In 1904, James B. Herrick was the first to describe sickle cells when his intern found “peculiar elongated and sickle-shaped” red blood cells (RBCs) in a peripheral blood smear from a patient suffering from anemia.1,2 In 1949, Linus Pauling and colleagues were the first to demonstrate that sickle cell anemia occurs as a result of an abnormality in the hemoglobin molecule.1,2 The pathophysiology of sickle cell disease (SCD), a group of inherited RBC disorders that includes sickle cell anemia, is well-known. However, since SCD's discovery, little progress has been made in preventing acute episodes of anemia, vaso-occlusive pain crises, organ damage, and other life-threatening complications in patients with SCD. A major public health concern, SCD cost an average of $11,702 in medical expenditures for children with Medicaid coverage and $14,772 for children with employer-sponsored insurance in 2005.3 About 40% of both groups had at least one hospital stay.3
According to the CDC, an estimated 90,000 to 100,000 Americans are affected by SCD, including 1 out of every 500 African Americans and 1 out of every 36,000 Hispanic Americans.3 SCD affects millions of people throughout the world and is particularly common among those whose ancestors come from sub-Saharan Africa, South America, the Caribbean, Central America, Saudi Arabia, India, and Mediterranean countries including Turkey, Greece, and Italy.3
Hemoglobin, which transports oxygen via blood in the body, is composed of two pairs of alpha and beta polypeptide chains; each of the four chains consists of a globin and heme unit. Adult hemoglobin (HbA) consists of 2 alpha chains and 2 beta chains. Fetal hemoglobin (HbF) consists of 2 alpha chains and 2 gamma chains and accounts for 50% to 80% of total hemoglobin in newborns (the remainder is HbA).4 After the child reaches 6 months of age, HbF production ceases and HbA is produced, with HbF now representing 1% of total hemoglobin in the blood.4
Patients with SCD have a mutation in the amino acid sequence of the hemoglobin beta chain, in which valine takes the place of glutamic acid at the sixth position.5–7 Because of their abnormal hemoglobin, RBCs in a patient with SCD become C-shaped or sickled when the patient's oxygen saturation is low. Their reduced flexibility impairs their flow through vessels.6 Repeated deoxygenation can damage the cells enough to make sickling permanent.5 As a result of cell sickling and impaired flow, cellular dehydration, inflammatory response, and reperfusion injury occur, leading to the manifestations of SCD.
In addition to their abnormal shape, sickled RBCs are generally short-lived (10 to 20 days instead of the normal 120 days). As abnormally shaped RBCs become wedged in blood vessels, blood supply is interrupted, leading to decreased distribution of hemoglobin and the oxygen it carries to organs, resulting in ischemia. To compensate, the bone marrow produces more RBCs at a much faster rate than normal and releases them into the bloodstream as immature RBCs or reticulocytes.
HbF has a slightly higher affinity for oxygen compared to HbA, and inhibits the formation of sickled hemoglobin (HbS). Subsequently, HbF levels in the body have been identified as a major marker for determining a patient's prognosis for complications of SCD.7–9 Patients with SCD who inherit a genetic marker for high HbF will experience a very mild form of the disease.7–9
Variations of SCD can be determined by hemoglobin electrophoresis, the diagnostic tool used to identify different hemoglobin types:
* HbSS designates patients who have inherited two sickle cell genes (S); one from each parent. The most common type of SCD, this variant accounts for 60% to 65% of cases.10 Commonly called sickle cell anemia, this usually is the most severe form of the disease.
* HbSC identifies patients who have inherited a sickle cell gene (S) from one parent and a gene for abnormal hemoglobin (C) from the other parent. The abnormal hemoglobin C is a variant in the beta-chain gene (alpha2betaC2). Accounting for 20% to 30% of cases, this is usually a milder form of SCD.10
Other variations of SCD include HbS beta thalassemia, HbSD, HbSE, and HbSO. HbS beta thalassemia is another type of hemoglobinopathy that identifies persons who have inherited one sickle cell gene from one parent and one gene for beta thalassemia from the other parent. HbS beta thalassemia has two forms: HbS beta 0-thalassemia usually is a severe form of SCD; HbS beta +-thalassemia tends to be a milder form.
