eMedicine Specialties > Pediatrics: General Medicine > Hematology

Sickle Cell Anemia

Author: Ashok B Raj, MD, Associate Professor, Section of Pediatric Hematology and Oncology, Department of Pediatrics, Kosair Children's Hospital, University of Louisville
Coauthor(s): Salvatore Bertolone, MD, Director, Division of Pediatric Hematology/Oncology, Department of Pediatrics, Kosair Children's Hospital; Professor, University of Louisville School of Medicine
Contributor Information and Disclosures

Updated: Jul 9, 2009

Introduction

Background

Sickle cell disease denotes all genotypes that contain at least 1 sickle gene in which hemoglobin (Hb)S makes up at least half of the Hb present. In addition to homozygotic HbSS (sickle cell anemia), in which only HbS is produced, at least 5 other major genotypes are linked to the disease. These include the following:

• HbS– β -0 thalassemia - Severe double heterozygote for HbS and β -0 thalassemia; almost indistinguishable from sickle cell anemia phenotypically
• HbSC disease - Double heterozygote for HbS and HbC, with intermediate clinical severity
• HbS/hereditary persistence of fetal Hb (S/HPHP) - Mild form or symptom free
• HbS/HbE syndrome - Rare and generally mild clinical course
• Rare combinations of HbS with HbD Los Angeles, HbO Arab, G-Philadelphia, among others

Sickle cell anemia is the most severe and most common form. Affected individuals present with a wide range of clinical problems that result from vascular obstruction and ischemia. Although a diagnosis of the disease can be made at birth, clinical abnormalities usually do not occur before age 6 months, when functional asplenia develops. Functional asplenia results in susceptibility to overwhelming infection with encapsulated respiratory bacteria. Subsequently, other organs are damaged. Typical manifestations include recurrent pain and progressive incremental infarction.

Pathophysiology

The molecular defect responsible for the diverse manifestations of sickle cell disease is the substitution of valine for glutamic acid at the sixth position of the β -globin chain. The association of heme plus 2 normal alpha-globin and 2 abnormal β -globin chains forms HbS. It carries oxygen normally but begins to form semisolid aggregate structures once oxygen is unloaded to the tissues. These HbS aggregates distort RBCs and cause them to lose their normal elasticity.

At first, HbS retains its ability to return to its soluble form, and red cells can regain their elasticity upon reoxygenation. However, this process harms red cells, and, with repeated deoxygenation cycles, permanent red-cell damage ensues. Although HbS polymerization and red cell sickling under deoxygenated conditions are central to the pathophysiology of this disease, growing evidence indicates that sickle cell disease is a state of inflammation characterized by vascular endothelium activation and increased blood cell–endothelium interactions. Abnormal interaction of sickle red cells with vascular endothelium is considered a key contributor to the initiation of vaso-occlusion in this disease.

In addition to leukocyte recruitment, inflammatory activation of endothelium may have an indispensable role in enhanced sickle red cell–endothelium interactions. Sickle red cell adhesion in postcapillary venules can cause increased microvascular transit times and initiate vaso-occlusion. Several studies have shown involvement of an array of adhesion molecules expressed on sickle red cells (CD36, α -4-β -1 integrin, ICAM-4, basal cell adhesion molecule [B-CAM]), activated endothelium (P-selectin, vascular cell adhesion molecule-1 [VCAM-1], alpha-V-beta-3 integrin), and an important role of plasma factors and adhesive proteins (thrombospondin [TSP], von Willebrand factor [vWf], laminin) in this interaction.

For example, the induction of VCAM-1 and P-selectin on activated endothelium is known to enhance sickle red cell interactions. In addition, α -V-β -3 integrin is up-regulated in activated endothelium in patients with sickle cell disease. α -V-β -3 integrin binds to several adhesive proteins (TSP, vWf, red-cell ICAM-4, and, possibly, soluble laminin) involved in sickle red cell adhesion, and antibodies to this integrin dramatically inhibit sickle red cell adhesion. In addition, under inflammatory conditions, increased leukocyte recruitment in combination with adhesion of sickle red cells may further contribute to stasis.

