Chapter 142: Sickle Cell Disease In Children

Sickle cell disease is a spectrum of blood disorders of which sickle cell anemia (SCA) is the most serious. SCA is found primarily in children of African, Arab, or Mediterranean descent. It is caused by a single amino acid substitution in the sixth position of the β-globulin chain of normal adult hemoglobin (HbA), which creates the abnormal sickle hemoglobin (HbS). The HbS chain found in patients with SCA creates a hydrophobic region of the hemoglobin tetramer when it is deoxygenated.¹ In this state, noncovalent polymerization of the hemoglobin molecules creates chains that distort the shape of the membrane, causing the characteristic sickle appearance. The altered red blood cell shape and its associated rigidity and decreased deformability cause sickle cells to impede blood flow. This is responsible for most of the clinical manifestations of SCA through two primary mechanisms: hemolytic anemia and vaso-occlusion with subsequent ischemia-reperfusion injury. Interruption of blood flow created by the abnormal cells leads to poor tissue perfusion, acidosis, and hypoxia, which cause further sickling. The need to reverse these conditions is central to the management of SCA-related complications.

Children homozygous for this genetic abnormality have two genetic copies of the HbS mutation and are described as having classic hemoglobin SS (HbSS) disease, whereas heterozygotes for HbS with a second β-globulin chain that is normal (HbA) are considered to have sickle cell trait. These patients have enough HbA to prevent polymerization of the hemoglobin chains and subsequently avoid the more severe complications of the disease. Other patients may be heterozygous for HbS coupled with a second hemoglobin abnormality such as HbC, HbO, or β-thalassemia. Although some of these combinations can cause the severe pathology of SCA, patients with HbSC and the 90% of HbS/β-thalassemia patients with some normal β chains have fewer ischemic and infectious complications than patients with HbSS.

Because fetal hemoglobin (HbF) is unaffected by these genetic mutations, symptoms of SCA do not appear until HbF is replaced by the abnormal HbA. HbF predominates until 4 months of age, after which it rapidly declines, reaching baseline low levels just before 1 year of age. One of the first organs affected by the emerging sickle cells is the spleen. Recurrent splenic infarcts lead to a gradual decline in splenic function between 4 and 12 months of age, resulting in susceptibility to serious infections with encapsulated bacteria.

In the United States, all neonates are screened for SCA using highly sensitive and specific tests, so the diagnosis is rarely made in the ED. The clinical manifestations and potential complications of SCA, however, include symptoms that overlap considerably with diseases not related to SCA. Therefore, the diagnostic portion of this chapter is organized in a symptom-based fashion, and the treatment portion is grouped by disease physiology.

EXTREMITY PAIN

Vaso-occlusive crises causing severe extremity pain are the most common manifestation of SCA, accounting for 79% to 91% of ED visits.² Common triggers include stress, cold, dehydration, altitude, hypoxia, or illness. Pain preferentially affects the long bones and lower back. Individual patients tend to manifest their pain crises in characteristic locations, but the frequency of vaso-occlusive pain crisis is variable, even among SS homozygotes. Five percent of children with SCA account for 33% of total episodes, averaging between 3 and 10 pain crises per year.³ Children display variable degrees of tenderness over affected sites and may have slight temperature elevations without true fever. Because anemia can precipitate a crisis, assess patients for an acute drop in hemoglobin; experienced families may know the patient's baseline values.

Severe vaso-occlusive crises can lead to bony infarction. Pain episodes caused by bony infarcts typically cause more debilitating and refractory pain than past episodes, and there is often significant localized bone tenderness and an elevated peripheral WBC count. Fat embolism can be a complication. Signs and symptoms of fat embolism include acute respiratory distress, hypoxia, and systemic symptoms of petechiae, altered mental status, liver damage, and renal failure. Fat embolism can occur without acute extremity pain, and the aforementioned symptoms should prompt consideration of fat embolization.

When vaso-occlusive crises affect the nutrient arteries of the metacarpals and/or metatarsals, dactylitis results, and children develop tender, painful, swollen hands and feet, which may be accompanied by a low-grade fever (Figure 142-1). Dactylitis occurs in children <2 years old and may be the initial clinical presentation of SCA, but dactylitis is extremely rare beyond 5 years of age. Any number of extremities can be affected, and symptoms can last from days to 2 weeks. Recurrences are common.

Avascular necrosis of the femoral head occurs in 30% of patients by age 30 years old. Children present with afebrile inguinal pain with weight bearing. Radiographs may demonstrate flattening and collapse of the femoral head (Figure 142-2). Less commonly, ischemia can cause similar pain in the humeral head.

