Diagnostic Considerations
SCD is suggested by the typical clinical picture of chronic hemolytic anemia and vaso-occlusive crisis. The diagnosis is confirmed when electrophoresis demonstrates the presence of homozygous HbS. In addition to HbSS, this test may also document other hemoglobinopathies (eg, HbSC, HbS-beta+ thalassemia).
Sickling variants and sickle trait must be distinguished from HbS disease. HbS exists in combination with other hemoglobins in a double heterozygous state. The clinically important diseases involved, observed in patients in the United States, are HbSC and Hb-beta thalassemia.
HbSC disease is a milder sickling disorder. It is present in 1 in 1100 African Americans. In the HbC mutation, lysine replaces glutamic acid in position 6 on the beta chain. HbA is not present. The RBCs contain 50% HbS and 50% HbC. Anemia is much milder, with Hb levels of 11 g/dL or higher.
Symptoms of HbSC disease are similar to SCD but less frequent and less severe. Splenomegaly often persists well into adult life. Aseptic necrosis of the femoral head is not more common than in SCD. A proliferative retinopathy may lead to progressive loss of vision.
The diagnosis of HbSC disease is made with Hb electrophoresis. The peripheral blood smear may have some sickled cells and a high proportion of target cells. In addition, microcytic, dehydrated, dense RBCs are seen. These may contain crystal-like condensations. Treatment and management strategies are similar to those employed in Hb S disease.
In HbS–beta 0 thalassemia, only HbS is found on electrophoresis. HbA2 is elevated and splenomegaly usually is present. The clinical picture is similar to SCD but is slightly less severe. Management is similar to that for SCD. In HbS–beta+ thalassemia, Hb A is present, usually between 10% and 30%. The spleen is usually enlarged. This disease is otherwise similar to SCD but is milder.
Sickle cell trait is the heterozygous carrier state of HbS. These individuals have approximately 40% HbS and 60% HbA, less so with coexisting alpha-thalassemia trait.
People with sickle trait generally are well and have the following characteristics:
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Normal life expectancy
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Not at excessive risk for infection
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Not subject to painful crisis under normal circumstances
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No anemia
Nevertheless, providing genetic counseling to prospective parents with sickle cell trait is important. Reports exist of excessive deaths under extreme conditions, such as military basic training involving strenuous exertion; however, this is very uncommon. Similarly, isolated reports exist of organ infarction and crisis under unusual circumstances. Many of these patients lose urine-concentrating capacity. Painless hematuria may be present.
HbS variants may occur as double heterozygotes with other Hb variants. These include HbD, HbE, and HbO Arab. These are observed very infrequently in the United States, and information about them can be found in hematology texts.
Other problems to be considered
Gaucher disease also expands the marrow cavity and causes bone marrow infarction. Unlike sickle cell disease, which causes splenic infarction, Gaucher disease causes splenomegaly.
Depending on the clinical presentation, the differential diagnosis may also include the following:
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Valvular heart disease
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Septic arthritis
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Sepsis
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Upper respiratory tract infection
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Aortic arch syndrome
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Facioscapulohumeral muscular dystrophy
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Incontinentia pigmenti
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Familial exudative vitreoretinopathy
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Lupus erythematosus
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Macroglobulinemia
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Polycythemia vera
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Talc and cornstarch emboli
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Uveitis, including pars planitis
Differential Diagnoses
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Molecular and cellular changes of hemoglobin S.
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Skeletal sickle cell anemia. H vertebrae. Lateral view of the spine shows angular depression of the central portion of each upper and lower endplate.
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Peripheral blood with sickled cells at 400X magnification. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
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Peripheral blood smear with sickled cells at 1000X magnification. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
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Peripheral blood smear with Howell-Jolly body, indicating functional asplenism. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
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Effects of therapy with hydroxyurea.
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Skeletal sickle cell anemia. Bone-within-bone appearance. Following multiple infarctions of the long bones, sclerosis may assume the appearance of a bone within a bone, reflecting the old cortex within the new cortex.
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A 12-year-old boy with HgbSS disease presents to the pediatric emergency department after his mother tried to wake him for school this morning and noted altered mental status, left-sided gaze paralysis with his head tilted to the left, and flaccid paralysis of the right arm and leg. A CT scan of the brain was obtained immediately.
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Embolic stroke of the left middle cerebral artery. SCD is the most common cause of stroke in children and one of the most devastating complications of SCD. Clinically overt strokes are typically due to embolism of the intracranial internal carotid artery and proximal middle cerebral artery (MCA), while "silent strokes" more typically occur in the smaller lacunar and penetrating arteries. As RBCs undergo sickling and hemolysis within the cerebral circulation, they adhere to the vascular endothelium and promote a hypercoaguable state and fuel thromboembolism formation. Treatment options include prophylactic therapy with hydroxyurea to promote HgbF concentrations and monitoring via transcranial Doppler to evaluate MCA blood flow velocity. Children found to have high velocities are at increased risk for stroke and commonly receive RBC transfusions to decrease the concentration of HgbS.