Frequency

United States

In the United States, approximately 8% of blacks have the sickle trait, and 1 in 500 have the disease. Prevalence among individuals whose families originated from the Caribbean, Central America, or South America is approximately 4%, and their disease prevalence at birth is approximately 1 in 2000.

International

The  mutation that results in HbS is believed to have originated in several locations in Africa and India. Its prevalence varies but is high in these countries because of the survival advantage to heterozygotes in regions of endemic malaria. As a result of migration, both forced and voluntary, it is now found worldwide.

Mortality/Morbidity

Data generated prior to the use of penicillin prophylaxis demonstrated a median survival age of 42 black population. Earlier diagnosis and improved supportive care were expected to substantially decrease mortality for children. A careful study of a large cohort, identified through newborn screening and treated in a single comprehensive sickle cell center, found the predicted overall survival rate of patients with HbSS and Hb S– β -0 at age 18 years to be 86%.

Race

In the United States, sickle cell disease is primarily found in the black population. Sickle cell disease is also found in individuals who are originally from Central America, South America, and the Caribbean. The disease also occurs in individuals of Arab, East Indian, Greek, or Italian descent.

Sex

HbS is transmitted as an autosomal codominant characteristic. The male-to-female ratio is equal.

Age

Clinical characteristics are generally not seen in children younger than 6 months, when fetal Hb levels sufficiently decline for abnormalities caused by HbS to be recognized.

Clinical

History

Sickle cell anemia results in several complications. Clinical severity widely varies, and patients may exhibit some or all of the symptoms described.

