Current Management of Sickle Cell Anemiaperspectivesinmedicine.cshlp.org/content/3/8/a011817... · 2013. 7. 29. · Current Management of Sickle Cell Anemia Patrick T. McGann 1,2,

Current Management of Sickle Cell Anemia

Patrick T. McGann1,2, Alecia C. Nero3, and Russell E. Ware1,2

1Texas Children’s Center for Global Health, Houston, Texas 770302Texas Children’s Hematology Center, Baylor College of Medicine, Houston, Texas 770303University of Texas Southwestern Medical Center, Dallas, Texas 75390

Correspondence: [email protected]

Proper management of sickle cell anemia (SCA) begins with establishing the correct diag-nosis early in life, ideally during the newborn period. The identification of affected infants byneonatal screening programs allows early initiation of prophylactic penicillin and pneumo-coccal immunizations, which help prevent overwhelming sepsis. Ongoing education offamilies promotes the early recognition of disease-released complications, which allowsprompt and appropriate medical evaluation and therapeutic intervention. Periodic evalua-tion by trained specialists helps provide comprehensive care, including transcranial Dopplerexaminations to identify children at risk for primary stroke, plus assessments for other paren-chymal organ damage as patients become teens and adults. Treatment approaches thatpreviously highlighted acute vaso-occlusive events are now evolving to the concept ofpreventive therapy. Liberalized use of blood transfusions and early consideration of hydroxy-urea treatment represent a new treatment paradigm for SCA management.

The natural history of untreated sickle cellanemia (SCA) is well described and docu-

ments serious morbidity and early mortality(Powars 1975; Platt et al. 1994; Serjeant 1995;Powars et al. 2005). Hemolytic anemia, acutevaso-occlusive events (VOEs), and chronic end-organ damage begin early in life, and complica-tions accumulate throughout childhood. With-out early identification or specific interventions,many patients with SCA have poor qualityof life,and most die as young adults of SCA-relatedcomplications (Diggs 1973; Rogers et al. 1978).

Fortunately great strides have occurred overthe past 40 years, and better management strat-egies have altered this previously bleak outlook.Despite the complexity and multifactorial path-

ophysiology of vaso-occlusion (Ware 2010a),relatively straightforward measures have greatlyimproved outcomes for children with SCA: (1)early identification by neonatal screening pro-grams; (2) education of parents and patientsabout medical complications and early recogni-tion; (3) preventive measures with prophylacticpenicillin and pneumococcal immunizations;(4) aggressive treatment of acute VOEs includ-ing hydration, analgesics, antibiotics, and trans-fusions; (5) screening programs for early signsof organ damage, especially primary stroke riskusing transcranial Doppler (TCD) examina-tions; and (6) therapeutic intervention withtransfusions, hydroxyurea, or stem cell trans-plantation. For children receiving medical care

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at comprehensive care programs, 95%–99%survival rates into adulthood are documented(Telfer et al. 2007; Quinn et al. 2010). For adultswith SCA, screening programs and anticipatoryguidance are less standardized but still critical,and the benefits of preventive therapy using hy-droxyurea are even more compelling.

Here we will focus primarily on the manage-ment of SCA (HbSS or HbS/b0-thalassemia).We emphasize and summarize general princi-ples of care and management, rather than dis-cussing details of pathophysiology or mecha-nisms of disease. The management of specificexamples of acute VOEs will be highlighted.

EARLY IDENTIFICATION

Perhaps the most critical aspect of optimizingSCA management is early identification of af-fected patients, before the onset of signs andsymptoms of disease. Without early diagnosisand intervention, SCA often acts as a swift andinvisible killer, with many infants dying sud-denly of bacterial sepsis or acute splenic seques-tration crisis (ASSC) within the first few years oflife (Pearson et al. 1969, 1977; Rogers et al. 1978;Powars et al. 1981). Sometimes fatal complica-tions occur even before families or medical pro-viders are aware the infants have SCA.

With the recognition that infants with SCAhave greatly increased risk of bacterial sepsis,the landmark multicenter double-blinded pla-cebo-controlled PROPS trial proved that peni-cillin prophylaxis significantly lowered the risk

of bacteremia and death (Gaston et al. 1986).This simple intervention provided the justifica-tion needed for newborn screening of SCA, toidentify affected infants soon after birth and toallow lifesaving prophylactic antibiotic therapy.Although a 1987 NIH Consensus Conferencerecommended newborn screening for SCA,universal screening was not accomplished inall U.S. states and territories until 2006.

Newborn screening programs in the UnitedStates, Jamaica, and Europe have documentedthe utility of early identification of SCA, with amarked reduction in morbidity and mortality,especially in the first 5 years of life (Rogers et al.1978; Vichinsky et al. 1988; Almeida et al. 2001;Bardakdjian-Michau et al. 2001). Figure 1 illus-trates that early identification of SCA throughneonatal screening programs has contributed tothe improved survival rates (Quinn et al. 2010).

Testing of newborns in the United States forSCA began with targeted screening, which in-volves selecting at-risk populations to screen,such as babies whose parents are African-Amer-ican. Such an approach is problematic in severalways, and has evolved now to universal screeningfor all newborns. In contrast, most Europeancountries still perform targeted screening for in-fants most likely to be affected, such as those ofAfricanancestry.Althoughpotentiallycost-effec-tive, targeted screening almost certainly missessome babies with SCA, and presents difficultiesrelated to both equity and logistics (Grosseet al. 2005). Despite the high burden of disease,newborn screening has yet to be implemented

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Figure 1. Survival curves of infants with SCA in the United States and Jamaica, byera. This research was originallypublished in Blood. (From Quinn et al. 2010; reprinted, with permission, # American Society of Hematology.)

