cell Anemia often do not experience classic ‘sickle cell crises’ after birth secondary to the fetal hemoglobin (HbF) still present in their blood, aiding in supporting adequate tissue oxygenation [29]. It takes about 6-9 months for HbF to diminish [29].

Sickle Cell Anemia presents with various phenotypes, not all of which are identical, and these can either co-exist or appear as a range within the disease spectrum [29]. A higher hematocrit (Hct) level compared to other forms of the disease characterizes the vaso-occlusive sub phenotype in Sickle Cell Anemia [29]. This increased Hct leads to greater blood viscosity, which in turn contributes to more frequent vaso-occlusive crises and instances of acute chest syndrome [29].

The hemolysis and vascular sub phenotype in Sickle Cell Anemia show a lower hematocrit (Hct) but elevated levels of lactate dehydrogenase (LDH) and serum bilirubin, display more extensive hemolysis and severe anemia [29] [30]. This subtype has a higher risk of complications such as gallstones, pulmonary hypertension, ischemic stroke, priapism, and nephropathy [29] [30]. Severe anemia increases cardiac workload and organ blood flow, heightening organ damage risk. Increased free heme and hemoglobin in the blood vessels contribute to oxidative damage [30].

In individuals with the high Hb F subtype of Sickle Cell Anemia (SCA), having 10 to 15% levels of fetal hemoglobin (HbF) helps to mitigate the symptoms of the disease [29]. This type of distribution of HbF varies across various parts of the body [29]. The pain-sensitive sub phenotype in Sickle Cell Anemia (SCA) and individual differences in neurophysiology makes some individuals more prone to pain than others [29]. This variation in pain sensitivity means that the experience of pain can differ among individuals with SCA [29].

Epidemiological studies show that around 5.2% of individuals with sickle cell disease experience between three to ten severe pain episodes per year [67] [73]. A pain crisis often resolves in five to seven days, but a more intense crisis can lead to pain lasting weeks or even months [66].

If a vaso-occlusive crisis extends beyond seven days, it is crucial to investigate alternative causes including osteomyelitis, avascular necrosis, or compression deformities [68]. In cases where a bone crisis recurs and persists for weeks, an exchange transfusion may be necessary to break the cycle [69]. Transfusion therapy serves as a critical treatment choice for patients, functioning in both primary and secondary prevention of stroke. Simple and exchange transfusions are employed to manage unrelenting and frequent pain crises, as well as pulmonary hypertension [69]. The frequency, severity, location, and duration of pain crises vary even within the same disease subtype [60]. Those with homozygous sickle cell and sickle cell–β°-thalassemia may experience more frequent vaso-occlusive pain crises compared to individuals with hemoglobin SC and sickle cell–β+-thalassemia genotypes [70]. A complex interplay of genetic, rheological, hematological, microvascular, and endothelial factors influences the severity of the disease [70].

Clinical Signs and Symptoms

Individuals with Sickle Cell Anemia (SCA) may experience a range of acute or chronic complications due to the condition. A prevalent acute complication in SCA is the Vaso-occlusive crisis (VOC) [29]. Every individual with Sickle Cell Anemia (SCA) will experience a Vaso-occlusive crisis (VOC) at some point. One of the earliest manifestations in children, often as young as six months, is dactylitis [24]. Vaso-occlusive crisis (VOC) associated with Sickle Cell Anemia (SCA) can affect any organ in the body, including the head and eyes, but often involves the extremities and chest. When the characteristics of VOC pain seem atypical, it is important to collect a detailed history to exclude other potential causes [24] [29].

In Sickle Cell Disease (SCD), symptomatic anemia is a prevalent symptom in Sickle Cell Anemia (Homozygous S) often causing the lowest hemoglobin levels [29]. Asymptomatic patients have varying steady-state hemoglobin levels based on their specific SCD phenotype, with levels ranging from 60–80 g/L in more severe forms to 100–110 g/L in milder variants [25].

