Hemoglobinopathies are genetic disorders affecting the hemoglobin molecule. Hemoglobin S was the first abnormal hemoglobin to be identified. Homozygotes (about 0.3% of blacks in the United States) have sickle cell anemia; heterozygotes (8 to 13% of blacks) are typically not anemic but have an increased risk of other complications.
Pathophysiology of Sickle Cell Disease
Hemoglobin (Hb) molecules consist of polypeptide chains whose chemical structure is genetically controlled. The normal adult hemoglobin molecule (Hb A) consists of 2 pairs of chains designated alpha and beta. Normal adult blood also contains ≤ 2.5% hemoglobin A2 (composed of alpha and delta chains) and < 2% hemoglobin F (fetal hemoglobin), which has gamma chains in the place of beta chains (see also Hemoglobinopathies in Pregnancy Hemoglobinopathies in Pregnancy Normally during pregnancy, erythroid hyperplasia of the marrow occurs, and red blood cell (RBC) mass increases. However, a disproportionate increase in plasma volume results in hemodilution... read more ). Hemoglobin F predominates during gestation and gradually decreases, particularly in the first months of life; its concentration increases in certain disorders of hemoglobin synthesis and in aplastic anemia Aplastic Anemia Aplastic anemia is a disorder of the hematopoietic stem cell that results in a loss of blood cell precursors, hypoplasia or aplasia of bone marrow, and cytopenias in two or more cell lines ... read more and myeloproliferative neoplasms Overview of Myeloproliferative Neoplasms Myeloproliferative neoplasms are clonal proliferations of bone marrow stem cells, which can manifest as an increased number of platelets, red blood cells (RBCs), or white blood cells (WBCs)... read more .
Some hemoglobinopathies result in anemias that are severe in patients who are homozygous but mild in those who are heterozygous. Some patients are compound heterozygotes for 2 different hemoglobinopathies and have anemia of varying severity.
Different hemoglobins (Hbs), as distinguished by electrophoretic mobility, are alphabetically designated in order of discovery (eg, A, B, C), although the first abnormal hemoglobin, sickle cell hemoglobin, was designated Hb S. Structurally different hemoglobins with the same electrophoretic mobility are named for the city or location in which they were discovered (eg, Hb S Memphis, Hb C Harlem). Standard description of a patient’s hemoglobin composition places the hemoglobin of greatest concentration first (eg, AS in sickle cell trait).
In the US, important anemias are caused by genetic mutations resulting in Hb S or Hb C disease Hemoglobin C Disease Hemoglobin C disease is a hemoglobinopathy that causes symptoms of a hemolytic anemia. (See also Overview of Hemolytic Anemia.) The prevalence of hemoglobin (Hb) C in blacks in the US is about... read more , and the thalassemias Thalassemias Thalassemias are a group of inherited microcytic, hemolytic anemias characterized by defective hemoglobin synthesis. Alpha-thalassemia is particularly common among people of African, Mediterranean... read more . Immigration of people of Southeast Asian ancestry has made Hb E disease Hemoglobin E Disease Homozygous hemoglobin E (Hb E) disease is a hemoglobinopathy that causes a mild hemolytic anemia, usually without splenomegaly. (See also Overview of Hemolytic Anemia.) Hemoglobin (Hb) E is... read more common.
In hemoglobin S, valine is substituted for glutamic acid in the 6th amino acid of the beta chain. Oxygenated Hb S is much less soluble than oxygenated Hb A; it forms a semisolid gel that causes red blood cells (RBCs) to deform into a sickle shape at sites of low PO2. Distorted, inflexible RBCs adhere to vascular endothelium and plug small arterioles and capillaries, which leads to infarction. Vaso-occlusion also causes endothelial injury, which results in inflammation and can lead to thromboses. Because sickled RBCs are fragile, the mechanical trauma of circulation causes hemolysis (see Overview of Hemolytic Anemia Overview of Hemolytic Anemia At the end of their normal life span (about 120 days), red blood cells (RBCs) are removed from the circulation. Hemolysis is defined as premature destruction and hence a shortened RBC life span... read more ). Chronic compensatory marrow hyperactivity deforms the bones.
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 ischemia, tissue hypoxia, and infarction, typically of the bones, but also of the spleen, lungs, or kidneys.
Aplastic crisis occurs when 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 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.
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, 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 failure causes shortness of breath and fatigue, and right ventricular failure causes peripheral and abdominal fluid... 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 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.
Symptoms and Signs of Sickle Cell Disease
Most symptoms occur only in patients who are homozygous and result from
Vaso-occlusive events resulting in tissue ischemia and infarction
Anemia is usually severe but varies among patients and is usually compensated; mild jaundice Jaundice Jaundice is a yellowish discoloration of the skin and mucous membranes caused by hyperbilirubinemia. Jaundice becomes visible when the bilirubin level is about 2 to 3 mg/dL (34 to 51 micromol/L)... read more and pallor are common.