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systematically in Africa, although pilot studiesdocument a high incidence of trait and disease.

Newborn screening for SCA requires a smalldried blood spot (DBS) for analysis, collectedfrom cord blood or the infant’s heel/toe. Collec-tion technique is important; DBS specimenshave variable quality by the amount and distri-bution of blood on the filter paper. Specimensare most easily collected in the neonatal periodfor babies born in the hospital, or during initialimmunization visits for babies born at home.Testing in the United States is most commonlyperformed by hemoglobin electrophoresis usingisoelectric focusing (IEF), which easily distin-guishes abnormal sickle hemoglobin (Hemoglo-bin S, HbS) from normal hemoglobin (HbA)and fetal hemoglobin (HbF), as illustrated inFigure 2. High-performance liquid chromatog-raphy (HPLC), capillary electrophoresis (CE)techniques, and even DNA-based laboratory di-agnosis also can be used for accurate diagnosis.When possible, parental studies should also beperformed to confirm the diagnosis of SCA.

EDUCATION

Parental and family sickle cell education shouldbegin once the diagnosis is made and continuethroughout childhood. Given variable parental

education and literacy, education should be pro-vided in written and spoken form, and shouldbe repeated with each visit to ensure informa-tion is comprehended. When possible, both par-ents should receive education, plus extendedfamily members and other caregivers, to becomeknowledgeable about SCA.

Education in the early newborn periodshould focus on the basics of SCA, includingits genetics and inheritance, need for penicil-lin prophylaxis, and benefits of protein-conju-gated pneumococcal immunizations. At eachvisit these key points should be repeated to par-ents and caregivers. The importance of regularmedical care should be emphasized, especial-ly the need for prompt medical evaluation forfever. Antipyretics should never be given for fe-ver at home, because this treatment can maska serious infection. Education for young pa-tients should also include signs and symptomsof ASSC: pallor, fussiness or irritability, andtender splenomegaly. Teaching parents to pal-pate their baby’s spleen regularly, ideally severaltimes a day during routine diaper changes, al-lows early diagnosis of ASSC and potentiallyprompt and lifesaving intervention.

As the child grows, education should focusmore on recognition and early medical inter-vention for acute vaso-occlusive complications

Figure 2. Isoelectric focusing (IEF) electrophoresis technique for identification of SCA. Blood specimens fromAA, AS, and SS patient controls are shown on the left, along with a manufactured Hb AFSC control in the center.Newborn samples, typically obtained from dried blood spots, are tested for the abnormal FS pattern indicatingSCA, versus the normal FA pattern or FAS pattern indicating sickle cell trait.

Management of Sickle Cell Anemia

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such as dactylitis and other painful events, res-piratory distress, acute chest syndrome, andstroke. Parents should learn to manage mildpain at home with oral hydration and analgesia.At an early age, families should be introducedto possible treatment options including hy-droxyurea and transfusions, and even stem celltransplantation, if available. As affected childrengrow up and enter adolescence, it is critical toprovide ongoing education about SCA and itscomplications, to provide young patients withthe skills necessary to understand and advocatefor their own medical care. Such self-awarenessand investment in their medical care becomescritically important on transition from pedi-atric to adult hematology care. Unfortunate-ly, evidence suggests increased morbidity andmortality in late adolescence and early adult-hood following this transition of care (Brous-seau et al. 2010; Quinn et al. 2010).

PREVENTIVE MEASURES

As the result of vascular congestion, intrapar-enchymal sickling, and hypoxic injury to thespleen, infants with SCA have early loss of fil-trative splenic function and are susceptible toacute life-threatening infections, particularlyfrom encapsulated bacteria such as Streptococ-cus pneumoniae and Haemophilus influenzaetype b (Winkelstein and Drachman 1968; Pear-son et al. 1969; Pearson 1977). This risk remainsincreased throughout life, but is most signifi-cantly increased in the first 5 years, when bac-teremia incidence is the highest (Overturf et al.1977; Powars et al. 1981; Gill et al. 1995).

The PROPS trial showed that prophylacticoral penicillin reduced the frequency of bacterialinfection by 84% among young children (age 3–36 mo) with SCA (Gaston et al. 1986). However,the follow-up PROPS 2 study was unable toshow benefit from penicillin after age 5 yr, pri-marily owing to their lower incidence of bacter-emia (Falletta et al. 1995). After introduction ofprotein-conjugated pneumococcal vaccines, theincidence of invasive pneumococcal disease de-creased by 93.4% among young children withSCA (Halasa et al. 2007). In Africa the dangersof pneumococcal sepsis for children with SCA

have been questioned, but recent data confirmits prevalence and lethality (Williams et al.2009).

Based on overwhelming evidence, earlypneumococcal prophylaxis is recommendedfor all infants with SCA. Penicillin 125 mg bymouth twice daily should begin by 3–4 mo ofage, as a liquid formulation or crushed tablet.The penicillin dose should be increased to250 mg by mouth twice a day as the child grows,typically at 3 yr of age. Some international pro-grams recommend monthly IM penicillin tohelp ensure compliance. Oral erythromycin canbe used as a substitute if penicillin allergy or rashdevelops, but this is uncommon.

