Sickle Cell Disease

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

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 Pulmonary Hypertension Pulmonary hypertension is increased pressure in the pulmonary circulation. It has many secondary causes; some cases are idiopathic. In pulmonary hypertension, pulmonary vessels may become constricted... read more .

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 Priapism Priapism is painful, persistent, abnormal erection unaccompanied by sexual desire or excitation. It is most common in boys aged 5 to 10 years and in men aged 20 to 50 years. The penis is composed... read more , 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 Ischemic Stroke Ischemic stroke is sudden neurologic deficits that result from focal cerebral ischemia associated with permanent brain infarction (eg, positive results on diffusion-weighted MRI). Common causes... read more , seizures Seizure Disorders A seizure is an abnormal, unregulated electrical discharge that occurs within the brain’s cortical gray matter and transiently interrupts normal brain function. A seizure typically causes altered... read more , avascular necrosis of the hips, renal concentrating defects, renal papillary necrosis, chronic kidney disease Chronic Kidney Disease Chronic kidney disease (CKD) is long-standing, progressive deterioration of renal function. Symptoms develop slowly and in advanced stages include anorexia, nausea, vomiting, stomatitis, dysgeusia... read more , heart failure Heart Failure (HF) Heart failure (HF) is a syndrome of ventricular dysfunction. Left ventricular (LV) failure causes shortness of breath and fatigue, and right ventricular (RV) failure causes peripheral and abdominal... read more , pulmonary hypertension Pulmonary Hypertension Pulmonary hypertension is increased pressure in the pulmonary circulation. It has many secondary causes; some cases are idiopathic. In pulmonary hypertension, pulmonary vessels may become constricted... read more , 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 Chronic Kidney Disease Chronic kidney disease (CKD) is long-standing, progressive deterioration of renal function. Symptoms develop slowly and in advanced stages include anorexia, nausea, vomiting, stomatitis, dysgeusia... read more and pulmonary embolism Pulmonary Embolism (PE) Pulmonary embolism (PE) is the occlusion of pulmonary arteries by thrombi that originate elsewhere, typically in the large veins of the legs or pelvis. Risk factors for pulmonary embolism are... read more . In addition, rhabdomyolysis Rhabdomyolysis Rhabdomyolysis is a clinical syndrome involving the breakdown of skeletal muscle tissue. Symptoms and signs include muscle weakness, myalgias, and reddish-brown urine, although this triad is... read more 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 Chorionic Villus Sampling All procedures used to diagnose genetic disorders, except ultrasonography, are invasive and involve slight fetal risk. If testing detects a serious abnormality, the pregnancy can be terminated... read more 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 Autoimmune Hemolytic Anemia Autoimmune hemolytic anemia is caused by autoantibodies that react with red blood cells at temperatures ≥ 37° C (warm antibody hemolytic anemia) or < 37° C (cold agglutinin disease). Hemolysis... read more , 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).

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 Pulmonary Embolism (PE) Pulmonary embolism (PE) is the occlusion of pulmonary arteries by thrombi that originate elsewhere, typically in the large veins of the legs or pelvis. Risk factors for pulmonary embolism are... read more 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 Overview of Pneumonia Pneumonia is acute inflammation of the lungs caused by infection. Initial diagnosis is usually based on chest x-ray and clinical findings. Causes, symptoms, treatment, preventive measures, and... read more . 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.

Painful crises are managed with liberal administration of analgesics, usually opioids. IV morphine (continuous or bolus) is effective and safe; meperidine is avoided. During crises, pain and fever may persist for as long as 5 days. Nonsteroidal anti-inflammatory drugs (NSAIDs) are often useful in reducing opioid requirements; however, they must be used cautiously in patients with renal disease.

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

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 Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers ( leukemias, lymphomas, myeloma) and other hematologic disorders... read more 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:

Supplemental folic acid, 1 mg orally once a day, is usually prescribed.

Hydroxyurea, by increasing Hb F and thereby reducing sickling, decreases painful crises (by 50%) and decreases acute chest syndrome and transfusion requirements. It is indicated in patients with recurrent pain crises or other complications. The dose of hydroxyurea is variable and is adjusted based on blood counts and adverse effects. Hydroxyurea causes neutropenia and thrombocytopenia. It is also a teratogen and should not be given to females of child-bearing age.

Three additional drugs are available to treat sickle cell disease. Both L-glutamine and crizanlizumab target vaso-occlusion and were found to decrease pain crises in controlled, randomized studies (1, 2 Treatment references Sickle cell disease (a hemoglobinopathy) causes a chronic hemolytic anemia occurring almost exclusively in people with African ancestry. It is caused by homozygous inheritance of genes for hemoglobin... read more ). L-glutamine is thought to reduce oxidative stress in sickle erythrocytes, while crizanlizumab inhibits P-selectin, which contributes to adhesion of sickle erythrocytes to the vascular endothelium. Voxelotor inhibits polymerization of Hb S, stabilizes oxygenated hemoglobin, and was shown to increase hemoglobin levels in a randomized, controlled trial (3 Treatment references Sickle cell disease (a hemoglobinopathy) causes a chronic hemolytic anemia occurring almost exclusively in people with African ancestry. It is caused by homozygous inheritance of genes for hemoglobin... read more . 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 Secondary Iron Overload Secondary iron overload results from excess absorption of iron, repeated blood transfusions, or excess oral intake, typically in patients with disorders of erythropoiesis. Consequences can include... read more 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.