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 as well as other factors 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 males.

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, moyamoya, seizures, avascular necrosis, 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 (1). In addition, rhabdomyolysis may occur rarely 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 patients who are homozygous, and there is an association with the extremely rare medullary carcinoma of the kidney.

1. 1. Naik RP, Smith-Whitley K, Hassell KL, et al. Clinical Outcomes Associated With Sickle Cell Trait: A Systematic Review. Ann Intern Med 2018;169(9):619-627. doi:10.7326/M18-1161

PCR (polymerase chain reaction) is sensitive when used for prenatal diagnosis. 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 recommended. Testing for sickle cell disease is frequently one of a battery of newborn screening tests. To distinguish between hemoglobin (Hb) F, Hb S, Hb A, and Hb 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 and normocytic anemia (particularly if hemolysis is present) require laboratory tests for hemolytic anemia, hemoglobin electrophoresis, and examination of RBCs for sickling. 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 hemoglobinopathies by electrophoresis showing only Hb S with a variable amount of Hb F. The heterozygous state is differentiated by the presence of more Hb A than Hb S on electrophoresis.

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 severe infections or crisis. 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. Vaso-occlusive crisis is a clinical diagnostic and cannot be confirmed by specific laboratory findings, though certain lab findings may suggest the severity of the presentation and risk for decompensation (e.g. thrombocyopenia, reticulocytopenia, elevation in liver function tests or creatinine, and troponin elevation).

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. New hypoxemia without pulmonary infiltrates may suggest 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 systematically studied. 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, acute 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. If the initial hemoglobin is low (< 7 g/dL [< 70 g/L]), an exchange transfusion 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 increase the amount of Hb F recently became available. This field is rapidly evolving, and use of stem cell therapy to treat sickle cell disease will likely continue to expand.

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

• Pneumococcal, Haemophilus influenzae (inactivated, not live), and meningococcal vaccines.. COVID-19 and influenza vaccinations are also recommended. RSV vaccination may be beneficial in adults over 60 years.

• Early identification and treatment of serious bacterial infections

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

1, 2); it decreases acute chest syndrome and transfusion requirements (2

3, 45). While these medications are incorporated into treatment regimens for patients with sickle cell disease, data on their efficacy are limited and conflicting.

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. Charache S, Terrin ML, Moore RD, et al: Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med 332(20):1317–1322, 1995. doi:10.1056/NEJM199505183322001

2. 2. Rankine-Mullings AE, Nevitt SJ: Hydroxyurea (hydroxycarbamide) for sickle cell disease. Cochrane Database Syst Rev 9(9):CD002202, 2022. Published 2022 Sep 1. doi:10.1002/14651858.CD002202.pub3

3. 3. 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

4. 4. 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

5. 5. 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

1. 1. Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med 1994;330(23):1639-1644. doi:10.1056/NEJM199406093302303

2. 2. Wierenga KJ, Hambleton IR, Lewis NA. Survival estimates for patients with homozygous sickle-cell disease in Jamaica: a clinic-based population study. Lancet 2001;357(9257):680-683. doi:10.1016/s0140-6736(00)04132-5