Sickle Cell Anemia Guidelines

Updated: Aug 04, 2020
  • Author: Joseph E Maakaron, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Guidelines

Guidelines Summary

The American Society of Hematology (ASH) has published evidence-based guidelines on the screening, diagnosis, and management of cardiopulmonary, renal, and cerebrovascular complications of sickle cell disease (SCD), as well as on management of SCD-related pain and transfusion support in SCD. (Note that conditional recommendations—actions for which there is very low certainty in the evidence about effects—are listed as suggestions.) [91, 92, 75, 93]

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Pulmonary Hypertension

Given the risk for cardiopulmonary disease in individuals with SCD, it is good practice to routinely take a targeted history for signs and symptoms that might indicate a need for further evaluation, including consideration for a diagnostic echocardiogram. [91] In asymptomatic children and adults with SCD, the ASH guideline panel suggests against performing a routine screening echocardiogram to identify pulmonary hypertension (PH). However, the following findings may warrant a consultation with a PH expert or a diagnostic echocardiogram to evaluate for PH:

  • Dyspnea, hypoxemia, or chest pain, at rest or with exertion, that is out of proportion to known condition, increased compared with baseline, or unexplained
  • Increase in exercise limitation compared with baseline that is unexplained by other factors
  • History of recurrent hypoxemia at rest or with exertion
  • Evidence for sleep-disordered breathing with or without hypoxemia
  • History of syncope or presyncope
  • Loud P2 component of second heart sound or unexpected or new murmur on examination
  • Signs of heart failure and/or fluid overload on examination
  • History of pulmonary embolism

In addition, a diagnostic echocardiogram should be considered for patients with SCD who also have comorbid conditions (eg, connective tissue disease) or disease complications (eg, leg ulcers, priapism) known to be associated with PH, when signs or symptoms of PH are present.

The ASH panel considers it good practice to obtain echocardiograms at steady state and not during acute illness, such as hospitalization for pain or acute chest syndrome, when the results will be used as the basis for decisions about the need for right-heart catheterization.

Recommendations for patients with an abnormal echocardiogram are as follows:

  • For asymptomatic children and adults with SCD and an isolated peak tricuspid regurgitant jet velocity (TRJV) of 2.5 to 2.9 m/sec, the ASH guideline panel suggests against right-heart catheterization.
  • For patients with peak TRJV of ≥2.5 m/sec who are asymptomatic, measurement of N-terminal pro-B-type natriuretic peptide (NT-BNP) levels and 6-minute walk distance (6MWD) may help to improve the diagnostic accuracy for PH. Cutoff values for abnormal NT-BNP and 6MWD have not been firmly determined for patients with SCD. However, NT-BNP values of ≥160 pg/mL and 6MWD values of < 333 m represent reasonable thresholds for adults with SCD, based on published studies in this population. Referrals for right-heart catheterization should also account for clinical judgment and discussion with a PH expert.
  • For children and adults with SCD and a peak TRJV of ≥2.5 m/sec who also have a reduced 6MWD and/or elevated NT-BNP, the ASH guideline panel suggests right-heart catheterization.
  • Patients whose echocardiograms demonstrate elevated peak TRJV should undergo repeat echocardiography prior to referral for right-heart catheterization under the guidance of a PH expert, because reproducibility of TRJV measurements may vary due to technical factors, severity of anemia, or increased cardiac output.
  • For patients with peak TRJV of ≥2.5 m/sec who have normal 6MWD and NT-BNP, serial noninvasive monitoring with echocardiograms should be considered if clinically indicated.
  • Consultation with a PH expert regarding the need for a right-heart catheterization should be considered for patients with TRJV of >2.9 m/sec who have normal 6MWD and NT-BNP or other echocardiographic findings, in addition to elevated peak TRJV, that could suggest significant PH (eg, right atrial enlargement, pericardial effusion, right ventricular failure, or septal flattening).
  • PH is defined hemodynamically by right-heart catheterization using a mean pulmonary artery pressure threshold of > 20 mm Hg (recently reduced from ≥25 mm Hg). However, the mean pulmonary artery pressure alone does not distinguish pulmonary artery hypertension (PAH) from other forms of PH. Additional criteria for the diagnosis of PAH include a pulmonary artery wedge pressure of ≤15 mm Hg and a pulmonary vascular resistance of ≥3 Wood units (240 dyn × seconds × cm −5).