Pneumococcal immunization should beginwith locally available pneumococcal conjugatevaccines (7, 10, or 13 valency) and supplement-ed at age 2 and 5–7 yr with the 23-valent pneu-mococcal polysaccharide vaccine (Pneumovax).Additional recommended vaccinations includethe H. influenzae type b series, meningococcalconjugate vaccine (Menactra), and yearly influ-enza. When locally feasible, the published im-munization schedule for high-risk childrenas recommended by the American Academyof Pediatrics (www2.aap.org/immunization/IZSchedule.html) should be followed.

Penicillin prophylaxis should continuethrough age 5, when the risk of invasive bacterialdisease is lower. Once the immunization series isup to date, including the Pneumovax booster,children with SCA may discontinue penicillinprophylaxis. However, penicillin should be con-tinued indefinitely if a child has had culture-positive sepsis or a surgical splenectomy.

The dramatically increased risk of over-whelming and rapidly fatal infection amongyoung patients with SCA must be understoodby all caregivers and medical providers. Fe-ver .38.58C is a medical emergency requiringprompt medical evaluation, including physicalexamination with vital signs and splenic palpa-tion, blood culture, complete blood count, re-ticulocytes, urinalysis, and chest X-ray if clini-cally warranted. Type and crossmatch should beobtained if there is extreme pallor, splenome-galy, clinical instability, or acute respiratory orneurologic symptoms. Afterobtaining the blood

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culture, broad-spectrum antibiotics (e.g., ceftri-axone) should be administered intravenously.Addition of another broad-spectrum antibiotic(e.g., vancomycin) should be considered if thechild appears toxic, has high fever, or suspicionof central nervous system (CNS) infection.

Hospitalization is recommended if clinicalor laboratory indicators suggest sepsis, such ashemodynamic compromise including hypoten-sion, child ,1 yr of age, prior history of sepsis,temperature .408C, WBC .30 � 109/L, or,3 � 109/L, concurrent symptoms such aspain or acute anemia, or if close follow-up isnot reliable (Lane et al. 2001).

ACUTE VASO-OCCLUSION

Pain Events

The sudden onset of pain that occurs frequentlyin patients with SCA results from acute intra-vascular sickling, so is often referred to as pain-ful VOE or vaso-occlusive “crisis” (VOC). Al-though many providers and patients use thesimple phrase “pain crisis,” VOE is preferablebecause it broadly defines the process andavoids stigma about pain perception and man-agement.

The VOE results from erythrocyte sickling,microvascular occlusion, and tissue ischemia/reperfusion, and is a hallmark clinical featureof SCA. Pain is the most common cause of acutemorbidityof SCA, and is associated with severityof disease and early mortality among youngadults (Platt et al. 1991). Pain often accompaniesacute chest syndrome (ACS), a serious and po-tentially life-threatening complication of SCA,in 72% of cases (Platt et al. 1994; Vichinsky et al.2000). This association usually follows sternal ortruncal pain, which leads to splinting and poorinspiratory effort, and lack of active and com-plete inspiration following opioid-induced se-dation. The frequency and severity of pain inSCA is more than just episodic and acute, how-ever; pain in SCA is often chronic, underrecog-nized and underreported, and therefore under-treated (Solomon 2008). Pain diaries of 232adult patients showed that SCA pain is commonand often chronic; pain was present on 54.5% of

days and 29.3% of patients reported pain on.95% of days (Smith et al. 2008).

The pathophysiology of vaso-occlusive painis multifactorial and complex, and includesvarious blood cells including reticulocytes andneutrophils, plus plasma factors and vascularendothelium (Ware 2010a). Several factors havebeen identified as triggers of painful VOE, withindividual patients often recognizing their ownspecific triggers. The most commonly describedtriggers include cold temperatures and especial-ly cold water, as well as dehydration, overexer-tion, and menses (Redwood et al. 1976; Resarand Oski 1991; Yoong and Tuck 2002).

A combination approach of nonpharmaco-logic and pharmacologic agents should be usedfor acute management of vaso-occlusive painfulevents. Nonpharmacologic interventions withshown effectiveness include oral hydration,heat, massage, and various cognitive-behavioraland self-relaxation techniques (Rees et al. 2003;Dampier et al. 2004). Cold packs can increaselocal sickling and may exacerbate pain, so shouldbe avoided. Pharmacologic interventions shouldbegin at home with nonopioid analgesics, in-cluding acetaminophen and nonsteroidal an-ti-inflammatory drugs (NSAIDs); ibuprofen(10 mg/kg or 800 mg for adults .40 kg every6–8 h) is an effective oral agent given its po-tent analgesic and anti-inflammatory proper-ties. Corticosteroids may reduce the durationof painful VOE but on discontinuation, are as-sociated with an increased frequency of re-bound painful episodes requiring readmission(Griffin et al. 1994), and so are relatively con-traindicated for routine pain management. Ifpain is not controlled with increased hydration,oral analgesia, and other conservative measures,opioids should be used. Oral narcotic therapysuch as codeine and its derivatives can often beused effectively at home, in selected settings andpatients.

In the event of severe vaso-occlusive painrequiring formal medical evaluation, aggressivepain management should be implementedpromptly with intravenous hydration and opi-oid (morphine or hydromorphone) analgesia,and adjuvant intravenous NSAID therapy. His-torically, the most painful VOEs have been



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evaluated and treated in the local emergencyroom, but given the relative lack of sickle cellknowledge and familiarity among some health-care providers, such evaluations have delays ininitiating appropriate analgesia, poor pain con-trol, and a high rate of hospital admission. Asickle cell day hospital approach, which featuresstaffing by experienced sickle cell providers, isincreasingly used and results in improved painmanagement, better patient satisfaction, anddecreased rates of hospitalization for bothadults and children with SCA (Benjamin et al.2000; Raphael et al. 2008).

