Sickle Cell Disease

Acute exacerbations (crises) occur intermittently, often for no known reason. In some cases, crisis appears to be precipitated by

• Fever

• Viral infection

• Local trauma

Vaso-occlusive crisis (pain crisis) is the most common type; it is caused by tissue hypoxia and leads to ischemia and infarction, typically in the bones, but also in the spleen, lungs, or kidneys.

Aplastic crisis occurs when bone marrow erythropoiesis slows during acute infection due to human parvovirus, during which an acute erythroblastopenia may occur.

Acute chest syndrome results from pulmonary microvascular occlusion and is a common cause of death, with mortality rates of up to 10%. It occurs in all age groups but is most common in childhood. Repeated episodes predispose to chronic pulmonary hypertension.

Sequestration crisis typically occurs in children whose spleen has not yet become fibrotic due to repeated splenic infarction. Acute sequestration of sickled cells in the spleen exacerbates anemia.

Hepatic sequestration may occur in children or adults, causing right upper quadrant pain. Rapid enlargement of the liver can occur and may be accompanied by intrahepatic cholestasis and renal failure.

Priapism, a serious complication that can cause erectile dysfunction, is most common in young men.

Chronic spleen damage can lead to autoinfarction and increases susceptibility to infection, particularly pneumococcal and Salmonella infections (including Salmonella osteomyelitis). These infections are especially common in early childhood and can be fatal.

Recurrent ischemia and infarction can cause chronic dysfunction of multiple different organ systems. Complications include ischemic stroke, seizures, avascular necrosis of the hips, renal concentrating defects, renal papillary necrosis, chronic kidney disease, heart failure, pulmonary hypertension, pulmonary fibrosis, and retinopathy.

Patients who are heterozygous (Hb AS) do not experience hemolysis or painful crises. However, they do have an increased risk of chronic kidney disease and pulmonary embolism. In addition, rhabdomyolysis and sudden death may occur during sustained, exhausting exercise. Impaired ability to concentrate urine (hyposthenuria) is common. Unilateral hematuria (by unknown mechanisms and usually from the left kidney) can occur but is self-limited. Typical renal papillary necrosis can occur but is less common than among homozygous patients, and there is an association with the extremely rare medullary carcinoma of the kidney.

The sensitivity of prenatal diagnosis has been greatly improved with the availability of PCR (polymerase chain reaction) technology. It is recommended for families at risk for sickle cell (eg, couples with medical or family histories of anemia or of suggestive ethnic background). DNA samples can be obtained by chorionic villus sampling at 10 to 12 weeks' gestation. Amniotic fluid can also be tested at 14 to 16 weeks. Diagnosis is important for genetic counseling.

Universal testing is currently recommended and is frequently one of a battery of newborn screening tests. To distinguish between hemoglobin (Hb) F, S, A, and C, the recommended tests are hemoglobin electrophoresis using cellulose acetate or acid citrate agar, thin-layer isoelectric focusing, or hemoglobin fractionation by high performance liquid chromatography (HPLC). Repeat testing at age 3 to 6 months may be necessary for confirmation. Solubility testing for Hb S is unreliable during the first few months of life.

Patients with a family history of sickle cell disease or trait should be screened with peripheral smear, hemoglobin (Hb) solubility testing, and hemoglobin electrophoresis.

Patients with symptoms or signs suggesting the disorder or its complications (eg, poor growth, acute and unexplained bone pain, particularly in the fingers, aseptic necrosis of the femoral head, unexplained hematuria), and patients with African ancestry with normocytic anemia (particularly if hemolysis is present) require laboratory tests for hemolytic anemia, hemoglobin electrophoresis, and examination of RBCs for sickling. If sickle cell disease is present, the red blood cell count is usually between 2 and 3 million/microL (2 and 3 x 10¹²/L) with hemoglobin reduced proportionately; cells are normocytic (microcytosis suggests a concomitant alpha or beta thalassemia). Nucleated RBCs frequently appear in the peripheral blood, and reticulocytosis ≥ 10% is common. Dry-stained smears may show sickled RBCs (crescent-shaped, often with elongated or pointed ends).

Sickle Cells

Image

By permission of the publisher. From Tefferi A, Li C. In Atlas of Clinical Hematology. Edited by JO Armitage. Philadelphia, Current Medicine, 2004.

The homozygous state is differentiated from other sickle hemoglobinopathies by electrophoresis showing only Hb S with a variable amount of Hb F. The heterozygote is differentiated by the presence of more Hb A than Hb S on electrophoresis. Hb S must be distinguished from other hemoglobin types with a similar electrophoretic pattern by showing the pathognomonic RBC morphology.

Bone marrow examination is not used for diagnosis. If it is done to differentiate other anemias, it shows hyperplasia, with normoblasts predominating; bone marrow may become aplastic during sickling or severe infections. The erythrocyte sedimentation rate, if done to exclude other disorders (eg, juvenile rheumatoid arthritis causing hand and foot pain), is low.

