Sickle Cell Disease (SCD)


Sickle cell disease (SCD), a genetic disorder with autosomal recessive inheritance, is a hemoglobinopathy caused by mutations in the gene that codes for the beta subunit of hemoglobin.1 As a result of the mutations, the form and function of the hemoglobin molecule change, causing red blood cells to take on a sickle shape.2 SCD manifests in a variety of ways, from acute generalized discomfort to the early onset of stroke, leg ulcers, and fatal multiorgan failure. Because of the presence of the fetal form of hemoglobin, HbF, the clinical features of SCD do not appear until the second half of the first year of postnatal life, when the transition to adult hemoglobin takes place.3 

In general, the clinical features associated with sickle cell disease can be divided into 2 types, depending on the underlying cause. Clinical features of the first type are those caused by hemolysis and functional nitric oxide deficiency, which lead to large-vessel vasculopathy manifesting as cerebrovascular disorders, pulmonary hypertension, priapism, nephropathy, and leg ulcers. Clinical features of the second type are those due to vaso-occlusion, which results in ischemic painful episodes and progressive organ damage potentially manifesting as osteonecrosis, hyposplenism, retinopathy, and liver damage.​​4

Acute Clinical Features

Vaso-occlusive Crisis

Vaso-occlusive crisis is the most common presentation of SCD. Blockage of the post-capillary venules causes ischemia, with consequent ischemia-reperfusion injury and acute episodes of painful sickle cell crisis. Patients report excruciating pain in all parts of the body, especially the back, long bones, chest, pelvis, and abdomen. Pain and swelling in both hands and feet may begin in children as young as 6 months of age.4,5 

Acute Chest Syndrome

The most common complication of sickle cell anemia (SCA) is acute chest syndrome (ACS). ACS is also the leading cause of death and the second-leading cause of hospitalization in patients with SCD. Previous episodes of ACS or asthma and recent surgery, pulmonary embolism, fluid overload, and infection are all risk factors for ACS. Shortness of breath and a cough of sudden onset are 2 clinical characteristics. Fever, if present, is a sign of infection.1

Anemia 

The most prevalent manifestation of SCD is symptomatic anemia, which is more common in HbSS. Steady-state hemoglobin levels in asymptomatic patients differ according to their phenotype, varying from 60 to 80 g/L in those with HbSS or HbSβ0-thal to 100 to 110 g/L in those with double heterozygous HbSC or HbSβ+-thal variants of disease. A rapid fall in an individual’s steady-state hemoglobin level can cause hypoxia (aplastic crisis) or a shocklike state such as acute splenic sequestration.3 

Jaundice

Because of the premature breakdown of sickled RBCs, levels of bilirubin are increased, leading to jaundice. If the bilirubin remains elevated for a long time, gallstones may form.6 

Infectious Disease

Infection is a major cause of morbidity and mortality in patients with SCD. Functional asplenia, which is evident from a young age, is the main reason for the predisposition to bacterial infection. Streptococcus pneumoniae is the most common pathogen; however, serious systemic infections with Haemophilus influenzae, Neisseria meningitidis, and Salmonella are also seen.4 

Cerebrovascular Accident/Stroke

Cerebrovascular accident (CVA) can occur in children starting at the age of 2 years. Eleven percent of patients with SCD have a stroke by the age of 20 years. Silent cerebral infarct (SCI) in association with small-vessel disease is more frequent than overt stroke. Signs of SCI are seen in 34% of patients with SCD by the age of 14 years.5 

Acute Kidney Injury

In acute kidney injury, also known as acute renal failure, a sudden collapse of kidney function leads to increased serum creatinine levels and/or decreased urine output. Vaso-occlusion causes ischemic changes in the renal medulla. Contributing factors for volume depletion include hyposthenuria, recurrent and chronic use of nonsteroidal anti-inflammatory medications (NSAIDs), severe hemolysis, infection, and rhabdomyolysis.4 

Splenic Sequestration

Splenic sequestration is a fatal complication of SCD in which an abrupt fall in hemoglobin levels causes severe abdominal discomfort and collapse of the circulatory system. It is more common in children, particularly in those with HbSS. Sequestration is caused by a splenic auto-infarction that occurs at approximately the age of 6 years.This complication may also develop in adults with HbSC and other hemoglobinopathies.5 

Hepatobiliary Complications

The hepatobiliary tract is one of the intra-abdominal organ systems most frequently affected in SCD. Sickle hepatopathy comprises a range of acute and chronic liver abnormalities (eg, vaso-occlusive hypoxic liver injury, cholelithiasis, sequestration in the liver, venous outflow obstruction, intrahepatic cholestasis, viral hepatitis, and biliary cirrhosis) seen in patients with SCD.4

Priapism 

Priapism is an unwanted and protracted state of penile erection, with or without pain, that occurs without any sexual stimulation. Priapism may be ischemic (veno-occlusive, low flow), stuttering (recurrently ischemic), or non-ischemic (arterial, high flow). Most cases of priapism in SCD are ischemic in nature.4 

Chronic Clinical Features/Complications

In addition to acute episodes of vaso-occlusive pain, patients with SCD have chronic pain.4 Pulmonary arterial hypertension (PAH) afflicts 6% to 11% of individuals with SCA.1 Renal complications also occur frequently. In adults, chronic renal failure may develop in 30% of cases.5 One of the most severe musculoskeletal manifestations of SCD is avascular necrosis, also called osteonecrosis or ischemic necrosis.

Blockage of the peripheral retinal vasculature results in proliferative retinopathy. This is the most frequent ophthalmological complication of SCD. It is more common in HbSC, seen in up to 70% cases.5 

Leg ulcers develop in locations where subcutaneous fat is less abundant and blood flow is reduced. The malleoli of each ankle is the most commonly afflicted area.4’

References

  1. Mangla A, Ehsan M, Agarwal N, Maruvada S. Sickle cell anemia. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2021.
  2. Tanabe P, Spratling R, Smith D, Grissom P, Hulihan M. CE: Understanding the complications of sickle cell disease. Am J Nurs. 2019;119(6):26-35. doi:10.1097/01.NAJ.0000559779.40570.2c
  3. Inusa BPD, Hsu LL, Kohli N, et al. Sickle cell disease—genetics, pathophysiology, clinical presentation and treatment. Int J Neonatal Screen. 2019;5(2):20. doi:10.3390/ijns5020020
  4. Houwing ME, de Pagter PJ, van Beers EJ, et al. Sickle cell disease: clinical presentation and management of a global health challenge. Blood Rev. 2019;37:100580. doi:10.1016/j.blre.2019.05.004
  5. Sedrak A, Kondamudi NP. Sickle cell disease. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2021.
  6. Sickle cell disease (for teens). Hematology at Nemours Children’s Health. Reviewed July 2018. Accessed November 29, 2021.

Reviewed by Kyle Habet, MD, on 11/30/2021.

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