Sickle cell disease D57.1

Sickle cell disease (SCD) is a globally prevalent recessive blood disorder with a significant impact on affected individuals and healthcare systems. The epidemiology of SCD varies by region and population. Crisis-like circulatory disorders of the microcirculation with occlusive symptoms characterize the clinic. Dermatologically, solitary or multiple, usually painful ulcers appear, preferably on the lower legs, usually after the age of 20.

Various factors, including genetic inheritance patterns, geographic location and socioeconomic factors, influence the epidemiology of SCD. SCD primarily affects populations whose ancestors originate from regions where malaria is or was endemic, including sub-Saharan Africa, the Mediterranean region, the Middle East and parts of India and Southeast Asia. These regions are characterized by a higher prevalence of sickle cell genes (which are carriers of a mutated gene), as these protect against malaria. Consequently, the incidence of SCD is highest in these areas.

It is estimated that millions of people worldwide are affected by SCD. Sub-Saharan Africa alone accounts for over 70% of all SCD cases, with around 300,000 children born with the disease each year (Piel FB et al. 2010). In the United States, SCD primarily affects people of African descent, with an estimated prevalence of 1 in 365 African American births. Other populations with a higher prevalence of SCD include people of Hispanic, Mediterranean, Middle Eastern and South Asian descent (Piel FB et al. 2017).

The prevalence of SCD varies within population groups and between geographic regions. In Africa, the prevalence in certain tribal groups can range from 10 % to 40 %. In Saudi Arabia, the prevalence of SCD reaches up to 4%. (El-Hazmi MA et al. 2011).

SCD is primarily caused by a genetic mutation that affects hemoglobin, the protein responsible for transporting oxygen in red blood cells. The underlying cause of SCD is a point mutation in the beta-globin mode on chromosome 11 that results in the production of abnormal hemoglobin known as HbS. The specific mutation involves the substitution of a single nucleotide, where adenine is replaced by thymine, resulting in the substitution of glutamic acid for valine at the sixth position of the beta-globin chain. This change affects the structure and function of haemoglobin and causes it to polymerize under certain conditions, such as low oxygen tension or dehydration (Rees DC et al. 2010). The polymerization of HbS leads to the deformation of red blood cells into a characteristic sickle shape, which is rigid and susceptible to hemolysis. The sickle-shaped red blood cells cannot flow freely through the blood vessels, leading to vascular occlusion, tissue ischemia and subsequent organ damage.

SCD follows an autosomal recessive pattern of inheritance, which means that a person must inherit two copies of the mutated gene (one from each parent) to develop the disease. Individuals who inherit one copy of the mutated gene and one normal gene have the sickle cell trait and are usually symptom-free, but can pass the trait on to their offspring.

SCD is characterized by a complex pathophysiology that includes abnormal red blood cell sickling, altered blood rheology and resulting tissue damage. The pathophysiologic processes in SCD are primarily driven by structural and functional changes in hemoglobin and the resulting sickled red blood cells.

HbS polymerization: The primary abnormality in SCD is the substitution of glutamic acid for valine at the sixth position of the beta-globin chain, resulting in the formation of abnormal hemoglobin, known as HbS. Under certain conditions, such as low oxygen tension or dehydration, HbS polymerizes and forms long, rigid polymers within red blood cells (Bunn HF 1997).

Sickle formation of red blood cells: The polymerization of HbS leads to a deformation of the red blood cells into a sickle shape. The sickle-shaped red blood cells are rigid, less deformable and prone to hemolysis. These cells cannot flow freely through the blood vessels, which leads to vascular occlusion and tissue ischemia (Hebbel RP 2014).

Vascular occlusion: Sickle-shaped red blood cells can adhere to endothelial cells and other sickle-shaped cells and form aggregates that obstruct blood flow in small blood vessels. These vascular occlusions contribute to tissue ischemia, leading to acute pain crises, organ damage and increased susceptibility to infection.

Increased blood viscosity: The presence of crescent-shaped red blood cells and increased concentrations of circulating inflammatory cells and plasma proteins lead to increased blood viscosity in people with SCD. This increased viscosity further contributes to impaired blood flow, vaso-occlusion and tissue damage (Hebbel RP 2014).

Oxidative stress and inflammation: SCD is associated with increased oxidative stress due to the presence of free heme and iron from hemolysis. Oxidative stress triggers inflammatory responses, activation of endothelial cells and adhesion of sickle-shaped red blood cells to the vascular endothelium. This inflammatory cascade further promotes vaso-occlusion and endothelial dysfunction (Belcher JD et al. 2006).