Bone and joint infections affect patients with SCA at higher rates than the general population. Infections are often difficult to distinguish from bony infarcts. Symptoms of tenderness, warmth, and swelling may be indistinguishable from those of a vaso-occlusive crisis, although a high fever is more typical of infection. Limited range of motion of a joint is unusual in vaso-occlusive crisis and should prompt evaluation for a septic joint. Although leukocytosis occurs with vaso-occlusive crisis, a left shift is unique to infection. Erythrocyte sedimentation rates are unreliable in patients with SCA. Radionuclide imaging or MRI may distinguish infection from infarct.

ABDOMINAL PAIN

Abdominal pain is a difficult symptom to assess in any child and is complicated by the potential abdominal manifestations of SCA. Any acute abdominal condition, such as appendicitis, pancreatitis, and hepatitis, must be considered. However, the abdomen is the next most common site of pain from a vaso-occlusive crisis after the extremities and back. Abdominal vaso-occlusive crises are due to mesenteric, splenic, and hepatic ischemia and present as sudden onset of poorly localized abdominal pain. Physical examination may reveal tenderness and guarding but typically should not demonstrate rebound or rigidity.

Gallstones are common due to the elevated bilirubin levels from hemolysis in SCA and can occur as early as 2 to 4 years of age. Diagnosis is by US. Although symptoms in children may resolve with time, occasionally, cholecystitis can be severe, and infection can progress rapidly (see chapters 79, "Pancreatitis and Cholecystitis," and 131, "Gastrointestinal Bleeding in Infants and Children"). Right upper quadrant syndrome due to intrahepatic cholestasis is not common. Signs and symptoms include sudden right upper quadrant pain, jaundice, anorexia, tender hepatomegaly, and, often, fever. Bilirubin levels can be as high as 50 milligrams/dL. Although patients with SCA often have bilirubin levels above baseline, bilirubin levels rarely exceed 4 milligrams/dL and are predominantly unconjugated bilirubin. Confirm the diagnosis by US. Acute hepatic sequestration is another cause of abdominal pain, and the liver enlarges rapidly. Laboratories are variable, except for low hemoglobin. US or CT scan shows diffuse hepatomegaly in hepatic sequestration.

RESPIRATORY DISTRESS AND CHEST PAIN

Acute chest crisis, due to pulmonary ischemia and infarction, is frequently a complication of pneumonia (Figure 142-3). The incidence of acute chest crisis in children is higher than in adults (21 per 100 person-years in patients with HbSS), but is associated with better outcomes. Children develop any combination of pleuritic chest pain, cough, fever, and dyspnea. Examination findings include retractions, hypoxia, tachypnea, rhonchi, or rales, although dehydration can minimize the presence of rales on examination. An elevated WBC count is often present in both infarct and pneumonia, and thrombocytopenia may accompany severe crises. Chest radiograph is indicated in any patient with chest symptoms or hypoxia, although findings may be minimal early on and should not dissuade treatment of a patient with potential chest crisis on clinical grounds only. Radiography demonstrates a new alveolar pulmonary infiltrate, which is typically located in the upper or middle lobe in children, although adults often have multilobar disease. The cause of pneumonia is typically Chlamydia, Mycoplasma, viral, Streptococcus pneumoniae, Staphylococcus aureus, or Haemophilus influenzae. Sputum or blood cultures are rarely positive and not generally recommended, except in patients ill enough to require mechanical ventilation. Multilobe involvement, history of cardiac disease, and low platelets predict poor outcomes.⁴ Chest crisis can result in decreased lung function,⁵ poor integrity of the pulmonary vessels, and a propensity to pulmonary edema. Asthma is common in patients with SCA, occurring in 17% to 53%. Asthma not only complicates the diagnosis of acute chest crisis but also increases the likelihood of chest syndrome by four- to six-fold.⁵

Pulmonary hypertension develops in 16% to 35% of children with SCA. By adulthood, about one-third have pulmonary hypertension, a condition that is associated with diastolic dysfunction and increased mortality. Increased intensity of the second heart sound, evidence of right ventricular enlargement, or unexplained desaturation should suggest pulmonary hypertension (see chapters 57 and 58, "Systemic Hypertension" and "Pulmonary Hypertension," respectively, section on pulmonary hypertension). Diagnosis is made by echocardiogram and right heart cardiac catheterization demonstrating a pulmonary artery pressure above 25 mm Hg. Progressive disease can cause chest pain, dyspnea on exertion, resting hypoxia, right-sided heart failure, syncope, and pulmonary thromboembolism.