During treatment of VOE, frequent evalua-tion of pain is important to assess the degree ofrelief and potential side effects of narcotic anal-gesia. When hospitalization is required, contin-uous opioid infusion by patient-controlled an-algesia (PCA) is recommended (van Beers et al.2007; Jacob et al. 2008). Figure 3 illustrates aconvenient algorithm to consider for manage-ment of mild to severe painful VOE, but flexi-bility should exist for individual patient prefer-ences. When opioids are used, an aggressivebowel regimen should be used concurrently toreduce gastrointestinal complications, especially

Conservative measures at home(increase fluid intake, heating pad, massage, rest)

Oral NSAID(Ibuprofen 10 mg/kg PO q6h [max 800 mg q6h])

Add oral narcotic(acetaminophen with codeine, oxycodone, etc.)

If pain persists, seek medical attention

Home

- Morphine 0.1 mg/kg IV- Ketorolac 0.5 mg/kg (max 30 mg)- Intravenous hydration (normal saline 10–15 mL/kg)

ER/dayhospital

(Moderate to severe pain) Reassess q15–30

min

If pain improves, discharge home with oral pain regimen

If pain persists, repeatmedications above

If pain persists despite repeat interventions, initiatepatient-controlled analgesia (PCA) in ED andarrange for inpatient hospitalization

- Morphine/hydromorphone PCA

- Ketorolac 0.5 mg/kg IV q6h

- Intravenous hydration 1.5× maintenance

- Bowel regimen (polyethylene glycol, etc.)

- Incentive spirometry q10–15 min while

awake

- Frequent pain assessments

Inpatient

(Severe andunrelenting pain)

(Mild tomoderate pain)

Figure 3. Algorithm for the management of painful vaso-occlusive events.

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hypomotility (O’Brien et al. 2010). Teachingand encouraging frequent incentive spirometrywith ambulation can reduce the risk of develop-ing complications including ACS (Bellet et al.1995; Ahmad et al. 2011).

Acute Splenic Sequestration Crisis

ASSC remains an important cause of morbidityand mortality for young children with SCA.Most ASSC events occur in infants or toddlersbefore age 2 yr. In some cases, ASSC may be thefirst clinical manifestation of SCA, and henceshould be emphasized in the education of fam-ilies during the first year of life.

The pathophysiology of ASSC involveserythrocyte sickling and rapid accumulationwithin the spleen. ASSC is clinically defined asa decrease in baseline hemoglobin concentra-tion by �2 g/dL, in the presence of active retic-ulocytosis and splenomegaly; mild thrombocy-topenia is common. The acute sequestrationevent can result in severe anemia, occasionallywith hypovolemia, and even can evolve to cir-culatory shock or death (Topley et al. 1981;Emond et al. 1985; Powell et al. 1992).

Medical management of ASSC begins withearly recognition and diagnosis; parents andcaregivers must be educated about early signsand symptoms and the need to seek urgentmedical evaluation. After initial assessment in-cluding vital signs and physical examination,laboratory studies should include completeblood count with reticulocytes, blood cultureif febrile, and type and crossmatch. Transfu-sion volumes should not be excessive because atransfusion “overshoot” phenomenon can occurwhen the spleen abruptly unloads trappederythrocytes, raising the hemoglobin level abovethe target goal. Small aliquots (from the sameunit) should be administered every 12–24 h totreat anemia and hypovolemia, while avoidinghyperviscosity following splenic release.

Recurrent ASSC events are common, occur-ring in about half of the children who survivethe first episode. Chronic transfusions can beimplemented after the first episode, but theirbenefits on reducing recurrent events or avoid-ing splenectomy are limited (Kinney et al. 1990).

The benefits of splenectomy for ASSC must becompared to its infectious and other postoper-ative risks; surgery is usually recommendedonly after one severe or life-threatening ASSCevent, or after several recurrent ASSC events.Pneumococcal immunizations should be com-pleted before surgery, and then lifelong peni-cillin prophylaxis is recommended (Ammannet al. 1977; Deodhar et al. 1993). Partial or sub-total splenectomy could potentially preservesome filtrative and immunological splenicfunction, but published reports in SCA aresparse and anecdotal experiences have been un-successful (Rice et al. 2003).

Acute Chest Syndrome

ACS is a common cause of morbidity and aleading cause of death among adults with SCA(Castro et al. 1994; Gill et al. 1995; Vichinskyet al. 2000; Powars et al. 2005). First describedover 30 years ago (Charache et al. 1979), ACS hasa complex pathophysiology that remains poorlydefined. Numerous etiologies have been pro-posed including typical and atypical bacterialpathogens (Miller et al. 1991; Vichinsky et al.2000; Neumayr et al. 2003), viral infection(Lowenthal et al. 1996), fat embolism (Vichin-sky et al. 1994), intrapulmonary sequestrationof erythrocytes (Vichinsky et al. 1994), and ni-tric oxide–hemoglobin interactions (Gladwinet al. 1999).