Treatment of PAH is as follows:

  • For children and adults with SCD who do not have PAH confirmed by right-heart catheterization, the ASH guideline panel strongly recommends against the use of PAH-specific therapies. 
  • For children and adults with SCD and a diagnosis of PAH confirmed by right-heart catheterization, the ASH guideline panel recommends considering initiation and/or optimization of disease-modifying therapy such as hydroxyurea or chronic transfusions.
  • For children and adults with SCD and a diagnosis of PAH confirmed by right-heart catheterization, the ASH guideline panel suggests the use of PAH-specific therapies under the care of a PH specialist, given the lack of alternative treatment options, associated high morbidity and mortality, and the possibility of increased adverse effects (eg, pain) with PAH-specific therapy such as sildenafil.
  • Consider potential differences in the pathophysiologic basis of PAH (eg, contribution of chronic anemia and high-output cardiac states) and differences in adverse-effect profiles (eg, pain) when determining treatment options for PAH confirmed by right-heart catheterization in SCD.
  • The recommendation for PAH-specific therapy in SCD applies to patients with SCD who have no other clear reason for their PAH confirmed by right-heart catheterization (eg, obstructive sleep apnea, significant lung disease, left-heart failure).

End points for monitoring the benefits of PAH-specific therapy in these patients include the following:

  • Improvements in cardiopulmonary hemodynamics, as determined by right-heart catheterization
  • Improvements in clinical status, such as a change in PAH symptoms or functional status, initiation of other PAH drugs, or diuretic requirements (eg, in the setting of right-heart failure)

Pulmonary function testing

For asymptomatic children and adults with SCD, the ASH guideline panel suggests against routine screening pulmonary function testing (PFT).

The following signs, symptoms, or diagnoses may warrant diagnostic PFT to evaluate for abnormal lung function:

  • Wheezing or increased cough at rest, with exertion, or during episodes of acute upper respiratory infection
  • Dyspnea at rest or with exertion that is increased compared with baseline or that is unexplained
  • Chest pain at rest or with exertion that is out of proportion to a known condition, that is increased compared with baseline, or that is unexplained
  • Increase in exercise limitation compared with baseline or that is unexplained (eg, not resulting from sickle cell pain or musculoskeletal disease)
  • Abnormal 6MWD defined by either reduced 6MWD or oxygen desaturation during test
  • History of recurrent hypoxemia at rest or with exertion
  • History of syncope or presyncope
  • History of recurrent acute chest syndrome
  • History of pulmonary embolism

Comprehensive PFT should include full spirometry as well as complete evaluation of diffusion capacity and lung volumes.

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Sleep-Disordered Breathing

For asymptomatic children and adults with SCD, the ASH guideline panel suggests against screening with formal polysomnography (sleep study) for sleep-disordered breathing. [91]

When appropriate, validated tools (eg, Epworth Sleepiness Scale or Pittsburgh Sleep Quality Index) should be used to further identify patients who should be considered for formal sleep testing. The following signs or symptoms may warrant a diagnostic sleep study for otherwise healthy patients to evaluate for sleep-disordered breathing:

  • Snoring
  • Witnessed apneas or respiratory pauses
  • Nonrestorative sleep and/or excessive daytime sleepiness
  • Obesity
  • Early morning headaches
  • Unexplained desaturation or hypoxemia during sleep, while awake, or with exertion
  • Carbon dioxide retention on arterial blood gas
  • History of poorly controlled hypertension or congestive heart failure
  • History of nocturnal enuresis in an older child (eg, ≥10 years old)
  • History of recurrent priapism or frequent daytime or nocturnal vaso-occlusive pain
  • History of PH confirmed by right-heart catheterization
  • History of ischemic stroke without evidence for vasculopathy
  • History of memory loss, difficulty with concentration, or unexplained episodes of mental confusion
  • Symptoms of attention deficit–hyperactivity disorder, poor academic achievement, and performance or behavior problems in children

For patients in whom a sleep study is warranted, the ASH panel notes that American Academy of Sleep Medicine guidelines currently recommend in-laboratory, “attended” sleep studies for children and for adults with chronic disease and known comorbidities, specifically cardiopulmonary. Additionally, it is important for formal sleep studies to be conducted in a certified sleep center that meets standards as required by accreditation groups.