Endothelial dysfunction: The interactions between sickle-shaped red blood cells and endothelial cells lead to activation and dysfunction of the endothelium. Endothelial dysfunction produces proinflammatory mediators, vasoconstriction and increased adhesion of sickle-shaped cells to the endothelium, which exacerbates vascular occlusion and tissue damage (Solovey A et al. 2004)

Ischemia-reperfusion injury: Repeated episodes of vascular occlusion followed by reperfusion during restoration of blood flow may contribute to ischemia-reperfusion injury. This process involves the generation of reactive oxygen species, inflammation and tissue damage, further exacerbating the pathophysiologic consequences of SCD.

Understanding the underlying pathophysiological mechanisms of SCD is crucial for the development of targeted therapeutic interventions. Current treatment approaches aim to prevent or mitigate vaso-occlusive crises, treat complications and improve the overall quality of life of people with SCD.

SCD is characterized by a variety of symptoms that can vary in severity and expression from person to person. The symptoms are primarily caused by the abnormal sickling of red blood cells and the resulting complications. This section provides a detailed overview of the most common symptoms associated with SCD.

Pain crises: Recurrent episodes of severe pain, known as vaso-occlusive crises or pain crises, are a hallmark of SCD. These painful episodes occur due to the blockage of blood vessels by crescent-shaped red blood cells, leading to tissue ischemia and inflammation. The pain can occur in different parts of the body, including the chest, abdomen, bones and joints (Platt OS et al. 2014)

Anemia: SCD causes chronic hemolytic anemia, which is characterized by accelerated destruction of red blood cells. Anemia can lead to fatigue, weakness, pallor and shortness of breath (Platt OS et al. 2014).

Ulcerations: Painful solitary or multiple ulcers usually occur on the lower extremity, preferably in areas with thin skin. The development of new ulcers is usually heralded by localized painfulness. About 25% of patients are prone to recurrences. Around 25% suffer from a chronic ulcer, which can manifest for years (BurgMR et al. 2025).

Infections: People with SCD are more susceptible to infections, especially bacterial infections, due to functional asplenia (absence of the spleen) and impaired immune function. Common infections include pneumonia, urinary tract infections and bacterial sepsis.

Acute chest syndrome: This is a severe complication of SCD characterized by chest pain, fever, cough and difficulty breathing. It is often caused by infection, pulmonary infarction or fat embolism and can be life-threatening.

Delay in growth and development: Children with SCD may show a delay in growth and development compared to their peers. Chronic anemia, nutritional deficiencies, and the impact of recurrent pain crises on daily activities may contribute to growth and developmental delays.

Stroke: SCD increases the risk of stroke, especially in children. The blockage of blood vessels in the brain by sickle-shaped red blood cells can lead to an ischemic stroke. Risk factors for stroke include a history of transient ischemic attacks and a circulatory disorder detected by transcranial Doppler ultrasonography (Ohene-Frempong K et al. 1998).

Organ damage: SCD can lead to long-term organ damage. Commonly affected organs are the spleen (leading to functional asplenia), the kidneys (leading to renal dysfunction), the eyes (leading to retinopathy) and the bones (increasing the risk of avascular necrosis).

The diagnosis of SCD involves a combination of clinical examination, laboratory tests and genetic testing. The aim is to determine the presence of abnormal HbS and assess the extent of the disease.

CBC:A CBC helps to assess the concentrations of hemoglobin, red blood cells and other cell types. Due to chronic hemolysis, individuals with SCD usually have lower hemoglobin levels and higher reticulocyte counts[1].

Hemoglobin electrophoresis: Hemoglobin electrophoresis is a crucial diagnostic test that can detect the presence of abnormal hemoglobin variants. It separates different types of hemoglobin based on their electrical charge. The test provides information on the relative amounts of HbS and other hemoglobin types, such as hemoglobin A (HbA) and hemoglobin F (HbF).

Sickledex/solubility test: The Sickledex or solubility test is a rapid screening test that detects the presence of HbS in a blood sample. It is based on the insolubility of HbS under certain conditions, which leads to the formation of sickle-shaped cells. However, this test is less specific than haemoglobin electrophoresis and may need to be confirmed by additional tests].

High performance liquid chromatography of hemoglobin: High performance liquid chromatography of hemoglobin is a more advanced technique for accurate quantification and identification of different hemoglobin variants. It provides a detailed analysis of the relative proportions of HbS, HbA, HbF and other hemoglobin types[29].

Genetic testing: Genetic testing is performed to confirm the diagnosis of SCD and identify specific mutations in the HBB. This may include DNA analysis, including polymerase chain reaction, gene sequencing and other molecular techniques to detect the presence of the HbS mutation and potentially identify genetic variants.

Newborn screening: In many countries, newborn screening programs are carried out to detect infants with SCD at an early stage. This usually involves testing a blood sample from newborns to detect abnormal hemoglobin patterns. Early diagnosis through newborn screening allows for early intervention and comprehensive care of affected infants (Adamkiewicz TV et al. 2008).