• Anemia
  • Repeated cycles of deoxygenation and morphologic sickling irreversibly damage red cell membranes and result in hemolysis. Bone marrow increases red cell production but is unable to compensate for the rate of hemolysis. This results in moderate-to-severe anemia.
  • Children exhibit few manifestations of anemia because they readily adjust by increasing heart rate and stroke volume; however, they have decreased stamina, which may be noted on the playground or when participating in physical education class.
  • Acute anemic episodes may be due to many causes, including aplastic crisis, splenic sequestration crisis, delayed transfusion reactions from alloantibodies, or, rarely, through hepatic sequestration or hyperhemolysis.
  • Infection with parvovirus B-19 frequently causes aplastic crises. This virus causes "fifth disease," a normally benign childhood disorder associated with fever, malaise, and a mild rash. The virus has trophism for erythroid progenitor cells and impairs cell division for a few days during the infection. Healthy people experience, at most, a slight drop in hematocrit, since the half-life of erythrocytes in the circulation is 40-60 days.
  • The picture is different in patients with hemolytic anemias, who maintain reasonable hematocrits only through increased production of new red cells. A shutdown in erythroid production for a few days in these patients can lead to potentially deadly declines in hematocrit. Often, but not always, aplastic crises coincide with painful crises. In patients with sickle cell disease, the reticulocyte count should be checked upon admission to the emergency room or to the hospital. Treatment of aplastic crisis is supportive, with transfusions to maintain an acceptable hematocrit until marrow activity is restored.
  • Splenic sequestration occurs with highest frequency during the first 5 years of life in children with sickle cell anemia. Splenic sequestration occurs at any age in individuals with other sickle syndromes. This complication is characterized by the onset of life-threatening anemia with rapid enlargement of the spleen and high reticulocyte count.
  • Splenic sequestration is a medical emergency that demands prompt and appropriate treatment. Parents should be familiar with the signs and symptoms of splenic sequestration crisis. Children should be seen as rapidly as possible in the emergency room. Treatment of the acute episode requires early recognition, careful monitoring, and aggressive transfusion support. Because these episodes tend to recur, many advocate long-term transfusion in young children and splenectomy in older children.
• Infection
  • As hemoglobin (Hb)S replaces fetal Hb in the early months of life, problems associated with sickling and red cell membrane damage begin. The resulting rigid cells progressively obstruct and damage the spleen, which leads to functional asplenia. This, along with other abnormalities, results in extreme susceptibility to infection.
  • Organisms that pose the greatest danger include encapsulated respiratory bacteria, particularly Streptococcus pneumoniae. The mortality rate of such infections has been reported to be as high as 10-30%. Consider osteomyelitis when dealing with a combination of persistent pain and fever. Bone that is involved with infarct-related vaso-occlusive pain is prone to infection. Staphylococcus and Salmonella are the 2 most likely organisms responsible for osteomyelitis.
  • Meningitis is 200 times more common in children with HbSS. Consider lumbar puncture in children with fever who appear toxic and in those with neurologic findings such as neck stiffness, positive Brudzinski or Kernig signs, or focal deficits. Meningeal signs are not reliable if the children are irritable and inconsolable.
  • Treatment includes early recognition; aggressive diagnostic evaluation including CBC count, urinalysis, chest radiographs, and blood cultures; prompt administration of intravenous antibiotics active against S pneumoniae; and close observation. Children younger than 12 months with a temperature of higher than 390C who appear toxic, with an infiltrate on chest radiograph and an elevated WBC count, should be admitted to the hospital. Consider only outpatient treatment if no high-risk features appear on history, physical examination, or laboratory evaluation; if the child is older than 12 months; and if outpatient follow-up care can be ensured.
• Acute chest syndrome
  • Acute chest syndrome (ACS) refers to the combination of respiratory symptoms, new lung infiltrates, and fever. Because the appearance of radiographic changes may be delayed, the diagnosis may not be recognized immediately. Children have a higher incidence of acute chest syndrome but a lower mortality rate than adults. In children, acute chest syndrome is usually due to infection. Other etiologies include pulmonary infarction and secondary fat embolism due to sickling with bone infarction. Recognition of the specific cause is less critical in the management of acute chest syndrome than the ability to assess the management and pace of the lung injury.