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Kidney Disease

Albuminuria

The ASH guideline panel did not assess the evidence to inform decisions about albuminuria screening, but notes that Kidney Disease Improving Global Outcomes (KDIGO) guidelines state that albuminuria should be confirmed by either a first morning urine sample or 2 consecutive untimed urine samples. The National Heart, Lung, and Blood Institute (NHLBI) 2014 expert panel report states that screening for albuminuria should occur annually beginning at 10 years of age for patients with SCD. However, more recent evidence suggests a potential benefit of earlier screening.

For children and adults with SCD and albuminuria, the ASH guideline panel suggests the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs).

The initiation of ACEIs and ARBs for patients with SCD requires adequate follow-up and monitoring of side effects (eg, hyperkalemia, cough, hypotension).

As recommended by the KDIGO guidelines for the general population, the following attention to baseline and changes in renal function are appropriate when prescribing ACEIs or ARBs for patients with SCD:

  • Start medication at a lower dose in individuals with a glomerular filtration rate (GFR) of < 45 mL/min/1.73 m 2
  • Assess GFR and measure serum potassium within 1 week of starting medication or following any dose escalation
  • Temporarily suspend medication during interval illness, planned IV radiocontrast administration, or bowel preparation for colonoscopy or prior to major surgery. 

Chronic kidney disease

In children and adults with SCD and worsening anemia associated with chronic kidney disease (CKD), the ASH guideline panel suggests combination therapy with hydroxyurea and erythropoiesis-stimulating agents. This recommendation is based on evidence available only from patients with hemoglobin SS or S/β0 thalassemia, for whom erythropoiesis-stimulating-agent dosing in the studies reviewed was higher than that typically used in the general population.

For patients with SCD and CKD who are already on steady-state hydroxyurea, starting erythropoiesis-stimulating agents is appropriate when a simultaneous drop occurs in the hemoglobin concentration and absolute reticulocyte count. Optimizing adherence to hydroxyurea therapy while on erythropoiesis-stimulating agents may help maximize fetal hemoglobin responses for patients treated with combination therapy.

For patients with SCD undergoing treatment with erythropoiesis-stimulating agents, a conservative hemoglobin threshold is advised above which treatment should be decreased or held. The ASH guideline panel advises not exceeding a hemoglobin threshold of 10 g/dL (hematocrit of 30%) to reduce the risk of vaso-occlusion–related complications, stroke, and venous thromboembolism.

For children and adults with SCD and advanced CKD or end-stage renal disease, the ASH guideline panel suggests referral for renal transplantation. Judicious use of corticosteroids as part of the posttransplant immunosuppression regimen is advised given the potential relationship between steroid exposure and vaso-occlusive pain for patients with SCD.

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Cardiovascular Disease

Management of blood pressure

For adults with SCD, the ASH guideline panel recommends a blood pressure goal of ≤130/80 mm Hg over a goal of ≤140/90 mm Hg.90 There is a lack of evidence to suggest that blood pressure goals should differ for individuals with and without SCD. The impact of hypertension on patient-important outcomes is significant for African Americans and therefore requires adherence to guidelines developed for the general population independent of having SCD.

Management of venous thromboembolism

The ASH panel considers SCD to be a chronic underlying risk factor for initial and recurrent venous thromboembolism (VTE). Consequently, for adults with SCD and first unprovoked VTE, the ASH guideline panel suggests indefinite anticoagulation over shorter, defined periods of anticoagulation.

For adults with SCD and first provoked VTE (whether surgically or nonsurgically provoked), the ASH guideline panel suggests defined periods of anticoagulation (3-6 months) over indefinite anticoagulation. Anticoagulation should continue as long as any provoking risk factor (eg, a central venous line) continues to be present.

In adults with SCD and recurrent provoked VTE, the ASH guideline panel suggests indefinite anticoagulation. However, the type, strength, and duration of the provoking events are important to take into account when considering indefinite anticoagulation for those patients.

Whether to continue anticoagulation should be re-evaluated regularly, and should involve shared decision-making based on patient values and preferences. Discussions of the benefits vs harms of anticoagulation, as well as duration of therapy, should take into consideration bleeding risk, including from existing use of other medications that could further increase risk of bleeding (eg, nonsteroidal anti-inflammatory drugs).