ACS is defined as a constellation of signs andsymptoms including respiratory distress withtachypnea and dyspnea, hypoxemia, fever, ele-vated WBC count, mild anemia, and new infil-trate on chest X-ray (Castro et al. 1994; Vichin-sky et al. 2000; Ballas et al. 2010). ACS is oftencharacterized by rapid clinical decline, so a highindex of suspicion is needed for early identifi-cation and intervention. The onset of ACS maybe insidious, often including pain, with nearly50% of patients admitted with a different diag-nosis. Sternal and rib pain often leads to splint-ing and poor inspiration, which coupled withmild respiratory depression from opioids, canquickly deteriorate into a serious condition re-quiring aggressive respiratory and hematologi-cal support. To avoid this sequence of events,



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incentive spirometry can reduce the incidenceof ACS and should be mandatory for all hospi-talized patients with SCA (Bellet et al 1995; Ah-mad et al. 2011).

Worsening hypoxemia or tachypnea, andearly radiographic changes should lead to ag-gressive incentive spirometry, and oxygen ther-apy to correct hypoxemia. Close management offluid status is warranted to prevent fluid over-load. Although hyperhydration is typically rec-ommended for painful VOE to improve bloodflow, intravenous fluids should be limited to50%–75% maintenance in the setting of evolv-ing ACS, to reduce the risks of developing pul-monary edema or pleural effusions and wor-sening respiratory distress. Despite the lack ofrandomized clinical trials investigating the effi-cacy of antibiotics for ACS (Martı-Carvajal etal. 2007), coverage is provided for typical com-munity-acquired and atypical pathogens, suchas a broad-spectrum third-generation cephalo-sporin and macrolide (Lottenberg and Hassell2005). Bronchodilators are not effective for allpatients but are recommended for patients withACS and concurrent reactive airways disease orasthma (Knight-Madden and Hambleton 2003;Knight-Madden et al. 2005).

Transfusions are often used for ACS (Lanz-kowsky et al. 1978; Vichinsky et al. 2000), im-proving both anemia and oxygen-carrying ca-pacity. Early simple transfusions are beneficialand can avert clinical deterioration that mightwarrant later exchange transfusion. Significantrespiratory distress or clinical decompensation,hemoglobin �2 g/dL below baseline, and oxy-gen saturation .5% below baseline are all in-dications for packed red blood cell (PRBC)transfusion (Miller 2011). Automated erythro-cytapheresis should be used for severe ACS as-sociated with significant respiratory distress orhypoxia (Kleinman et al. 1984; Velasquez et al.2009). There is no current evidence that inhalednitric oxide (NO) has a beneficial role in thecurrent management of ACS (Gladwin et al.1999; Al Hajeri et al. 2008), but several clinicaltrials are ongoing. For recurrent ACS, bothchronic transfusion programs (Miller et al.2001a; Hankins et al. 2005a) and hydroxyurea(Steinberg et al. 2003; Hankins et al. 2005b;

Wang et al. 2011) can reduce the frequencyand severity of additional ACS events.

Stroke

Cerebrovascular accidents are a relatively com-mon and devastating complication of SCA, withan overt stroke incidence rate of 11% by age 20years and 24% by age 45 (Ohene-Fremponget al. 1998). Clinical stroke events representonly a fraction of the cerebrovascular complica-tions of SCA, which include silent cerebral in-farctions (Miller et al. 2001b; Pegelow et al.2001; DeBaun et al. 2012) and other neurocog-nitive deficits (Schatz et al. 2001; Thompsonet al. 2002).

In the setting of acute clinical stroke, quicklyreestablishing cerebral blood flow is crucial;new-onset weakness or aphasia suggests strokeand intervention should never depend on con-firmatory radiological imaging. Modest IV hy-dration can help acutely, and should be pro-vided while blood is being crossmatched fortransfusion. Particularly for children with severeanemia, a simple PRBC transfusion can rapidlyreduce intravascular sludging and help improvecerebral blood flow, which is critical to helpreverse acute symptoms and prevent stroke pro-gression. When available, exchange transfusionshould be performed promptly to reduce HbS,30%, with a target hemoglobin concentrationof �10 g/dL (Swerdlow 2006). A retrospectiveanalysis of children with overt stroke suggestedchildren receiving exchange transfusion had asignificantly lower risk of recurrent stroke, com-pared to children receiving only simple transfu-sion (Hulbert et al. 2006).

After an initial stroke, the risk of recurrentstroke events is 47%–93% without specifictreatment (Powars et al. 1978; Balkaran et al.1992; Pegelow et al. 1995). Chronic transfusionsprovided every 3–4 wk to maintain HbS of�30% are recommended to prevent recurrentevents (Lusher et al. 1976; Pegelow et al. 1995;Strater et al. 2002; Platt 2006). Once initiated,transfusions should be continued indefinitely,because discontinuation of transfusions is asso-ciated with increased risk of recurrent events(Wang et al. 1991; Adams and Bramilla 2005).

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Although efficacious, 10%–20% of patients willdevelop a second stroke despite transfusions(Pegelow et al. 1995; Scothorn et al 2002). Re-cent evidence further shows progression of vas-culopathy and silent cerebral infarctions amongchronically transfused patients (Hulbert et al.2011). Hydroxyurea for the prevention of recur-rent stroke, coupled with phlebotomy to removeiron overload, has shown efficacy (Ware et al.1999, 2004), but in a phase III randomized clin-ical trial was inferior to transfusions and chela-tion therapy (Ware and Helms 2012). In certainclinical settings in which chronic transfusionsare unsafe or otherwise not feasible, however,hydroxyurea may be a viable treatment option(Ali et al. 2011).