  • In acute chest syndrome, arterial blood oxygen saturation commonly falls to a greater degree than that seen in simple pneumonia of the same magnitude. Patients with acute chest syndrome often have progressive pulmonary infiltrates despite treatment with antibiotics. Infection may set off a wave of local ischemia that produces focal sickling, deoxygenation, and additional sickling.
  • Treatment measures include oxygen therapy with close monitoring for hypoxemia with continuous pulse oximetry or frequent assessment of blood gases, empiric treatment with intravenous antibiotics active against S pneumoniae after appropriate cultures are obtained, and empiric addition of a macrolide antibiotic because chlamydial and mycoplasmal infections are common. Antibiotic changes are based on response to therapy and results of cultures and sensitivities.
  • Simple transfusion administered early may halt progressive respiratory deterioration, preventing complications such as increasing tachypnea and need for supplemental oxygen. Transfused red cells should be matched for C, D, E, and Kell antigens to minimize the risk of alloimmunization.
  • Analgesics are required. Agents that do not suppress respiration, including acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), can be used. Narcotic agents may be used judiciously for more severe pain. Other supportive measures include careful hydration that avoids volume overload, which may contribute to pulmonary infiltrates and exacerbate hypoxia. The role of corticosteroids in nonasthmatic patients with acute chest syndrome remains a topic of clinical research. Elevated levels of serum phospholipase A2 levels have been found to be associated with acute chest syndrome and might predict its occurrence. In pilot studies, transfusion of patients who had pain, no obvious acute chest syndrome, and increased serum phospholipase A2 levels have thwarted its development.
  • For episodes of severe hypoxia, rapid progression, diffuse pulmonary involvement, and failure to improve, erythrocytapheresis is indicated. Intensive care is indicated for patients in severe hypoxia or respiratory distress, as respiratory decompensation can rapidly require mechanical ventilation.
• Pain
  • Pain, resulting from vascular occlusion and ischemia, is the most common feature of sickle cell disease and can affect any body part. Bone pain is often due to bone marrow infarction. Certain patterns are predictable since pain tends to involve bones with the most bone marrow activity and because marrow activity changes with age. During the first 18 months of life, the metatarsals and metacarpals can be involved, presenting as dactylitis or hand-foot syndrome.
  • Hand-foot syndrome, which affected children develop by age 10 years, has been a strong predictor of overall severity (ie, death, risk of stroke, high pain rate, recurrent acute chest syndrome). Those that have an episode before age 1 year are at high risk of a severe clinical course. The risk is further increased if the child's baseline hemoglobin level is less than 7 g/dL or the baseline WBC count is elevated.
  • As the child grows older, pain often involves the long bones of the extremities, sites that retain marrow activity during childhood. Proximity to the joints and occasional sympathetic effusions lead to the belief that the pain involves the joints. As marrow activity recedes further during adolescence, pain involves the vertebral bodies, especially in the lumbar region. Although the above patterns describe commonly encountered presentations, any area with blood supply and sensory nerves can be affected. Abdominal pain can result from referred pain from other sites or intraabdominal solid organ or soft tissue infarction. Reactive ileus leads to intestinal distention and pain.
  • Triggers: Because deoxygenated HbS becomes semisolid, the most likely physiologic trigger is hypoxemia. This may be due to acute chest syndrome or accompany respiratory complications. Dehydration can precipitate pain, since acidosis results in a shift of the oxygen dissociation curve (Bohr effect), causing hemoglobin to desaturate more readily. Hemoconcentration is a common mechanism, as is a lowered body temperature, likely the result of peripheral vasoconstriction. Patients should wear proper clothing and avoid exposure to ensure normal core temperature. Ironically, swimming during the heat of summer is more likely to decrease the core temperature, which is always cooler than the body temperature.
  • Prevention: Family counseling is useful in preventing the above-mentioned triggers, whenever possible. Hydroxyurea may decrease frequency and severity of pain episodes.¹ A recent study concluded that hydroxyurea reduces hospitalization and increases total and fetal Hb levels in children with sickle cell anemia.²
    