Parvovirus B19, known for causing the fifth disease, is a trigger for Acute Aplastic Crisis in Sickle Cell Disease (SCD) [31]. Parvovirus B19 exacerbates anemia through the temporary suppression of bone marrow erythropoietic activity [31]. In healthy children, this infection is often mild, marked by malaise, fever, and light rash. However, in Sickle Cell Disease (SCD), the impact is more severe due to the virus targeting and destroying red blood cell progenitors in the bone marrow, which impedes new red blood cell production [31]. In healthy individuals this infection resolves within a week. In SCD patients, they often experience a substantial decrease in hemoglobin levels and may require blood transfusions. A rapid drop in Hb at least 3 to 6 gm/dL below the baseline defines an aplastic crisis (Compromised RBC production within the bone marrow) [31].

Individuals with Sickle Cell Disease (SCD) have increased vulnerability to infections, (bacterial sepsis and malaria) in children under five [32]. Children under five with Sickle Cell Disease (SCD) face a risk of infection that is thirty to a hundred times greater than that of healthy children [32]. This elevated risk makes them more susceptible to invasive pneumococcal diseases such as pneumonia, meningitis, and septicemia [32]. In individuals with Sickle Cell Disease, respiratory infections may lead to the development of sickle-cell acute chest syndrome, a serious condition with a significant risk of mortality.

Several factors contribute to the increased infection risks in individuals with Sickle Cell Disease, such as functional asplenia or hyposalemia diminishing splenic immune functions, along with impaired complement fixation, weakened neutrophil activity, and less effective antibody responses [34]. Primary concerns include Streptococcus pneumoniae infections, with other serious infections often caused by Haemophilus influenzae, Neisseria meningitides, and Salmonella strains, the latter leading to osteomyelitis [32].

Splenic Sequestration Crisis in Sickle Cell Disease involves the spleen trapping sickled red blood cells, leading to hypoxia and further cell sickling [35]. This can either be hepatic or splenic sequestration. This cycle causes spleen enlargement and potential sudden circulatory failure due to blood pooling [35]. Symptoms include abdominal distension, weakness, thirst, rapid heartbeat, and breathing difficulties [35]. Splenic sequestration, a serious complication of sickle cell anemia affecting young children and characterized by a rapid decrease in hemoglobin levels by 2 g/dL along with an enlarged spleen [35] [36]. Individuals with non-SCA sickle cell variants, such as HbSC and HbS-beta+ thalassemia, do not experience ‘auto-splenectomy’ as often, a common occurrence in SCA patients [29]. These individuals are at risk of developing splenic sequestration later in life, often accompanied by chronic splenomegaly and hypersplenism [29].

Hepatic sequestration, occurring in all SCA phenotypes, involves the rapid enlargement of the liver, often without liver enlargement. A significant hemoglobin drop (over 2gm/dL) and liver capsule stretching defines the sequestration [29]. Liver enzyme levels may not rise.

Acute Chest Syndrome (ACS) is a major complication and the leading cause of death in Sickle Cell Anemia (SCA) [33]. ACS mimics pneumonia and is a major cause of illness, hospitalization, and death in those with sickle cell disease. It occurs when sickled cells obstruct blood vessels in the lungs, posing an emergency and potentially life-threatening situation [33]. ACS is a frequent reason for hospital admissions and can occur at the onset or develop during hospitalization for other reasons. Risk factors include prior ACS episodes, asthma, or recent events like surgeries or infections [33]. ACS presents with sudden cough and breathlessness, sometimes accompanied by fever. Diagnosis involves blood counts, chemistries, cultures, and a chest X-ray, which shows new pulmonary infiltrates, a key ACS indicator [33]. CT scans can help diagnose suspected pulmonary or fat embolism cases [33].

Acute stroke, a severe complication of Sickle Cell Anemia (SCA), has seen a reduced incidence due to transcranial doppler (TCD) screenings and primary prevention programs [37]. About 10% of children with SCA experience overt strokes, and 20-35% have silent cerebral infarcts [38]. TCD is less effective for adults [39]. Symptoms include severe headaches, altered mental status, slurred speech, seizures, and paralysis [37]. Immediate neurological consultation and imaging tests like CT scans, followed by MRI/MRA, are essential for diagnosis and treatment [37].