SCREENING PROGRAMS

Prevention of complications is the ideal way toreduce the morbidity of acute VOE and poten-tially limit chronic organ damage; this is espe-cially true when considering devastating neu-rologic events like stroke. Because blood flowvelocity is inversely related to vessel diameter,the measurement of intracerebral arterial bloodflow by transcranial Doppler ultrasonography(TCD) allows easy and noninvasive identifica-tion of large vessel stenosis and can accuratelyidentify children at increased risk of developingprimary stroke (Adams et al. 1992). Children

with SCA have increased mean flow velocitieswhen compared to children without anemia(Adams et al. 1989, 1992), and markedly elevat-ed TCD values represent a biomarker of cere-brovascular disease and a significant risk factorfor primary stroke.

Based on its utility of screening for strokerisk, both with efficacy in clinical trials (Adamset al. 1998) and effectiveness in clinical practice(McCarville et al. 2008; Enninful-Eghan et al.2010; Bernaudin et al. 2011; Kwiatkowski et al.2011), TCD screening is recommended annual-ly for children with SCA starting at the age of2–3 years. Figure 4 illustrates the recommendedscreening regimen and algorithm for manage-ment of TCD results (Platt 2006; McCarvilleet al. 2008). The risk of first stroke can be nearlyeliminated by the initiation of a chronic trans-fusion program to decrease HbS ,30% fortime-averaged maximum blood flow velocities.200 cm/sec in the internal carotid or middlecerebral artery (Adams et al. 1998; Lee et al.2006). Despite its clear efficacy for preventionof primary stroke, the risks of chronic transfu-sion therapy are significant and include ironoverload, alloimmunization, and cost (Rosseet al. 1990; Harmatz et al. 2000; Wayne et al.2000). Hydroxyurea therapy at maximum toler-ated dose (MTD) also can reduce TCD veloci-ties (Zimmerman et al. 2007) and the ongoingTWiTCH trial (ClinicalTrials.gov NCT00122980)

Transcranial Dopplerultrasound (TCD) screening

for all children with SCA,starting at age 2

NormalTCD <170 cm/sec

Repeat yearly untilnormal (<170 cm/sec) × 3

Repeat in 3–6months

Confirm abnormalresult in 1 month

RepeatTCD >200 cm/sec

Obtain MRI

Initiate transfusiontherapy

AbnormalTCD ≥200 cm/sec

ConditionalTCD 170–199 cm/sec

Figure 4. Transcranial Doppler screening algorithm for children with SCA.



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compares the efficacy of hydroxyurea versustransfusions for prevention of primary strokein children with abnormal TCD velocities.

ADULT CARE

Improved care of the child with SCA has led toincreased survival rates into adulthood, andnow attention must be focused on appropriatemanagement of this older population. The suc-cess of neonatal and pediatric care leads to theformidable task of transitioning patients to theadult healthcare arena, in which providers oftenare neither trained adequately nor prepared tomanage their unique needs. Written guidelinesexist for managing adults with SCA (Lottenbergand Hassell 2005) but most of these recommen-dations do not derive from evidence-based re-search. The upcoming National Heart, Lung,and Blood Institute (NHLBI) guidelines docu-ment for SCA care, anticipated for release anddistribution in 2013, will provide current evi-dence-based guidelines.

Adults with SCD should receive immuniza-tion boosters including pneumococcal, menin-gococcal, and even varicella vaccines based onage-specific recommendations. Management ofacute VOEs such as pain, ACS, stroke, and pri-apism are similar for adults as for pediatric pa-tients, but new issues may emerge related tochronic lung disease, especially restrictive pat-tern; leg ulcers that are difficult to manage andheal; and hepatic, endocrine, and even cardiacdamage related to transfusional iron overload.

Additional screening for specific organdamage is recommended for teens and adults.Baseline pulse oximetry readings will help estab-lish a baseline value and identify chronic hypox-emia. Blood pressure and serum creatinine aretypically lower than age-related published val-ues; hence, values at the upper limit of normalmay indicate renal dysfunction. Dipstick uri-nalysis identifies gross proteinuria, but quan-titative testing for microalbuminuria, using a24-h urine collection if warranted, detects sub-clinical renal disease. Screening for hepatitisB, C, and HIV is warranted for patients whoreceive chronic blood transfusions; serum ferri-tin with review of transfusion history may iden-

tify patients who need iron chelation. Periodicscreening for tricuspid regurgitation jet (TR jet)velocities can identify patients with pulmonaryhypertension and possible early mortality(Gladwin et al. 2004). Ophthalmological screen-ing for retinal disease is warranted every 1–3 yrwith specialist referral for patients with abnor-malities. Additional screening tests for the gene-ral adult population should also be provided,including strategies to prevent or identify cancer,hyperlipidemia, bone density loss, and even di-abetes. (In the latter case, the lack of HbA makesscreening with HbA1c innacurate, but serumfructosamine can be used.)

THERAPEUTIC INTERVENTION

Urgent erythrocyte transfusions are indicatedfor many acute complications of SCA includingACS, ASSC, transient aplastic crisis owing toparvovirus B19 infection, and acute stroke. Inthese settings, transfused blood helps to allevi-ate anemia, improve circulating blood volume,increase oxygen-carrying capacity, and provideerythrocytes that cannot sickle. If the posttrans-fusion target is high enough, transfusions alsohelp suppress endogenous sickle erythropoiesis.Elective transfusions are often given for preop-erative management, to prevent perioperativesickle-related complications. Chronic transfu-sions given on a monthly basis are also highlyefficacious for primary and secondary strokeprevention. In contrast, transfusions are not in-dicated for acute painful events or anemia per se(recognizing that almost all patients have a base-line steady-state partially compensated hemo-lytic anemia), and have little role in the man-agement of standard VOE (Smith-Whitley andThompson 2012).