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The spleen enlarges during the first year of life in SCD, as it becomes congested with trapped slow-flowing sickled cells within the splenic sinuses and reticuloendothelial system. The histology image shown demonstrates splenic congestion from sequestered sickled RBCs (arrows). Microvascular occlusions produce chronic tissue hypoxia and microinfarctions. Over time, fibrosis induces autosplenectomy. With functional asplenia, patients are particularly susceptible to infection by the encapsulated organisms Streptococcus pneumoniae and Haemophilus influenzae. Vaccination and prophylactic daily penicillin throughout childhood are mainstays of treatment to prevent sepsis and meningitis
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Splenic sequestration is an important cause of morbidity that occurs when sudden splenic pooling of blood within the reticuloendothelial system causes an acute drop in circulatory volume and shock-like symptoms (hypotension, tachycardia) with a rigid distended abdomen. It is an acute emergency and can be fatal in 1-2 hours secondary to circulatory hypovolemia. Treatment is with volume resuscitation and blood transfusion. The CT image shown demonstrates splenomegaly with a mass-like process (arrows) from splenic sequestration.
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Patients with SCD are also at increased risk of developing pulmonary arterial hypertension (PAH). The etiology is most likely multifactorial but likely related to increased cardiac output secondary to underlying chronic anemia. Impedance to the elevated blood flow will cause further dilation and increase in pulmonary pressures. Postsickling changes including interstitial fibrosis secondary to vaso-occlusive crisis of ACS and hypoperfusion with resultant hypoxia of the pulmonary vascular beds are both proposed offenders inciting further dilation and elevation of pulmonary pressures. A pulmonary arteriogram depicting the markedly dilated vascular supply of the lungs seen in PAH is shown.
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Proliferative sickle cell retinopathy. Sickle cell retinopathy is believed to be vaso-occlusion of peripheral arterioles of the retina leading to retinal hypoxia, ischemia, and infarction. New vessels then form at the junction of the vascular and avascular areas of retina. This neovascularization of retinal tissue and resultant traction of fibrovascularization places patients at risk for vitreous hemorrhage (arrows) and retinal detachment. Another common ocular manifestation is hyphema. Anterior chamber bleeding occurs spontaneously, but sickled erythrocytes obstruct the trabecular meshwork leading to significant elevations of intraocular pressure. Patients are particularly susceptible to glaucomatous optic nerve damage from even mildly elevated intraocular pressures. Pressures greater than 36 mm Hg for 24 hours are an indication for surgical drainage in both SCD and sickle cell trait, regardless of the size of hyphema. Image courtesy of the National Eye Institute, National Institutes of Health (NEI/NIH).
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A 19-year-old man with known HgbSS disease presents because his girlfriend reports his eyes are yellow. He has no complaints. Physical exam is notable for mild abdominal pain, but is otherwise within normal limits. What imaging test is warranted for this work-up? The image shown is of a male child with similar symptoms. Image courtesy of Wikimedia Commons.
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Right upper quadrant ultrasoundChronic hemolysis of sickled cells in HgbSS disease and high heme turnover yields hyperbilirubinemia and is associated with increased formation of bile stones. Stone formation occurs as substances in bile reach concentrations that approach the limits of their solubility. As saturation levels are reached, crystals precipitate, become trapped in mucus, and produce sludge (shown). Over time, the crystals aggregate and form stones. Occlusion of the biliary tree by sludge and/or stones produces clinical disease, typically right upper quadrant pain. The scleral icterus seen in the image of the previous slide is most likely secondary to the elevated circulating levels of bilirubin as a result of an acute hemolytic event (such as an acute vaso-occlusive crisis).
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Renal papillary necrosisThe microvascular beds of the renal parenchyma are susceptible to sickling and vaso-occlusive crisis because of their inherent low-oxygen and high-osmolarity state. Depending on the location of occlusion, symptoms vary from a decreased ability to concentrate urine (yielding nocturia and polyuria), a disruption of exchange mechanisms (yielding hyperkalemia) or hematuria, which further damages renal tubules. In renal papillary necrosis, repeated vascular occlusion infarcts the renal medullary pyramids and papillae. This causes sloughing of papillae, which obstructs the urinary tract. Treatment options include hydration, high-dose antibiotics for resulting pyelonephritis, and possible percutaneous nephrostomy tube or invasive retrieval of sloughed papillae in acute urinary obstruction. The intravenous pyelogram demonstrates the "egg-in-a-cup" appearance of sloughed renal papillae (arrows) secondary to renal papillary necrosis.