    

    

    Effects of therapy with hydroxyurea.

    [ CLOSE WINDOW ]

    

    Effects of therapy with hydroxyurea.

  • Chronic transfusion therapy designed to maintain the HbS concentration at less than 30% may prevent pain episodes in patients with recurrent debilitating painful crises.
• Stroke
  • Although stroke in children is unusual, approximately 11% of patients with sickle cell anemia experience strokes before they reach age 20 years. Hemiparesis is the usual presentation. Other deficits may be found, depending on the location of the infarct.
  • Convulsions are frequently associated with stroke. Convulsions occur as an isolated event but also appear in the setting of evolving acute chest syndrome, pain crisis, aplastic crisis, and priapism. Rapid and excessive blood transfusion to a hemoglobin level of greater than 12 g/dL increases blood viscosity and can lead to stroke.
  • Children with sickle cell disease may have various anatomic and physiologic abnormalities that involve the CNS even if they appear to be neurologically healthy. Abnormalities may be associated with deterioration in cognitive function with effects on learning and behavior and may increase the potential risk for clinical and subclinical damage to the CNS.
  • Transcranial Doppler ultrasound (TCD) is a useful tool to identify children at high risk for stroke before they have suffered a clinical stroke. Children with HbSS or HbS– β -0 thalassemia aged 2-16 years should be considered candidates for annual TCD screening. A clinical trial demonstrated that transfusion therapy decreased the risk of stroke in children with abnormal TCD blood flow patterns.³ During the transfusion period, most of the TCD studies reverted to or toward normal, but, once transfusion was stopped, an unacceptably high rate of TCD reversion to high risk was noted, as were actual strokes
  • Transfusion therapy has been shown to reduce the recurrence of ischemic neurologic events in patients with sickle cell disease. Many believe that life-long transfusions are necessary to completely eliminate recurrences. Iron overload requires chelation therapy after 2-3 years. Erythrocytapheresis is now increasingly used as alternative therapy. This procedure allows rapid dilution of HbS concentrations to less than 30% without significantly increasing total hemoglobin concentration posttransfusion. For children with a human leukocyte antigen (HLA)–matched sibling, a consortium has demonstrated that the risk of recurrent stroke can be greatly reduced with allogeneic bone marrow transplantation (an alternative to long-term transfusion and iron chelation).
  • Hemorrhagic stroke is often caused by rupture of aneurysms that might be a result of vascular injury and tend to occur later in life. Moya moya, a proliferation of small fragile vessels found in patients with stenotic lesions, can also lead to cerebral hemorrhage. Hemorrhagic stroke is associated with a mortality rate of more than 29%.
• Cholecystitis
  • Because of chronic hemolysis, cholelithiasis is common in children who are affected.
  • Cholecystitis or common bile duct obstruction can occur. Consider cholecystitis in a child who presents with right upper quadrant pain, especially if associated with fatty food.
  • Consider common bile duct blockage when a child presents with right upper quadrant pain and dramatically elevated conjugated hyperbilirubinemia.
  • Treatment of acute cholecystitis in patients with sickle cell disease does not differ from that for the general population. Patients receive antibiotics and general supportive care and may consider elective cholecystectomy several weeks after the acute episode subsides. Elective laparoscopic cholecystectomy in a well-prepared patient has become the standard approach for symptomatic patients.
• Avascular necrosis of the femoral or humeral head
  • Vascular occlusion can result in avascular necrosis (AVN) and subsequent infarction and collapse at either site.
  • AVN of the femoral head presents a greater problem because of weight bearing.
  • Patients with high baseline hemoglobin levels are at increased risk.
  • Approximately 30% of all patients have hip pathology by age 30 years.
  • The natural history of symptomatic hip disease in patients with sickle cell disease who are treated conservatively varies with the patient's age. In skeletally immature patients aged 12 years or younger, treatment with analgesics, NSAIDs, and protected weight bearing usually results in healing and remodeling of the involved capital epiphysis, similar to that observed in Legg-Calve-Perthes disease. This approach results in preservation of the joint despite the persistence of deformity, such as coxa magna and coxa plana. In contrast, conservative management of osteonecrosis usually fails in older adolescents and adults. Progressive flattening and collapse of the femoral head results in painful secondary degenerative arthritis.
  • The use of joint-preserving surgical procedures such as core decompression and osteotomy has been reported in patients with sickle cell disease who have precollapse femoral head involvement.
• Priapism
  • Priapism, defined as a sustained, painful, and unwanted erection, is a well-recognized complication of sickle cell disease. According to one study, the mean age at which priapism occurs is 12 years, and, by age 20 years, as many as 89% of males with sickle cell disease have experienced one or more episodes of priapism.
  • Priapism can be classified as prolonged if it lasts for more than 3 hours or as stuttering if it lasts for more than a few minutes but less than 3 hours and resolves spontaneously. Stuttering episodes may recur or develop into more prolonged events. Prolonged priapism is an emergency that requires urologic consultation.
  • Recurrent episodes of priapism can result in fibrosis and impotence, even when adequate treatment is attempted.
• Pulmonary hypertension
  • This is a recently appreciated complication that was previously included among complications of older patients but is also seen in children.
  • Pulmonary hypertension is characterized by a regurgitant pulmonary jet velocity of more than 2.5 m/s by echocardiography is associated with a high mortality rate in adult patients.
  • For symptomatic patients, hydroxyurea, transfusions, sildenafil, and bosentan have been used, but controlled trials that have studied the effectiveness of this treatment have not been reported.

Physical

In the absence of one of the above-described complications of the disease process, a child may simply be jaundiced or pale.

• Splenic enlargement may be present. Spleen size should be measured, and parents should be made aware of it. A tongue blade may be used as a "spleen stick" in a small child, with the upper end of the blade corresponding to the nipple in the midclavicular line and a marking made on the stick corresponding to the edge of the spleen.
• Almost all patients with sickle cell disease with moderate-to-severe anemia have a cardiac systolic flow murmur that usually does not require further evaluation.
• Growth parameters show patients falling below the growth isobars. This usually occurs around the prepubertal age because of delayed puberty. Bone marrow expansion often causes maxillary hypertrophy with overbite; orthodontics are recommended to prevent or correct this problem.

Causes

• Sickle cell disease denotes all genotypes that contain at least 1 sickle gene in which HbS makes up at least half the hemoglobin present.
• Sickle cell anemia is the most severe and most common form.

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