People with HbSD, HbSE, and HbSO have inherited one sickle cell gene and one gene for an abnormal type of hemoglobin. The severity of these rarer types of SCD varies. The signs and symptoms and complications of HbSD, HbSE, and HbSO are similar to those of a person with HbSS.3
Sickle cell trait (SCT) is expressed as HbAS, and identifies patients who have inherited a sickle cell gene from one parent and a normal gene (A) from the other parent. SCT occurs in 8% of African Americans.9 People with SCT usually do not have any of the signs and symptoms of the disease and live a normal life, but can pass the trait on to their children.3
Records from the US Sudden Death in Athletes Registry demonstrated that of 2,462 athlete deaths, 23 occurred in association with SCT.9 Although individuals with SCT do not have clinical symptoms, they are at an increased risk for unpredictable sudden rapid deterioration and death while under high physical stress, supporting the importance of identifying the severity of the disease to prevent potential life-threatening states.
Early identification of children with SCD can prevent complications of the disease. SCD can be diagnosed during pregnancy or routine newborn screening tests. According to the US Preventive Services Task Force, newborn screening for SCD is mandated in all 50 states and the District of Columbia.11 A blood sample is collected via heel stick in the newborn, and initial testing is performed using thin-layer isoelectric focusing (IEF) analysis, which is more sensitive than hemoglobin electrophoresis. In infants with SCD, HbS levels rise as HbF levels fall postnatally. The levels of these two variations of hemoglobin stabilize around age 2.2 At the infant's first healthcare visit, the result of heel stick is confirmed by high performance liquid chromatography (HPLC). This should be done no later than 2 months of age. IEF and HPLC have high sensitivity and specificity for SCD.12
From age 2 to 16, children with SCD should be screened annually with transcranial Doppler for stroke risk.13 Smooth muscle hyperplasia and vessel wall fibrosis caused by SCD can lead to progressive stenosis and occlusion of the internal carotid arteries and proximal middle and anterior cerebral arteries.13 Blood transfusions should be started for patients if abnormal findings are detected on transcranial Doppler.13
Pain is the number one complaint of patients with SCD, and acute vaso-occlusive crisis is the primary cause of hospitalizations.14 The best indicator of a vaso-occlusive crisis is the history provided by the patient. Among patients with SCD, vaso-occlusive crises differ in frequency and severity, and patients usually know if the pain they are experiencing is different from the typical pain they may experience with SCD. Signs and symptoms of a vaso-occlusive crisis include fever above 101° F (38.3° C), difficulty breathing, chest pain, abdominal swelling, severe headache, sudden weakness or loss of feeling and movement, seizure, priapism, sudden vision problems, and pain anywhere in the body that is refractory to home treatment. In young children, the first manifestation of SCD may be dactylitis, the inflammation of the metacarpal and metatarsal periosteum.4 Complications of vaso-occlusive crisis are listed in Table 1.
Although laboratory tests are not useful indicators of a vaso-occlusive crisis, they can help to identify an infectious process or active hemolysis occurring secondary to the patient's chief complaint. Early management of an acute vaso-occlusive crisis should be initiated as soon as vital signs are identified for fever (101°F or 38.3°C or higher), hypoxia (oxygen saturation <94%), tachycardia, tachypnea, or hypotension. After vital signs are addressed, blood samples are retrieved for further evaluation of presence of underlying disease (Table 2).
TREATMENT AND MANAGEMENT
Management for patients with SCD consists of interventions to control pain, minimize infection, and promote good health.