Cardiomegaly and heart murmurs are common in children with SCA. However, overt heart failure is uncommon in children, except in cases of iatrogenic volume overload associated with transfusion. Heart failure is managed by the usual methods and by correcting anemia.

FEVER

Across all ages, infection is the leading cause of death in patients with SCA.⁶ Splenic dysfunction and inability to form immunoglobulin G antibodies to polysaccharide antigens increase susceptibility to infection, particularly with encapsulated organisms. Children age 6 months to 3 years old are at the greatest risk for sepsis, with H. influenzae and S. pneumoniae more common in the very young, and Escherichia coli and Salmonella more frequent in older children. The rate of bacteremia in children ≤3 years old has been about 8 per 100 patient-years. In children who receive pneumococcal 7-valent conjugate vaccine, invasive pneumococcal disease has decreased by as much as 93.4%.⁷ Table 142-1 reviews risk factors for bacteremia. Workup of potential infection in SCA patients should include a CBC, urinalysis, chest radiograph, oxygen saturation measurement, and cultures of the blood, throat, urine, or other potential source of infection.

Children with SCA also have an increased prevalence of meningitis, pneumonia, arthritis, and osteomyelitis compared to the general population, and have poorer outcomes for these diseases. Similarly, viral infections, including influenza, result in greater morbidity, and yearly vaccination for influenza is recommended.

PARVOVIRUS INFECTION

Parvovirus B19 infection is of particular concern. The initial infection is usually asymptomatic or associated with nonspecific upper respiratory symptoms. However, parvovirus can cause several different clinical syndromes. Erythema infectiosum is characterized by fever, headache, nausea, coryza, and slapped cheek appearance with circumoral pallor followed by diffuse maculopapular rash. Gloves and socks syndrome describes well-demarcated painful erythema and edema of the hands and feet that evolves into petechiae, purpura, vesicles, and skin sloughing. Finally, parvovirus can cause symmetric or asymmetric arthropathy of knees and ankles. Regardless of the clinical presentation, parvovirus can cause a transient aplastic crisis, with the reticulocyte count dropping 5 days after exposure, followed by a decline in hemoglobin (see chapter 143, "Oncologic and Hematologic Emergencies in Children"). Because of the shortened life span of the red cells in SCA, parvovirus can cause serious anemia, which lasts for 2 weeks. Upon recovery, there is an outpouring of nucleated red blood cells from the marrow, and patients late in the illness may have a high reticulocyte count.⁸ Infection usually imparts subsequent lifelong immunity to parvovirus.

ANEMIA

Splenic sequestration, or intrasplenic trapping of red cells, is a major cause of mortality in children <5 years old. Two types exist, major and minor. Major splenic sequestration causes a rapid drop of more than three points in the hemoglobin, with the development of pallor, left upper quadrant abdominal pain, and splenomegaly. This can progress within hours to altered mental status, hypotension, and cardiovascular collapse. Minor splenic sequestration tends to be more insidious, with a smaller change in hemoglobin levels. Often, attacks occur along with bacterial or viral infections. Laboratory studies in either syndrome demonstrate a decline from baseline hemoglobin level, a normal to increased reticulocyte count, and no change in bilirubin, because there is no hemolytic component to this complication. Mild neutropenia or thrombocytopenia may be noted. Patients with HbSS rarely experience this complication beyond 5 years of age (peak, 3 months to 5 years old) due to infarction and scarring of the spleen, but most patients with HbSC and homozygous S/β-thalassemia have a spleen that persists into adulthood, and thus have a risk of splenic sequestration.

As noted earlier, aplastic crisis is an important cause of anemia in SCA patients and can be induced by parvovirus infection or medications. Signs are the gradual onset of pallor without pain or jaundice. Laboratories demonstrate a decline in hemoglobin and a low reticulocyte count. Full recovery is expected within weeks.

NEUROLOGIC COMPLAINTS

Stroke is 250 times more common in children with SCA than in the baseline population⁹: 11% of children with SCA suffer a clinically overt stroke, and another 20% are found to have silent strokes on imaging. The risk of recurrence, untreated, after one stroke is 49% to 90%, and children with HbSS are at four times greater risk than those with HbSC. SCA patients typically have cerebral vasculopathy involving the intima and media of large arteries, usually the middle cerebral artery. Screening transcranial Doppler studies can identify abnormal flow patterns associated with this vasculopathy, which, if untreated, are associated with a 10% risk of stroke within 2 to 3 years of diagnosis.³ Additionally some children will develop a moyamoya-like syndrome in which clotted vessels induce the development of diffuse small collateral vessels. These weak vessels are prone to aneurysm formation and spontaneous hemorrhage and demonstrate a characteristic "puff of smoke" appearance on cerebral angiography.