In most acute settings, simple transfusionswith packed erythrocytes (PRBC) should be ad-ministered. PRBC are readily available acrossthe United States, and are routinely tested forHIV as well as hepatitis B and C. As a generalprinciple, simple transfusions should be givenwith a target of alleviating anemia or treatingthe underlying condition; whole units (or halfunits for small pediatric patients) should be ad-ministered whenever possible, instead of fixed

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volumes (e.g., 10 mL/kg), to help limit foreignantigen exposure. The posttransfusion targethemoglobin concentration should not exceed10–11 g/dL in the untreated patient becausehyperviscosity can occur; in chronically trans-fused patients with low %HbS, however, theposttransfusion target can be raised to help sup-press endogenous erythrocyte production. It isalso important for the Blood Bank to be awarethat the patient has SCA, because extending redblood cell (RBC) phenotype matching for mi-nor blood group antigens is recommended tohelp prevent alloimmunization (Yazdanbakhshet al. 2012).

For patients with neurological indicationsfor chronic transfusion therapy such as abnor-mal TCD velocities or stroke, repeated simpletransfusions are effective in preventing primaryand secondary stroke, respectively, but ultimate-ly result in transfusional iron overload. For thisreason, partial exchange transfusions or isovo-lemic erythrocytapheresis is recommended tominimize iron accumulation. In most patients,intravenous access for exchange transfusions isfacilitated by the placement of an implantabledevice. With chronic transfusions, the goal istypically HbS �30% as a pretransfusion value,which typically requires transfusion every 3–5weeks depending on the type and volume ofeach transfusion, the patient’s own erythropoi-etic drive, and the response to transfusion ther-apy. Chelation therapy for transfusional ironoverload should be considered for all patientson chronic transfusions, but also for teens andadults who have a large cumulative number ofepisodic or sporadic transfusions.

HYDROXYUREA

Increased fetal hemoglobin (HbF) levels havebeen associated with a less severe phenotypeof SCA (Conley et al. 1963; Diggs 1973; Plattet al. 1991, 1994) and HbF induction has be-come a desired pharmacologic end point forSCA therapy (Charache 1990; Charache et al.1992). Hydroxyurea has been shown to potentlyincrease HbF and is currently the most effectivedisease-modifying therapy for both adults andchildren with SCA (Platt et al. 1984; Steinberg

et al. 2003; Zimmerman et al. 2004; Hankinset al. 2005b). The first clinical experience withhydroxyurea for SCA was reported nearly 30years ago in seminal proof-of-principles studies(Platt et al. 1984). Subsequently, a multicenterphase II study documented laboratory efficacy(increased Hb, %HbF, and MCV; decreasedWBC, ANC, ARC, and platelets) of hydroxyureausing a dose escalation schedule to MTD (Cha-rache et al. 1992). The Multi-Center Study ofHydroxyurea (MSH) double-blinded, placebo-controlled randomized clinical trial showedclinical efficacy of hydroxyurea for adults withsevere SCA, with significantly reduced time tofirst painful event, plus fewer episodes of ACS,transfusions, and hospitalizations (Characheet al. 1995).

In children with SCA, similar laboratory andclinical efficacy have been shown in open-labeltrials (Kinney et al. 1999; Wang et al. 2001; Zim-merman et al. 2004; Hankins et al. 2005b; Thorn-burg et al. 2009). In hydroxyurea study of long-term effects (HUSTLE), all pediatric patientswith medication adherence had HbF responses,although responses were variable and possiblyrelated to differences in drug absorption, phar-macokinetics, andpharmacogenetics (Wareetal.2011). The results from the double-blinded, pla-cebo-controlled multicenter randomized BABYHUG study show the safety and clinical efficacyof hydroxyurea for young infants with SCA, re-gardless of previous clinical severity (Wang et al.2011). The primaryend point of BABY HUG wasthe ability of hydroxyurea to prevent chronic or-gan damage (kidney, spleen), and the short-termstudy results were equivocal. Anecdotal reportssuggest prevention and even reversal of chronicorgan damage with hydroxyurea therapy (Zim-merman et al. 2007; Hankins et al. 2008; Thorn-burg et al. 2009), so further investigation of theBABY HUG cohort is necessary.

Long-term follow up from MSH and theGreek Laikon Study of Hydroxyurea in SickleCell Syndromes documented reduced mortalityfor adult patients with SCA on hydroxyurea(Steinberg et al. 2010; Voskaridou et al. 2010).There is now indisputable evidence that hy-droxyurea has laboratory and clinical efficacyfor all ages; a growing body of evidence also



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supports the long-term safety of hydroxyureaand the abilityof hydroxyureato prevent chronicorgan damage and reduce mortality (McGannet al. 2011). Whereas hydroxyurea previouslyhas been reserved for older patients with a severeclinical course, hydroxyurea use should be lib-eralized and offered to all adults with SCA. Anincreasing number of pediatric hematologistsbelieve hydroxyurea should now be consideredas a treatment option for all children with SCA,regardless of age or previous clinical course.