Complications arise due to the abnormal shape and function of the sickle-shaped red blood cells, leading to vascular occlusion, tissue ischemia and chronic hemolysis:

• Vascular occlusive crisis: Vascular occlusive crisis is the typical complication of SCD and is characterized by the sudden onset of severe pain, often affecting the bones, joints and abdomen. Vascular occlusive disease occurs when sickle-shaped red blood cells clog blood vessels, leading to tissue ischemia, organ damage and severe pain. [24]
• Acute chest syndrome (ACS):ACS is a potentially life-threatening complication characterized by fever, chest pain, coughing and shortness of breath. It is caused by blockage of the pulmonary blood vessels by crescent-shaped red blood cells, resulting in damage to the lung tissue and impaired gas exchange. ACS is a common cause of hospitalization in people with SCD.
• Cerebral apoplexy: People with SCD, especially children, can suffer strokes due to blockage of the blood vessels supplying the brain. Silent cerebral infarctions are common and can lead to cognitive impairment and neurodevelopmental disorders. Transcranial Doppler ultrasonography is used to identify children at high risk of stroke.
• Chronic anemia: Chronic hemolysis and destruction of the sickle-shaped red blood cells lead to chronic anemia in people with SCD. Anemia can lead to fatigue, weakness and reduced exercise tolerance. Regular monitoring of hemoglobin levels and iron status is essential for the treatment of anemia.
• Infections: People with SCD are more susceptible to infections, especially those caused by encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenza. Infections can range from mild to severe and can include pneumonia, meningitis and osteomyelitis. Vaccination against common bacterial pathogens is essential.

Organ damage: SCD can affect various organs and lead to long-term complications:

• Renal complications: SCD-associated nephropathy can lead to kidney damage and renal dysfunction, requiring chronic kidney disease and renal replacement therapy[40].
• Eye complications: SCD can cause retinopathy leading to visual impairment and blindness. Regular eye examinations are required to monitor changes in the retina.
• Priapism: Men with SCD may experience a persistent and painful erection of the penis called priapism. Priapism requires immediate medical attention to avoid permanent damage to the penis.
• Gallbladder disease: SCD increases the risk of gallstones and cholecystitis due to the deposition of bilirubin in the gallbladder. In severe cases, surgical removal of the gallbladder may be necessary.

The treatment of SCD aims to alleviate symptoms, prevent complications and improve the overall quality of life of those affected. The treatment of SCD involves a multidisciplinary approach that takes into account various aspects of the disease.

Supportive measures.

• Pain management: Acute pain attacks, a typical symptom of SCD, are treated with analgesic medications such as non-steroidal anti-inflammatory drugs, opioids and patient-controlled analgesia. Non-drug approaches such as heat therapy, relaxation and distraction techniques may also be used.
• Hydration: Adequate hydration helps to prevent vaso-occlusive crises. Patients are encouraged to drink plenty of fluids, especially if they are at increased risk, such as during infections or extreme temperatures.
• Blood transfusions: In certain situations, such as severe anemia, acute chest syndrome (ACA) or stroke, red blood cell transfusions may be administered. Transfusions help to increase the oxygen-carrying capacity of the blood and reduce the proportion of sickle cells.

1. Adamkiewicz TV et al. (2008) Effectiveness of the 7-valent pneumococcal conjugate vaccine in children with sickle cell disease in the first decade of life. Pediatrics. 121:562-569.
2. Belcher JD et al. (2006) Heme oxygenase-1 is a modulator of inflammation and vaso-occlusion in transgenic sickle mice. J Clin Invest 116:808-816.
3. Bunn HF (1997) Pathogenesis and treatment of sickle cell disease. N Engl J Med 337:762-769.
4. Burg MR et al (2025) Occlusive cutaneous vasculopathies: rare differential diagnoses. J Dtsch Dermatol Ges 23:487-506.
5. El-Hazmi MA et al. (2011) Sickle cell disease in Middle East Arab countries. Indian J Med Res 134:597-610.
6. Hebbel RP (2014) Ischemia-reperfusion injury in sickle cell anemia: relationship to acute chest syndrome, endothelial dysfunction, arterial vasculopathy, and inflammatory pain. Hematol Oncol Clin North Am 28:181-198.
7. Ohene-Frempong K et al. (1998) Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood 91:288-294.
8. Piel FB et al. (2010) Global distribution of the sickle cell gene and geographical confirmation of the malaria hypothesis. Nat Commun1:104.
9. Piel FB et al (2017) Sickle cell disease. N Engl J Med 376:1561-1573.
10. Platt OS et al. (2014) Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med 330:1639-1644.
11. Rees DC et al (2010) Sickle-cell disease. Lancet 376:2018-2031.
12. Solovey A et al. (2004) Endothelial cell expression of tissue factor in sickle mice is augmented by hypoxia/reoxygenation and inhibited by lovastatin. Blood 104:840-846.