Hepatosplenomegaly is common in children, but because of repeated infarctions and subsequent fibrosis (autosplenectomy), the spleen in adults is commonly atrophied. Cardiomegaly and systolic ejection (flow) murmurs are common. Cholelithiasis Cholelithiasis Cholelithiasis is the presence of one or more calculi (gallstones) in the gallbladder. In developed countries, about 10% of adults and 20% of people > 65 years have gallstones. Gallstones tend... read more and chronic punched-out skin ulcers around the ankles are common.
Painful vaso-occlusive crisis causes severe pain in long bones, the hands and feet, back, and joints. Hip pain may result from avascular necrosis of the femoral head. Severe abdominal pain may develop with or without vomiting and is usually accompanied by back and joint pain.
Acute chest syndrome is characterized by sudden onset of fever, chest pain, and pulmonary infiltrates. It may follow bacterial pneumonia. Hypoxemia may develop rapidly, causing dyspnea.
Diagnosis of Sickle Cell Disease
DNA testing (prenatal diagnosis)
Hemoglobin electrophoresis (or thin-layer isoelectric focusing)
The type of testing done depends on the age of the patient. DNA testing can be used for prenatal diagnosis or to confirm a diagnosis of the sickle cell genotype. Screening of neonates is available in most US states and involves hemoglobin electrophoresis. Screening and diagnosis in children and adults involve examination of the peripheral smear, hemoglobin solubility testing, and hemoglobin electrophoresis.
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 Genetic evaluation is part of routine prenatal care and is ideally done before conception. The extent of genetic evaluation a woman chooses is related to how the woman weighs factors such as... 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.
Screening and diagnosis of children and adults
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, aseptic necrosis of the femoral head, unexplained hematuria), and black patients 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 red blood cells 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.
Evaluation of exacerbations
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.
Prognosis for Sickle Cell Disease
The life span of homozygous patients has steadily increased to > 50 years. Common causes of death are acute chest syndrome, intercurrent infections, pulmonary emboli, infarction of a vital organ, and chronic kidney disease.
Treatment of Sickle Cell Disease
Broad-spectrum antibiotics (for infection)
Analgesics and IV hydration (for vaso-occlusive pain crisis)
Immunizations, folic acid supplementation, and hydroxyurea (for health maintenance)
Treatment includes regular health maintenance measures as well as specific treatment of the complications as they arise. Complications are treated supportively. No effective in vivo anti-sickling drug is available. Splenectomy is valueless.
Indications for hospitalization include suspected serious (including systemic) infection, aplastic crisis, acute chest syndrome, and, often, intractable pain or the need for transfusion. Fever alone may not be a reason to hospitalize. However, patients who appear acutely ill and have a temperature > 38° C should be admitted so that cultures can be obtained from multiple areas and IV antibiotics can be given.
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.
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
Cardiopulmonary symptoms or signs (eg, high-output heart failure, hypoxemia with PO2 < 65 mm Hg)
Life-threatening events that would benefit from improved oxygen delivery (eg, sepsis, severe infection, acute chest syndrome, stroke, acute organ ischemia)
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:
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
Use of hydroxyurea and folate supplementation
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.
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 HbS 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.
Three drugs have recently become 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. Voxelotor functions by stabilizing oxygenated hemoglobin and was shown to increase hemoglobin levels. While these drugs are currently being incorporated into treatment regimens for sickle cell patients, data on their efficacy remain limited.
Patients homozygous for hemoglobin S have an abnormal beta chain, resulting in fragile, relatively inflexible red blood cells that can plug capillaries, causing tissue infarction and that are prone to hemolysis, causing anemia.
Patients have various acute exacerbations including painful crisis, sequestration crisis, aplastic crisis, and acute chest syndrome.
Long-term consequences include pulmonary hypertension, chronic kidney disease, stroke, aseptic necrosis, and increased risk of infection.
Diagnose using hemoglobin electrophoresis.
For acute crises, give opioid analgesics for pain, check for worsening anemia (suggesting aplastic or sequestration crisis) and signs of acute chest syndrome or infection, restore normal intravascular volume using 0.9% saline and then give maintenance fluids.
Prevent infection by using vaccinations and prophylactic antibiotics; limit painful crises and risk of acute chest syndrome by giving hydroxyurea.
The following is an English-language resource that may be useful. Please note that THE MANUAL is not responsible for the content of this resource.
Sickle Cell Disease Association of America: provides comprehensive patient education and support, including peer mentoring, to patients with sickle cell disease