Cerebral ischemia can present with fleeting symptoms of transient ischemic attacks, or with hemiparesis, seizure, altered mental status, or coma. Common vascular territories involved include the internal carotid or middle cerebral arteries, but venous sinus thrombosis may cause parieto-occipital or thalamic involvement (Figure 142-4).⁹ As in adult stroke, the CT scan is less reliable to detect ischemic infarct in the first 36 hours, although CT scan does rule out hemorrhage. Diffusion-weighted MRI demonstrates changes within minutes and T2-weighted MRI within hours of ischemia.

Patients with SCA also have a higher rate of cerebral aneurysms and intra-cranial hemorrhage than the general population, although hemorrhagic stroke only accounts for 10% of strokes in SCA patients. This complication is rarely seen in children but becomes a concern during late adolescence. Hemorrhagic strokes typically present with headache, vomiting, and alterations in level of consciousness but may present with hemiparesis similar to an ischemic stroke if bleeding is intraparenchymal. There are three potential sites of hemorrhage: subarachnoid from an aneurysm, intraparenchymal from large-vessel vasculopathy or moyamoya, and intraventricular from moyamoya.

Neurologic symptoms are not uncommon in patients with acute chest crisis as well and have been noted in 7% to 10% of cases.⁹ Other considerations in the patient with altered mental status and SCA previously mentioned include severe anemia from splenic sequestration and meningitis.

GU COMPLAINTS

Priapism is common in males, with 27% having at least one episode by age 20 years old.¹⁰ There is a bimodal age peak—5 to 13 years old and 21 to 29 years old. Patients present with a painful, swollen, edematous, tender penis, often with difficulty urinating (Figure 142-5). The glans itself remains soft. Sickling of the red cells in the sinusoids of the corpus cavernosum cause decreased venous outflow from the penis.¹⁰

The most common renal abnormality is hyposthenuria, the inability to maximally concentrate urine. This may cause enuresis, nocturia, and a propensity for dehydration and hyperkalemia. Renal vaso-occlusive crises are also common and can be asymptomatic or accompanied by colicky intermittent flank pain, costovertebral angle tenderness, gross or microscopic hematuria, and passage of renal tissue. Chronic damage to the kidneys can lead to renal insufficiency at an early age.

Hematuria can also occur with papillary necrosis, a complication seen in both homozygous and sickle trait patients. Urinalysis demonstrates red blood cells without casts or associated pyuria or significant proteinuria.

ANEMIA

Severe and symptomatic anemia, as well as many of the other complications of SCA, may require transfusion. The general principles of transfusion discussed here are applicable to each of the crises described earlier. A typical pediatric transfusion of packed red blood cells is 10 mL/kg over a 2-hour period. In the case of severe anemia, smaller volume transfusions, typically 5 mL/kg, are given more slowly because of the risk of pulmonary edema associated with large fluid shifts. In this case, multiple lower volume transfusions are indicated with reassessment between each infusion. In general, transfusions are indicated in the case of symptomatic anemia with a hemoglobin <6 grams/dL and an inappropriately low reticulocyte count, or an acute vaso-occlusive crisis with a hemoglobin below 10 grams/dL. In these cases, a simple transfusion, rather than an exchange transfusion, is the indicated treatment with the goal of treatment being a hemoglobin >10 grams/dL.

Patients requiring transfusion for a specific crisis in which the hemoglobin is >10 grams/dL require an exchange transfusion, with the goal of reducing the proportion of HbS to <30%. Generally, this requires infusion of normal saline followed by removal of 50 to 60 mL/kg of blood prior to the transfusion. This process reduces vaso-occlusion by essentially replacing the patient's diseased erythrocytes with normal red blood cells. Many centers have an automated exchange transfusion machine, but in the event of an extreme emergency, this procedure can be performed manually at the bedside. All transfusions should be leukoreduced; washed cells are used in patients with a history of allergic reactions; irradiated cells (from an unrelated donor) are indicated for patients who may be candidates for a bone marrow transplantation.