Acute intrahepatic cholestasis (AIC) manifests with sudden right upper quadrant pain and characterized by worsening jaundice, an enlarging and tender liver, clay-colored stools, fever, and leukocytosis [29]. Laboratory tests often reveal high bilirubin levels, elevated alkaline phosphatase, and coagulopathy [40]. AIC is a critical medical emergency requiring prompt attention.

Priapism, a prolonged and painful erection lasting over four hours, is a common complication in individuals with Sickle Cell Anemia (SCA), affecting about 35% of all male patients [41]. This condition disrupts normal blood flow and causes persistent erection. Episodes of priapism can lead to fibrosis in the penile tissues resulting in permanent erectile dysfunction [41]. This complication underscores the importance of timely medical intervention during priapic events.

Acute ocular complications in patients with Sickle Cell Anemia (SCA), present unique challenges and require careful consideration. Proliferative Sickle Cell Retinopathy (PSR) is a severe complication of Sickle Cell Disease (SCD) that can threaten vision [45]. It develops due to ischemic events in the retina, which trigger angiogenesis, leading to the formation of new blood vessels in the retina [45].

Hyphema refers to the accumulation of blood within the anterior chamber of the eye, often resulting from blunt trauma [42]. The severity of a hyphema, the extent to which the accumulated blood obscures the cornea, receives grading based on the degree of obscuration [42]. A hyphema can manifest in individuals with both SCA and sickle cell trait [42]. The pathophysiology involves the sickling of red blood cells due to the low oxygen pressure and acidotic nature of the aqueous humor. This sickling process leads to a blockage in the trabecular meshwork, causing a rapid increase in intraocular pressure (IOP) [42].

Patients with SCA are vulnerable to complications arising from high IOP, including the development of Central Retinal Artery Occlusion (CRAO) and secondary hemorrhages [43]. Central Retinal Artery Occlusion (CRAO) is an acute ischemic stroke of the eye, leading to painless loss of vision due to infarction in the retina [44]. CRAO can arise without insult or as a secondary complication to increased IOP from hyphema, Moyamoya syndrome, or acute chest syndrome in patients with SCA [44].

Orbital complications are an uncommon manifestation in sickle cell disease [46]. Orbital Infarction is a rare but serious complication resulting from the infarction of the orbital bone, leading to inflammation and compression of surrounding structures [29]. Patients present with symptoms like proptosis, local pain, and edema of the lid or orbit [29]. Orbital Compression Syndrome (OCS), also known as orbital apex syndrome, is a significant concern. Vision loss due to events occurring at the orbital apex highlights ophthalmoplegia (paralysis or weakness of the eye muscles. [45]. This syndrome can involve cranial nerves II, III, IV, VI, and the first division of CN V [45]. Orbital Compression Syndrome varies in severity, with milder forms often responding to conservative treatment, while severe cases, posing a risk to vision, may require surgical intervention to remove hematomas and protect against vision loss [46].

Long-Term Complications

Iron (Fe) overload in Sickle Cell Anemia (SCA) patients often arises from frequent blood transfusions and ongoing hemolysis [48]. Each unit of transfused packed red blood cells introduces an added 200 to 250 mg of iron that can accumulate in the heart, lungs, and endocrine glands [49]. Hepatic cirrhosis due to iron overload is a significant cause of mortality in SCA patients. Studies in thalassemia patients have shown a direct correlation between systemic iron levels, survival rates, and cardiac complications [50].

Avascular Necrosis (AVN) of the head of the femur and humerus is a prevalent cause of chronic pain and disability in Sickle Cell Anemia (SCA) patients, with the hip being one of the most affected joints [51]. AVN arises in bone areas with poor collateral circulation, leading to blockage of capillaries by sickled red blood cells, resulting in hypoxia and bone death [29]. Key risk factors include age, frequency of pain episodes, hemoglobin levels, and alpha-gene deletion [29]. About 50 percent of patients with HbSS develop AVN by the age of 33, with those having HbSS-alpha thalassemia and HbSS-Beta-0 thalassemia facing a higher risk of early onset [29].