Analgesia The complexity of pain in SCD is often underestimated and misunderstood, leading to inadequate pain management. The pain associated with a vaso-occlusive crisis is described as being worse than postoperative pain and as intense as terminal cancer pain.15 Fear of drug-seeking behavior may lead providers to prescribe opioid analgesics at dosages and frequencies that are lower than those required to optimally control pain. Pain management in patients with SCD should be a multidisciplinary approach, including pharmacologic, behavioral, and complementary and alternative medicine such as heat or ice packs, relaxation, music, massage, prayer, therapeutic exercises, menthol cream rub, acupuncture, and transcutaneous nerve stimulation.16 The goal of acute and long-term treatment should be adequate analgesia through the use of opioids, nonopioids, and adjuvants.16
Opioids are most often used for SCD pain.16 Nonopioids have a ceiling effect—that is, after a certain dose, the drug no longer produces additive analgesic effects.Simultaneous administration of opioids with adjuvants such as antihistamines, antidepressants, anticonvulsants, benzodiazepines, and antiemetics can augment the analgesic effect.16 The opioid of choice, its dose, and the route of administration should be modified according to the patient's history and experience. The response to opioids depends on the type of opioid used as well as the quantity and activity of the opioid receptors in each patient.16
Hydroxyurea First synthesized in 1869, hydroxyurea, which can increase the body's production of HbF, was not studied in clinical trials for SCD treatment until the 1980s. Hydroxyurea was approved by the FDA in 1998 and recommended by the National Heart, Lung and Blood Institute (NHBLI) in 2002 for treatment of patients with SCD.17 Numerous clinical trials have been conducted to examine the benefits, adverse effects, and mortality of long-term hydroxyurea therapy.17
Hydroxyurea is indicated in patients who have had three or more vaso-occlusive crises requiring hospitalizations, two or more acute chest syndromes (infectious or noninfectious pulmonary crises), two or more joints with osteonecrosis, or symptomatic anemia. The primary effect of hydroxyurea therapy is reduction in the frequency of painful crises. Secondary benefits include a small mean increase in hemoglobin level and an increase in HbF compared to the placebo group.18 A major short-term adverse effect of hydroxyurea is reversible bone marrow suppression. Although sufficient data on the long-term adverse effects of hydroxyurea are limited, one study recorded hydroxyurea treatment outcomes over 17 years.18 Of patients in the study who died, 24% (31 of 129) died from pulmonary complications. The majority (87.1%) of these 31 deaths occurred in patients with less than 5 years of exposure or no exposure to hydroxyurea. Only two deaths due to pulmonary complications occurred in the patient group that had a cumulative hydroxyurea exposure of 5 to 10 years; two deaths occurred in the group with 10 to 15 years exposure, and none occurred in the group with 15 or more years exposure to hydroxyurea.18
RBC transfusion Blood transfusions to replace sickle cells with healthy cells and improve oxygen-carrying capacity remain a cornerstone of treatment in patients with SCD.19 Indications include conditions that have the potential to cause life-threatening hypovolemic states, including acute anemia (a decrease in hemoglobin to 6 to 8 g/dL), acute splenic sequestration, acute chest syndrome, and ischemic stroke. RBC transfusions have reduced mortality in 92% of high-risk patients.19 Chronic RBC transfusions are indicated for patients with recurrent splenic sequestration. In young children, because the spleen decreases the risk of pneumococcal infection, RBC transfusions may be administered to delay the need for splenectomy. The American Association of Blood Banks (AABB) generally recommends RBC transfusion in adults and children with hemoglobin of 7 g/dL or less.19 RBC transfusions should be administered to patients with SCD and a hemoglobin of 8 g/dL or less who are postsurgical or have symptoms including chest pain, orthostatic hypotension, tachycardia unresponsive to fluid resuscitation, or heart failure.19
Transfusions can have serious complications including bloodborne infections and hemosiderosis (also called iron overload). The most serious complication is erythrocyte alloimmunization, in which the body develops antibodies in response to donated blood or bone marrow or a transplanted organ. These antibodies attack and destroy the donated blood, marrow, or organ. Suspect alloimmunization if platelet counts 10 to 60 minutes after transfusion are significantly lowered compared to the patient's baseline.