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Skeletal sickle cell anemia. Hand-foot syndrome. Soft tissue swelling with periosteal new-bone formation and a moth-eaten lytic process at the proximal aspect of the fourth phalanx.
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Skeletal sickle cell anemia. Advanced dactylitis. Lytic processes are present at the first and fifth metacarpals, along with periostitis, which is most prominent in the third metacarpal.
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Skeletal sickle cell anemia. Expanded medullary cavity. The diploic space is markedly widened due to marrow hyperplasia. Trabeculae are oriented perpendicular to the inner table, giving a hair-on-end appearance.
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Skeletal sickle cell anemia. Detailed view of the expanded medullary cavity in the same patient as in the previous image.
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Skeletal sickle cell anemia. Osteonecrosis. Image shows flattening of the femoral heads with a mixture of sclerosis and lucency characteristic of osteonecrosis.
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Skeletal sickle cell anemia. Osteonecrosis. Detail of the right hip.
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Skeletal sickle cell anemia. Osteonecrosis. Detail of the left hip.
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Skeletal sickle cell anemia. Bone infarct. Image shows patchy sclerosis of the humeral head and shaft representing multiple prior bone infarcts.
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Skeletal sickle cell anemia. Chronic infarcts and secondary osteoarthritis. Image shows advanced changes of irregular sclerosis and lucency on both sides of the knee joint reflecting numerous prior infarcts. The joint surfaces are irregular and the cartilages are narrowed due to secondary osteoarthritis.
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Skeletal sickle cell anemia. Osteonecrosis. Coronal T1-weighted MRI shows a slightly flattened femoral head with a serpentine margin of low signal intensity around an area of ischemic marrow with signal intensity similar to that of fat.
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Skeletal sickle cell anemia. Osteonecrosis in the same patient as in the previous image. Coronal T2-weighted MRI shows a serpentine area of low signal intensity and additional focal areas of abnormal low signal intensity in the femoral head; these findings reflect collapse of bone and sclerosis.
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Skeletal sickle cell anemia. Osteomyelitis. CT scan in a soft tissue window demonstrates a large abscess in the left thigh encircling the femur, with hypoattenuating pus surrounded by a rim of vivid enhancement.
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Skeletal sickle cell anemia. Osteomyelitis and bone-within-bone. Bone-window CT scan in the same patient as in the previous image shows a bone-within-bone appearance (concentric rings of cortical bone) in the right femur. On the left, a sinus tract (cloaca) traverses the lateral aspect of the femoral cortex, and a small, shardlike sequestrum is present deep to the sinus tract.
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Skeletal sickle cell anemia. Bone scan of bone infarct shows an area of increased uptake in the distal femoral metaphysis corresponding to the infarct demonstrated on the previous plain radiograph.
Tables
Tests |
Age |
Frequency |
CBC count with WBC differential, reticulocyte count |
3-24 mo >24 mo |
every 3 mo every 6 mo |
Percent Hb F |
6-24 mo >24 mo |
every 6 mo annually |
Renal function (creatinine, BUN, urinalysis) |
≥ 12 mo |
annually |
Hepatobiliary function (ALT, fractionated bilirubin) |
≥ 12 mo |
annually |
Pulmonary function (transcutaneous O2 saturation) |
≥ 12 mo |
every 6 mo |
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- Overview
- Presentation
- DDx
- Workup
- Approach Considerations
- Baseline Blood Study Abnormalities
- Suggested Routine Clinical Laboratory Evaluations
- Laboratory Studies in the Ill Child
- Additional Tests
- Radiography
- Magnetic Resonance Imaging
- Nuclear Medicine Scans
- Transcranial Doppler Ultrasonography
- Abdominal Ultrasonography
- Echocardiography
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- Treatment
- Approach Considerations
- Hydroxyurea Therapy
- Transfusion
- Management of Ophthalmic Manifestations
- Vaso-Occlusive Crisis Management
- Control of Acute Pain
- Treatment of Acute Chest Syndrome
- Control of Chronic Pain
- Management of Chronic Anemia
- Prevention and Treatment of Infections
- Treatment of Gallstones
- Treatment of Priapism
- Treatment of Leg Ulcers
- Stroke Prevention
- Treatment of Pulmonary Hypertension
- Sickle Cell Nephropathy
- Treatment of Other Complications
- Stem Cell Transplantation
- Diet and Activity Restrictions
- Investigational Treatments
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- Medication Summary
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