Leg ulcers are more prevalent in patients with Sickle Cell Anemia (SCA) than in other sickle cell disease genotypes, affecting 2.5-30% of SCA patients over the age of ten [52]. They are more observed in men and older individuals and less frequent in those with higher total hemoglobin, homozygous genotype [Hb SS; sickle cell anemia (SCA), alpha-gene deletion, and elevated HbF levels [53]. Risk factors include trauma, infections, and severe anemia [29]. Ulcers appear on the medial and lateral aspects of the ankles and vary in size and depth, with chronic ulcers leading to osteomyelitis [29].

Pulmonary Artery Hypertension (PAH) affects 6 to 11% of Sickle Cell Anemia (SCA) patients and falls under the World Health Organization (WHO) Group V classification [54]. Chronic hemolysis in SCA causes pulmonary vascular changes, fitting WHO Group 1 criteria in about 10% of cases [29]. PAH in SCA may also arise from left heart dysfunction, chronic lung disease, chronic thromboembolism, or extra thoracic causes [29]. Symptoms include dyspnea on exertion and leg swelling [54]. Diagnosis involves echocardiography to estimate tricuspid regurgitant jet velocity and right heart catheterization. Elevated TRV and serum NT-pro-BNP levels correlate with higher mortality [29] [45].

Chronic Kidney Disease (CKD) is a major indicator of mortality risk in individuals with Sickle Cell Disease (SCD) [57]. Renal complications in Sickle Cell Anemia (SCA) patients including chronic kidney disease (CKD) and renal failure affect around 30% of adults [57]. The average age at which CKD onset occurred in this group was 37 years [57].

Sickle cell nephropathy (SCN) is a group of renal complications that play a significant role in the mortality of individuals with Sickle Cell Disease (SCD) and causing 16-18% of the deaths in this patient group [55] [56]. Complications and involvement encompass a range of physiologic issues including modified blood flow dynamics, organ enlargement, distinct types of glomerular diseases, chronic kidney disease, acute kidney injury, reduced ability to concentrate urine, distal nephron dysfunction, blood in urine, and heightened susceptibility to urinary tract infections and renal medullary carcinoma [55]. SCN signifies an inherent vascular pathology marked by increased blood flow in the cortex, reduced perfusion in the medulla, and an amplified, stress-provoked response causing narrowing of blood vessels [55].

Sickle Cell Disease (SCD) affects the psychological and social well-being of both patients and their families [59]. In pediatric patients with Sickle Cell Disease (SCD), there are broad impacts on quality of life, psychological and social well-being, daily personal and social interactions, emotional well-being, focus, concentration, and motivation [59]. This impact stems from how pain and other symptoms disrupt daily life, coupled with societal attitudes towards those affected [60]. Cultural influences play a crucial role in these challenges due to specific beliefs and practices [25] [60]. The ability of individuals with SCD to manage their condition differs as there is a wide variation in disease severity, overall health, and quality of life among those affected [25] [59].

SCD leads to a variety of acute and chronic health issues, requiring a collaborative approach that includes a range of medical experts. In the United Kingdom, specialized haemoglobinopathy teams orchestrate comprehensive care for SCD [61].

Treatment and Management

The treatment of sickle cell anemia focuses on preventing pain episodes, alleviating symptoms, and averting long-term complications [62]. Management involves medications and blood transfusions and for certain children and adolescents. In adults with sickle cell disease (SCD), chronic pain and anemia are the most prevalent complications [62]. Episodic pain impacts quality of life, functional capabilities, and the frequency with which patients with sickle cell disease use healthcare services [64].

Due to concerns about narcotic addiction, tolerance, perceived drug-seeking behavior, excessive sedation, respiratory depression, and lack of specific physical examination findings pain from vaso-occlusive crises in sickle cell disease (SCD) is often undertreated [72]. Data indicates the incidence of opioid addiction in SCD patients is as low as 3 percent [66].

The approach to pain management can differ from one patient to another, influenced by family dynamics, individual pain thresholds, and access to healthcare. Patients can manage episodes of mild to moderate pain at home without needing to visit a healthcare facility [65] [73]. Employing self-help psychological strategies, such as guided imagery, has proven to be an effective adjunct in pain management [65].

Patients who adopt these complementary coping strategies experience fewer hospitalizations [65]. The pain management process involves four stages: assessment, treatment, reassessment, and adjustment [25]. Despite advances in pain management, physicians are often reluctant to give patients adequate dosages of narcotic analgesics because of concerns about addiction, tolerance, and side effects [65].