Incidental findings on skeletal x-rays may include widening of the diploic spaces of the skull and a sun-ray appearance of the diploic trabeculations. The long bones often show cortical thinning, irregular densities, and new bone formation within the medullary canal.

Unexplained hematuria, even among patients not suspected of having sickle cell disease, should prompt consideration of sickle cell trait.

If patients with known sickle cell disease have acute exacerbations, including pain, fever, or other symptoms of infection, aplastic crisis is considered and a complete blood count and reticulocyte count are done. A reticulocyte count < 1% suggests aplastic crisis, particularly when hemoglobin decreases below the patient’s usual level. In a painful crisis without aplasia, the white blood cell count rises, often with a shift to the left, particularly during bacterial infection. The platelet count is usually increased but can fall with the acute chest syndrome. If measured, serum bilirubin is usually elevated (eg, 2 to 4 mg/dL [34 to 68 micromol/L]), and urine may contain urobilinogen.

In patients with chest pain or difficulty breathing, acute chest syndrome and pulmonary embolism are considered; chest x-ray and pulse oximetry are necessary. Because acute chest syndrome is the leading cause of death in sickle cell disease, early recognition and treatment are critical. Hypoxemia or pulmonary parenchymal infiltrates on chest x-ray suggest acute chest syndrome or pneumonia. Hypoxemia without pulmonary infiltrates suggests pulmonary embolism.

In patients with fever, infection and acute chest syndrome are considered; cultures, chest x-ray, and other appropriate diagnostic tests are done.

Patients with suspected serious bacterial infections or acute chest syndrome require broad-spectrum antibiotics immediately.

Although dehydration contributes to sickling and may precipitate crises, it is unclear whether vigorous hydration is helpful during crises. Nevertheless, maintaining normal intravascular volume has been a mainstay of therapy.

Oxygen is given if needed to treat hypoxia.

Transfusion is given in many situations in which its efficacy has not been demonstrated. However, chronic transfusion therapy is indicated for prevention of recurrent cerebral thrombosis, especially in children, in an effort to maintain the Hb S percentage less than 30%.

In the acute setting, specific indications for transfusion include

• Acute splenic sequestration

• Aplastic crises

• Cardiopulmonary symptoms or signs (eg, high-output heart failure, hypoxemia with PO2 < 65 mm Hg)

• Preoperative use

• Priapism

• Life-threatening events that would benefit from improved oxygen delivery (eg, sepsis, severe infection, acute chest syndrome, stroke, acute organ ischemia)

• Sometimes pregnancy

Transfusion is not helpful during an uncomplicated painful crisis.

Simple transfusion can be done when the goal is to correct anemia, such as during aplastic crisis or splenic or hepatic sequestration. Exchange transfusion is done during severe acute events such as the acute chest syndrome or stroke in order to decrease the Hb S percentage and prevent ischemia. It can be done with modern apheresis machines. If the initial hemoglobin is low (< 7 g/dL [< 70 g/L]), this process cannot be initiated before first transfusing red cells. Partial exchange transfusion minimizes iron accumulation and hyperviscosity.

Hematopoietic stem cell transplantation remains the only curative treatment for sickle cell disease. Given the risks associated with this therapy, it is generally restricted to patients with advanced disease complications.

Gene therapy or gene editing techniques that reduce the amount of Hb S are currently in clinical trials. This field is rapidly evolving and use of stem cell therapy to treat sickle cell disease will likely expand in the near future.

For long-term management the following interventions have reduced mortality, particularly during childhood:

• Pneumococcal, Haemophilus influenzae influenza (inactivated, not live), and meningococcal vaccines

• Early identification and treatment of serious bacterial infections

• Prophylactic antibiotics, including continuous prophylaxis with oral penicillin from age 4 months to 6 year

1, 23. While these drugs are currently being incorporated into treatment regimens for sickle cell patients, data on their efficacy remain limited.

Transcranial Doppler flow studies in children can help predict risk of stroke, and many experts recommend annual screening for children from age 2 to 16 years. Children at high risk appear to benefit from prophylactic, chronic exchange transfusions to keep Hb S at < 30% of total hemoglobin; iron overload is common and must be screened for and treated.

For patients receiving frequent red cell transfusions, chelation therapy to prevent or delay complications due to iron overload should be considered.

1. 1. Ataga KI, Kutlar A, Kanter J, et al: Crizanlizumab for the prevention of pain crises in sickle cell disease. N Engl J Med 376(5):429–439, 2017. doi: 10.1056/NEJMoa1611770

2. 2. Niihara Y, Miller ST, Kanter J, et al: A phase 3 trial of l-glutamine in sickle cell disease. N Engl J Med 379(3):226–235, 2018. doi: 10.1056/NEJMoa1715971

3. 3. Vichinsky E, Hoppe CC, Ataga KI, et al: A phase 3 randomized trial of voxelotor in sickle cell disease. N Engl J Med 381(6):509–519, 2019. doi: 10.1056/NEJMoa1903212