Anemia secondary to an aplastic crisis is often treated with simple transfusion and close follow-up. Acute splenic or hepatic sequestration with associated anemia is managed with good hydration, analgesia, simple transfusion, and exchange transfusion in refractory cases. Because the recurrence rate for splenic sequestration is 50%, chronic transfusion therapy and/or splenectomy are often considered.

VASO-OCCLUSIVE CRISES

Vaso-occlusive pain crises, regardless of location, are treated with pain control and gentle hydration and, in some cases, oxygen. Provide liberal analgesia with frequent reassessment of pain 15 to 30 minutes after medication, and repeat dosing until the patient is comfortable. Although standard drug dosing is presented here, patients with pain crises who require narcotics frequently may have tolerance to these drugs and may require much larger doses to achieve adequate analgesia. Commonly used analgesics are listed in Table 142-2. Ketorolac (Toradol^®) can be combined with narcotics. IV is the preferred route of administration of morphine, but IM injection can be a temporizing measure. Due to the histamine release from morphine, a frequent side effect is pruritus, which may require treatment with diphenhydramine (Benadryl^®) or use of alternative agents. Hydromorphone (Dilaudid^®) is a reasonable alternative to morphine and has a similar pharmacokinetic profile. Subsequent narcotic doses may be reduced to half the initial dose, depending on the response and side effects to the initial dose. Meperidine and fentanyl are not ideal opioid choices due to the side effect profile in the case of meperidine and the short duration of action of fentanyl. Ketamine is a possible alternative to narcotics, but its use is not yet widespread.¹¹

Provide IV hydration at a rate of 1.5 times maintenance with 5% dextrose in half-normal saline. Because of the risk of increased permeability of pulmonary vasculature and cardiomyopathy, normal saline boluses are not routinely used except to treat acute dehydration or hypovolemic shock. Consider transfusion for pain crises accompanied by a significant drop in hemoglobin or a total hemoglobin <5 grams/dL (see chapter 113, "Pain Management and Procedural Sedation in Infants and Children"). Oxygen is not useful in the nonhypoxic patient.¹² The decision to admit or discharge is often difficult and is usually made with input from the patient, family, and hematologist. Children requiring two or more doses of narcotic medications in the ED are likely to require admission. Patients discharged home should be instructed to take nonsteroidal anti-inflammatory drugs if no contraindications exist and may require an oral narcotic as well. Hydrocodone (Lortab^®, Vicodin^®) at a dose of 0.15 to 0.2 milligram/kg given every 3 to 4 hours is generally an effective choice and comes in a solution (Lortab^®) for younger children.

For acute chest crisis, treat pain and provide IV hydration and oxygen. Several papers have noted a possible association between morphine sulfate use and the development of acute chest syndrome,¹³ but morphine is still commonly and widely used in the treatment of pain associated with SCA. Because pneumonia is frequently a precipitant or complicating factor, give empiric antibiotic treatment with a third-generation cephalosporin and macrolide. For patients whose clinical status deteriorates despite all of these measures, transfusion (simple for hemoglobin <10 grams/dL, or exchange for hemoglobin >10 grams/dL) is indicated. Generally a partial pressure of arterial oxygen (PaO₂) below 70 mm Hg or an oxygen saturation that has fallen >10% from baseline in a chronically hypoxic patient should be a trigger for transfusion. Steroids are not beneficial. Respiratory distress associated with fat emboli may respond to prompt transfusion and/or exchange transfusion.

Other crises, such as renal infarct and right upper quadrant syndrome and papillary necrosis, are usually treated with hydration, analgesia, and other supportive measures.

PRIAPISM

Treat priapism with the use of hydration, analgesia, and transfusion and/or exchange transfusion depending on the current hemoglobin. Additionally, urologic consultation and aspiration of the corpora with a 23-gauge needle may be necessary, followed by irrigation and administration of a 1:1,000,000 epinephrine solution if the priapism continues for more than 4 to 6 hours. Procedural sedation may be required for children needing corporal aspiration. Patients with repeated episodes of priapism may be candidates for prophylaxis with pseudoephedrine, gonadotropin-releasing hormone analogues, diethylstilbestrol, or hydroxyurea.¹⁰

STROKE

Alteplase (t-PA^®) is not recommended for children and has no role in the management of stroke related to SCA. Interventions are aimed at limiting secondary brain injury through aggressive control of hyperpyrexia, correction of hypoglycemia, hypoxia, and hypovolemia, and urgent exchange transfusion to decrease the percentage of HbS below 30%. There is currently no consensus opinion on the management of blood pressure.¹⁴ Children with a history of clinical stroke or transient ischemic attack or with abnormal cerebral blood flow on cranial Doppler are often managed long term with a chronic transfusion protocol or hydroxyurea to decrease the risk of subsequent strokes. Neurosurgical consultation is required for management of hemorrhagic stroke.