It is important to recognize a pain crisis early, correct the inciting causes, control pain, maintain euvolemia and, when necessary, administer adequate hemoglobin to decrease the hemoglobin S level [66].

For mild pain, patients can often manage at home with oral fluids and nonnarcotic analgesics. Options include acetaminophen, acetaminophen with codeine or oxycodone, and nonsteroidal anti-inflammatory drugs, unless contraindicated due to conditions like peptic ulcer disease, renal disease, or hepatic dysfunction [73]. In cases of moderate to severe pain, titrated doses of narcotic analgesics can be effective pain control [73].

Opioids, including codeine and oxycodone are best for moderate pain due to side effects like sedation, nausea, and vomiting [73]. Severe pain requiring emergency care or hospitalization requires stronger opioids and patient-controlled analgesia (PCA) [65].

Adjuvant nonopioid agents such as antihistamines and antiemetics can help prevent or relieve opioid-related side effects. Providers may consider Tricyclic antidepressants for chronic pain syndromes resulting from recurrent acute pain crises [73][74].

Nonpharmacologic techniques including physical therapy, rest, heat application, transcutaneous electrical nerve stimulation (TENS), self-hypnosis, and diversional techniques can also be effective [66].

Oxygen therapy in vaso-occlusive crises as routine is unsupported and reserved for patients with hypoxemia [87]. Interpreting pulse oximetry readings in SCD patients requires caution due to differences in oxygen affinity between normal hemoglobin and sickle cell hemoglobin [75].

Transfusion therapy is based on a patient’s hemoglobin levels, with simple transfusion therapy guided by a significant decline from baseline levels. Exchange transfusions are for prolonged refractory vaso-occlusive crises, aiming to reduce hemoglobin S levels to below 20 percent [76] [77]. The goals of transfusion therapy in Sickle Cell Disease (SCD) include both enhancing the oxygen-carrying ability and reducing the proportion of sickle hemoglobin (HbS) in comparison to normal hemoglobin A (HbA) [76][77]. This approach aims to prevent or mitigate the complications associated with vaso-occlusion. In acute scenarios, a simple transfusion can increase oxygen transport ability, but with a risk of increased blood viscosity if the hemoglobin level rises above the patient’s usual baseline. For patients with homozygous HbS (HbSS), the ideal target hemoglobin level is set at 10 g/dL [77].

Providers consider fluid replacement to maintain euvolemia, with oral rehydration for milder crises and parenteral rehydration for severe cases [78]. Large fluid volumes can risk pulmonary edema in patients with renal, cardiac, or pulmonary conditions [78].

Prevention

Strategies to Prevent Pain Crises in Sickle Cell Disease Patients:

• Ensure adequate hydration to prevent dehydration during feverish periods and in hot weather [71].
• Avoid activities like mountain climbing or flying in unpressurized cabins (such as noncommercial flights) at altitudes above 10,000 feet.
• Avoid extreme cold, overexertion during exercise, and drugs that might cause acidosis, such as acetazolamide (Diamox) [88].
• Engage in genetic screening and seek vocational counseling about occupations or participation in intense physical activities (such as military training) in hot environments.
• Avoid hypoxemia during periods of surgery with general anesthesia or when procedures involve hypertonic radiographic dyes.

Figure 1. Management of a patient with Sickle Cell Disease (SCD) presenting to the Emergency Department with a Vaso-Occlusive Episode (VOE) [73].

Disease Modifying and Curative Treatments

A stem cell transplant may offer curative treatment in select individuals [62]. Recent and ongoing developments in CRISPR/Cas9 genome editing technology are showing promise as potential cures for individuals with sickle cell disease [62]. In December of 2023, the U.S. Food and Drug Administration (FDA) approved the first gene therapies for treating Sickle Cell Disease (SCD). The two pioneering treatments, Casgevy and Ligeia, for patients aged 12 and older, mark a significant advancement in SCD therapy [63].

For Sickle Cell Disease (SCD), the disease-modifying drugs include hydroxycarbamide and L-glutamine administered daily to decrease the frequency of acute complications, though their effectiveness can differ among individuals [79].