Hydroxyurea should be initiated by an expe-rienced clinician familiar with laboratory mon-itoring and appropriate dose escalation to MTD.Hydroxyurea treatment should commence at�20 mg/kg/d by mouth, once daily. Completeblood count (CBC) should be checked every4 wk to monitor for myelosuppression, whichis typically mild and dose dependent, and alwaysreversible by holding the hydroxyurea dose tem-porarily (Heeney and Ware 2008). Dose adequa-cy and medication compliance can be assessedby reviewing changes in CBC parameters andreviewing the peripheral blood smear (Fig. 5).To reach MTD, the daily dose should be escalat-ed by �5 mg/kg every 8 wk until MTD is mildneutropenia (e.g., ANC of 1500–3000 � 106/L) or reticulocytopenia (ARC of 100–150 �109/L) is reached on a stable dose. Drug toxicityis usually defined by cytopenias such as ANC,1.0 � 109/L, hemoglobin ,7.0 g/dL withlow reticulocyte count, ARC ,80 � 109/L,and platelets ,80 � 109/L (Heeney and Ware2008). Given the unlikelihood of true hydroxy-urea “nonresponders,” efforts must be made to

encourage medication compliance to reach andmaintain a stable and efficacious hydroxyureaMTD (Ware 2010b).

OTHER TREATMENTS

HbF induction can be achieved by a group ofshort-chain fatty acids that inhibit the enzymehistone deacetylase; such HDAC inhibitors, pri-marily butyrate, can alter chromatin structureand induce HbF production by altering thetranscription of the g-globin gene (McCaffreyet al. 1997; Ataga 2009; Bradner et al. 2010).Clinical experience with HDAC inhibitors forSCA is limited but anecdotal reports suggestrobust HbF induction in some patients withSCA (Atweh et al. 1999; Hines et al. 2008).

Decitabine is a nucleoside analog that in-duces HbF induction via epigenetic modula-tion, specifically hypomethylation of the g-glo-bin gene promoter. Experience with decitabinefor SCA is also relatively limited, but severalreports suggest clinical and laboratory efficacyof subcutaneously administered decitabine inadults who were not responsive to hydroxyurea(Creusot et al. 1982; DeSimone et al. 2002;Saunthararajah et al. 2003, 2008). Prospectivetrials of decitabine are warranted to determineif it has efficacy for a broad spectrum of patientswith SCA.

Additional treatments that target specificpathways of the pathophysiology of SCA arejust entering into clinical trials. One new prom-ising inhibitor of the Gardos channel was foundto have favorable effects on hemolysis and RBC

Figure 5. Blood smear changes with hydroxyurea therapy. A illustrates the untreated patient with anemia andnumerous sickled forms; B is after initiation of hydroxyurea treatment with macrocytosis and more target cells;and C is after reaching a stable hydroxyurea MTD with less anemia and fewer sickled forms. (From Ware 2010b;reprinted, with permission.)

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survival, yet did not have clinical efficacy in aphase III randomized clinical trial (Ataga et al.2011).

CONCLUDING REMARKS

Decades of observational studies and therapeu-tic trials have contributed to a greater under-standing of the pathophysiology and manage-ment of SCA. Based on these results, relativelysimple interventions can substantially improvethe survival of SCA, especially among children.Newborn screening, early preventive treatments,education about complications, and screeningprograms improve both the morbidity and mor-tality of SCA. Going forward, attention mustfocus on the care and management of teensand adults with SCA, and address quality oflife as well as medical complications. More ag-gressive treatment of SCA is supported by cur-rent evidence, and therapeutic options with hy-droxyurea should be considered early in life.

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24, 20132013; doi: 10.1101/cshperspect.a011817 originally published online MayCold Spring Harb Perspect Med

Patrick T. McGann, Alecia C. Nero and Russell E. Ware Current Management of Sickle Cell Anemia

Subject Collection Hemoglobin and Its Diseases

The Natural History of Sickle Cell DiseaseGraham R. Serjeant Hemoglobin Synthesis

Transcriptional Mechanisms Underlying

Nathaniel J. Pope, et al.Koichi R. Katsumura, Andrew W. DeVilbiss,

Current Management of Sickle Cell Anemia

WarePatrick T. McGann, Alecia C. Nero and Russell E. Disease

Iron Deficiency Anemia: A Common and Curable

Jeffery L. Miller

TherapiesTargetedNew Disease Models Leading the Way to

Cell-Free Hemoglobin and Its Scavenger Proteins:

Dominik J. Schaer and Paul W. Buehler

Management of the ThalassemiasNancy F. Olivieri and Gary M. Brittenham

-ThalassemiaαClinical Manifestations of Elliott P. Vichinsky

-ThalassemiaβThe Molecular Basis of Swee Lay Thein

Erythroid Heme Biosynthesis and Its DisordersHarry A. Dailey and Peter N. Meissner

Erythropoiesis: Development and DifferentiationElaine Dzierzak and Sjaak Philipsen

Clinical CorrelatesHemoglobin Variants: Biochemical Properties and

Gell, et al.Christopher S. Thom, Claire F. Dickson, David A.

ErythropoietinH. Franklin Bunn

The Prevention of ThalassemiaAntonio Cao and Yuet Wai Kan

Classification of the Disorders of HemoglobinBernard G. Forget and H. Franklin Bunn

The Switch from Fetal to Adult HemoglobinVijay G. Sankaran and Stuart H. Orkin

-ThalassemiaαThe Molecular Basis of Douglas R. Higgs

http://perspectivesinmedicine.cshlp.org/cgi/collection/ For additional articles in this collection, see

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Current Management of Sickle Cell Anemiaperspectivesinmedicine.cshlp.org/content/3/8/a011817... · 2013. 7. 29. · Current Management of Sickle Cell Anemia Patrick T. McGann 1,2,