FEVER

Well-appearing children >1 year old with isolated fever and no signs of sepsis may be candidates for discharge if they are stable for a 4-hour period of observation, have good follow-up, and do not meet the high-risk criteria detailed in the earlier "Fever" section. Give a dose of ceftriaxone before discharge pending culture results. Stable children with an identified source for fever (e.g., strep throat, otitis media) can be discharged with disease-specific treatment. Patients <1 year old or those meeting high-risk criteria or demonstrating signs of sepsis require admission. A third-generation cephalosporin (ceftriaxone, 100 milligrams/kg/d, one dose, not to exceed 4 grams/d) is frequently adequate empiric treatment against encapsulated bacteria pending culture results, but areas with high rates of resistant S. pneumoniae may consider the addition of vancomycin (10 milligrams/kg IV every 6 hours) as well. Pulmonary infections require the addition of a macrolide. For specific infections, such as bone and joint infections, treatment should be determined based on available culture results and consultation with appropriate subspecialty services. In the case of meningitis, patients are at increased risk of stroke, and the decision to administer a prophylactic exchange transfusion should be made in conjunction with the hematologist.

OTHER PROCEDURES

SCA patients may be admitted for surgery for reasons related or unrelated to the underlying disease. Before surgery, exchange transfusion can be given to decrease HbS to <30%. This should be considered in consultation with the hematologist for all but the most emergent conditions requiring major surgery.¹⁵ Minor procedures may not require transfusion. Transfusion is not indicated before the administration of nonionic contrast materials.

COMMON OUTPATIENT MEDICATIONS AND TREATMENTS

Due to the risk of bacteremia, children are maintained on oral penicillin through age 5 years old. Beyond 5 years of age, there does not seem to be any additional benefit from penicillin.¹⁶ Folate supplementation is standard due to the increased turnover of red blood cells.

Hydroxyurea is the only disease-modifying drug available for sickle cell disease and is used in SCA patients to decrease the frequency and severity of complications and to reduce mortality. Hydroxyurea induces the production of HbF in addition to other benefits such as decreasing the number of leukocytes and providing some vasodilation. The additional HbF lowers the percentage of HbS, which decreases hemoglobin polymerization, increases erythrocyte size, and improves cellular deformability, thus decreasing the amount of sickling and consequently reducing vaso-occlusion.^15,17 There is strong evidence that hydroxyurea should be started in all children over 9 months of age regardless of severity of the disease to reduce the risk of complications. Although this medication should be started by a primary care physician or sickle cell disease specialist, emergency physicians caring for SCA patients should counsel patients on the availability of this treatment and refer them appropriately. Side effects can include GI discomfort, modest neutropenia, hyperpigmentation, and renal toxicity.

Hypertransfusion or chronic transfusion therapy is an option in patients with severe or frequent crises, with the principle that the transfused red cells will decrease anemia and minimize the patient's own production of abnormal red cells. If the percentage of HbS is kept below 30%, the possibility of a sickle crisis is minimized. Clearly, the known risks of infection and transfusion reaction that pertain to any transfusion apply. Transfusion for sickle cell disease patients more frequently results in alloimmunization (5% to 36% of patients) compared to the general population. Alloimmunization is defined as immunization of the patient by donor RBC antigens. The risk can be minimized by using blood matched for minor red blood cell antigens such as C, E, and Kell. In these cases, patients experience a drop to below pretransfusion levels of hemoglobin, despite a negative direct antibody test, due to hemolytic anemia that can be life threatening. This phenomenon also increases the risk for future transfusion reactions in SCA patients.¹⁵

Finally, chronic iron overload is another complication of frequent transfusions and may contribute to cardiomyopathy. Iron overload is treated with deferoxamine chelation therapy, a treatment that is also associated with risk: deferoxamine may increase the susceptibility for fungal infections (and other infections such as Yersinia) and lead to growth failure, allergic reactions, ophthalmic toxicity, or ototoxicity.

Bone marrow or stem cell transplantation has been successfully used to cure SCA. However, due to the risks associated with transplantation, this is generally only considered in patients who have a human leukocyte antigen–matched sibling.

Acknowledgments: The author gratefully acknowledges the contributions of Peter J. Paganussi, Thom Mayer, Maybelle Kou, and Ilene Claudius, the authors of this chapter in previous editions.