Hydroxycarbamide, also known as hydroxyurea, is a pivotal medication and primary agent in the management of Sickle Cell Disease (SCD) [80]. Hydroxycarbamide’s effectiveness is in its ability to increase overall hemoglobin levels and the production of fetal hemoglobin (HbF) [80]. Hydroxycarbamide also lowers the white blood cell count and reduces the expression of surface adhesion molecules on neutrophils, red blood cells, and vascular endothelium [81]. These actions improve blood flow and lessen vaso-occlusive events.

In July 2017, the U.S. Food and Drug Administration (FDA) sanctioned the use of pharmaceutical-grade L-glutamine for patients with sickle cell disease aged five and above [81]. Clinical trials have shown that this refined form of glutamine lowers the occurrence of acute complications in sickle cell disease [81]. The associated side effects are mild and do not require laboratory monitoring.

Treatments Focused on Decreasing HbS Polymerization

GBT440 (Voxelotor) is an orally administered compound developed to enhance the oxygen affinity of HbS, causing a leftward shift in the oxygen dissociation curve of oxy-HbS [82]. It achieves this by reversibly attaching to the N-terminal valine of the alpha (α) chain of Hemoglobin, altering its structural shape, and stabilizing its oxygenated form [82]. This action leads to a reduction in deoxygenated HbS, which is the variant that polymerizes and results in the sickle cell shape [82].

Nutritional Supplements

Omega-3 fatty acids, extracted and purified from fish oil, provide antioxidant, antithrombotic, and anti-inflammatory effects. The beneficial properties of omega-3 fatty acids include anti-thrombotic eicosanoids, along with a new category of lipid mediators derived from EPA and DHA [83]. In patients with Sickle Cell Disease (SCD), the composition of fatty acids in blood cell membranes is atypical, marked by a high proportion of pro-inflammatory arachidonic acid (AA) compared to the anti-inflammatory fatty acids DHA and EPA, leading to an elevated omega-6/omega-3 ratio [83].

The use of folic acid in Sickle Cell Disease (SCD) may increase red blood cell production and raises the risk of folate deficiency [84]. Folate, also known as vitamin B9, plays a crucial role in the body’s production of red blood cells. Supplementing with folic acid, the synthetic form of folate found in fortified foods and supplements, can help manage the effects of SCD [84].

Conclusion

Sickle Cell Disease (SCD) is a complex hereditary condition characterized by the presence of sickle hemoglobin (Hb S) that leads to the formation of rigid, sickle-shaped red blood cells [11]. These malformed cells impede blood flow and oxygen transport, causing severe pain, heightened risk of infections, acute chest syndrome, stroke, and chronic anemia [1][11]. First reports of the disease occurred in the United States in 1904 and has a noted prevalence in African and Mediterranean populations [3]. Its protection against malaria has led to a higher frequency of sickle-cell mutation in these regions [7][10] [85].

The management of SCD requires a comprehensive approach, involving hydration, pain control, and the use of various therapeutic agents [78]. The disease’s impact extends beyond physical symptoms, affecting the psychological and social well-being of patients and their families [59]. Cultural factors, individual pain tolerance, and access to healthcare play significant roles in disease management [25][60].

The impact of SCD extends beyond physical symptoms, affecting the psychological and social well-being of patients and their families [59]. Challenges faced by individuals with SCD, and their caregivers include navigating societal misconceptions, cultural beliefs, and healthcare access disparities [86].

Recent advances in SCD research and treatment have opened new avenues for better management of the disease. The development of targeted therapies like GBT440 (Voxelotor), which alters the oxygen affinity of HbS, and nutritional interventions like omega-3 fatty acid supplementation and folic acid, address specific aspects of the disease’s pathophysiology [82] [83] [84]. These advancements, combined with increased awareness and improved healthcare practices, contribute to enhancing the quality of life for individuals with SCD.

Sickle Cell Disease remains a complex and challenging condition, requiring continued research, patient-centric care approaches, and an understanding of the diverse impacts on those affected. The ongoing developments in genetic treatments and comprehensive care strategies hold promise for improving outcomes and providing a more hopeful future for those living with SCD.

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