Alloimmunization increases the patient's risk for developing delayed hemolytic transfusion reaction (DHTR), which affects 4% to 11% of patients with SCD who receive transfusions, and usually occurs 5 to 15 days after transfusion.20,21 Patients with DHTR may present with pain and fever and may be misdiagnosed as having a vaso-occlusive crisis. When DHTR occurs in patients with SCD, the transfused RBCs and the patient's own RBCs become hemolyzed, a condition known as hyperhemolysis. This causes the patient's hemoglobin level to fall below the pretransfusion level, causing a life-threatening anemia.
Once DHTR is recognized, treatment is immediate cessation of RBC transfusion, if the patient's clinical state permits, and administration of adequate hydration to maintain good urine output.22
Not all patients develop alloantibodies after exposure to transfused RBCs. Observational studies support the idea that racial and ethnic antigenic variations between donors account for increased alloimmunization rates.20 Nevertheless, the long-term benefits of RBC transfusions outweigh the risks, and researchers are conducting ongoing studies in efforts to find therapies to prevent alloimmunization in patients with SCD.21
Splenectomy SCD can affect any part of the body, but the spleen is the organ most often affected and often is the first organ affected.1 In children with SCD, the spleen is commonly enlarged during the first decade of life, then undergoes progressive atrophy leading to autosplenectomy. Splenic complications of SCD are known to be associated with increased morbidity and may lead to mortality. To prevent this complication, splenectomy becomes a vital part of management.
In a study conducted from 1990 to 2004 of 170 children who underwent splenectomy, 76.9% had surgery as a result of acute splenic sequestration crisis, the most common indication for splenectomy, followed by hypersplenism (13.4%), splenic abscess (5.2%), and massive splenic infarction (1.2%).21 Splenectomy in children with SCD is safe given the appropriate operative setting. This surgery also reduces patients' need for transfusion and decreases splenic complications, further eliminating pain.21
Hematopoietic stem cell transplantation Allogeneic hematopoietic stem cell transplantation (also called bone marrow transplantation) from a healthy, compatible donor is the only cure for SCD.23 However, the success of bone marrow transplantation depends on the compatibility of bone marrow donor samples with the patient's bone marrow, which is limited. Complications of transplantation include graft versus host disease, graft rejection, and increased infection rates.
Indications for bone marrow transplantation are listed in Table 3. The first bone marrow transplantation for SCD was performed in 1983 on an 8-year-old patient with leukemia and SCD.23 The bone marrow transplantation cured both diseases.
Preventive health maintenance and supportive care Educate patients with SCD and their caregivers about daily preventive measures to promote good health. These include maintaining good hydration, avoiding high altitudes and extremely hot or cold environments, avoiding increased physiologic and emotional stress, taking time to relax, getting active and eating healthfully, preventing infection, and seeking medical attention at the first indication of a vaso-occlusive crisis.
Antibiotics Patients with SCD, specifically children under age 5, are at increased risk of life-threatening pneumococcal infection. The patient's spleen may have been removed or be unable to filter encapsulated bacteria such as Streptococcus pneumonia and Haemophilus influenzae from the bloodstream.24 These bacteria can cause serious illness in young children in as little as 24 hours. Infants and very young children are especially vulnerable because they are unable to develop antibodies against encapsulated organisms. The US Preventive Services Task Force and the American Academy of Pediatrics recommend penicillin prophylaxis in children under age 5 who have SCD, and in older children who have had a previous severe pneumococcal infection or have functional or surgical asplenia.11,25 Infants with SCD should receive prophylactic penicillin starting by age 2 months. According to the Prophylactic Penicillin (PROPS) study, the recommended dose for children age 5 and younger is 125 mg of penicillin V potassium twice daily; for children over age 5, the recommended dose is 250 mg of penicillin V potassium twice daily.11,25
According to the CDC and the Advisory Committee on Immunization Practices (ACIP), in addition to routine childhood immunizations, pneumococcal vaccines are indicated for all children ages 2 to 59 months and children ages 60 to 71 months with SCD or medical conditions that increase their risk for pneumococcal disease.26 These children should receive pneumococcal conjugate vaccine (PCV13) or Prevnar 13 at 2, 4, and 6 months, and between 12 and 15 months, and 23-valent polysaccharide vaccine (PPVSV23) Pneumovax at age 2.26 For prevention against H. influenzae infections, the ACIP recommends that all children receive the H. influenza vaccines beginning routinely at 2 months. Administration of the vaccine series may be initiated as early as age 6 weeks.26 SCD-related deaths among African American children younger than 4 fell by 42% from 1999 through 2002 after the implementation of routine childhood vaccinations.11
Patients with SCD have a decreased life expectancy and their quality of life is greatly compromised by their disease.7 The Pain in Sickle Cell Epidemiology Study (PiSCES) Project surveyed the physical and emotional function, bodily pain, vitality, social function, mental health, and general health of patients with SCD.27 Patients with SCD were found to have health-related quality of life scores worse than the general population and similar to patients undergoing hemodialysis.27 For these reasons, clinicians must be able to recognize SCD and identify signs of a vaso-occlusive crisis so that patients can obtain prompt treatment and avoid complications. Through education, disease recognition, therapy, and preventative measures, clinicians can improve the quality of life in patients with SCD.
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14. Lanzkron S, Strouse JJ, Wilson R, et al. Systematic review: hydroxyurea for the treatment of adults with sickle cell disease. Ann Intern Med. 2008;148;939–955.
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16. Ballas SK. Current issues in sickle cell pain and its management. Hematology Am Soc Hematol Educ Prog. 2007:97–105.
17. Segal JB, Strouse JJ, Beach MC, et al. Hydroxyurea for the treatment of sickle cell disease. Evidence Report/Technology Assessment. 2008;165:1–298.
18. Steinberg MH, McCarthy WF, Castro O, et al. The risks and benefits of long-term use of hydroxyurea in sickle cell anemia: a 17.5 year follow-up. Am J Hematol. 2010;403–408.
19. Yazdanbakhsh K, Ware RE, Noizat-Pirenne F. Red blood cell alloimmunization in sickle cell disease: pathophysiology, risk factors, and transfusion management. Blood. 2012;120(3):528–537.
20. Definition of alloimmunization. eMedicinehealth.com. Accessed November 28, 2012.
21. Al-Salem AH. Indications and complications of splenectomy for children with sickle cell disease. J Pediatr Surg. 2006;41(11):1909–1915.
22. Whitley-Smith K, Thompson AA. Indications and complications of transfusions in sickle cell disease. Pediatric Blood Cancer. 2012;59:258–364.
23. Hsieh MM, Fitzhugh CD, Tisdale JE. Allogeneic hematopoietic stem cell transplantation for sickle cell disease: the time is now. Blood. 2011;118(5):1197–1207.
24. Thompson LM, Ceja ME, Yang SP. Stem cell transplantation for treatment of sickle cell disease: bone marrow versus cord blood transplants. Am J Health-Syst Pharm. 2012;69(15):1295–1302.
25. Cober MP, Phelps SJ. Penicillin prophylaxis in children with sickle cell disease. J Pediatr Pharmacol Ther. 2010;15(3):152–159.
26. Nuorti JP, Whitney CG. Prevention of Pneumococcal disease among infants and children-use of 13-valent Pneumococcal conjugate vaccine and 23-valent Pneumococcal polysaccharide vaccine. Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases. December 2010. 59;1-18. http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5911a1.htm
27. McClish DK, Penberthy LT, Bovbjerg VE, et al. Health related quality of life in sickle cell patients: the PiSCES project. Health Quality Life. 2005;3:50.
sickle cell disease; hemoglobin; vaso-occlusive crisis; hydroxyurea; red blood cells
© 2013 American Academy of Physician Assistants.