Anticoagulant selection for patients with SCD should account for comorbidities such as renal impairment that may affect drug clearance. For example, because of the potential for decreased efficacy of edoxaban in the setting of increased creatinine clearance (CrCl), alternative anticoagulants should be considered for SCD patients with CrCl of > 95 mL/min.

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Cerebrovascular Complications

The ASH guidelines on prevention, diagnosis, and treatment of the most common neurological morbidities in SCD include recommendations stratified by income setting (low-middle or high). [92] Strong recommendations are summarized below.

Stroke prevention and treatment

Primary stroke prevention in children:

  • Annual transcranial Doppler (TCD) screening for children aged 2-16 years with hemoglobin SS (HbSS) or HbSβ0 thalassemia (all income settings)
  • Regular blood transfusions for a minimum of 1 year for children aged 2-16 years with HbSS or HbSβ0 thalassemia who have abnormal TCD velocities and live in a high-income setting; this refers to a setting that permits regular blood transfusion therapy, typically every 3-4 weeks, to maintain the maximum HbS level below 30% and the hemoglobin level above 9.0 g/dL, to reduce stroke risk.

Management of suspected or confirmed ischemic stroke or transient ischemic attack (all income settings):

Prompt blood transfusion is recommended for children or adults with SCD who have acute neurologic deficits, including transient ischemic attack (TIA). The transfusion should not be delayed beyond 2 hours of acute neurologic symptom presentation. Individual patient factors and local transfusion resources determine the type of transfusion provided (simple, modified exchange, or apheresis).

Secondary prevention of ischemic strokes:

  • For children with HbSS or HbSβ 0 thalassemia and a history of prior ischemic stroke, blood transfusion goals for secondary stroke prevention are to increase the hemoglobin level above 9 g/dL at all times and maintain the HbS level at < 30% of total hemoglobin until the time of the next transfusion.

Cognitive impairment

Screening for developmental delay or cognitive impairment in children and adults with SCD:

  • Conduct surveillance, using simplified signaling questions, for concerns about developmental delays in preschool-age children and concerns about neurodevelopmental disorders in school-age children, such as academic or behavioral problems or symptoms of inattention, hyperactivity, or impulsivity.
  • For children who have abnormal surveillance results suggesting increased risk for developmental delay or cognitive impairment, screen or referl for formal screening by a psychologist or a pediatrician able to perform screening with the available validated tools

  • For adults, conduct surveillance for cognitive impairment using simplified signaling questions; in those with abnormal results suggesting cognitive impairment, provide formal referral to a psychologist or a primary care physician able to perform more in-depth cognitive evaluation.

Rehabilitation for children and adults with cognitive impairments

The following are recommended for children with SCD and abnormal developmental or cognitive status screens:

  • Developmental, cognitive, and medical assessment to diagnose any related disorders and to identify any modifiable risk factors for developmental delays or cognitive impairments
  • Delivery of appropriate interventions by following the cognitive domain–specific, evidence-based guidelines for these disorders

The following are recommended for adults with SCD and abnormal cognitive status screens:

  • Cognitive and medical assessment to diagnose any related disorders and to identify any modifiable risk factors for cognitive impairments
  • Delivery of appropriate interventions by following the cognitive domain–specific, evidence-based guidelines for these disorders

Cerebral infarcts

Screening for silent cerebral infarcts in children and adults with HbSS or HbSβ0 thalassemia:

  • At least a one-time magnetic resonance imaging (MRI) screening, without sedation, is recommended to detect silent cerebral infarcts in early school-aged children. This recommendation is made in view of the fact that silent cerebral infarcts are highly prevalent in children with HbSS or HbSβ0 thalassemia (1 in 3) and are associated with cognitive impairment, poor school performance, and future cerebral infarcts.
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Pain

ASH 2020 guidelines for management of acute and chronic pain in patients with sickle cell disease (SCD) include the recommendations and suggestions (ie, conditional recommendations based on very low certainty in the evidence) summarized below. Unless otherwise specified, these apply to both adults and children. [75]

Acute pain

For patients with SCD presenting to an acute care setting with acute pain related to SCD, ASH strongly recommends rapid (within 1 hour of emergency department [ED] arrival) assessment and administration of analgesia with frequent reassessments (every 30 to 60 minutes) to optimize pain control. The panel notes that non-intravenous (IV) routes of administration (eg, subcutaneous and intranasal) can facilitate rapid analgesic treatment.

When opioid therapy is indicated for acute pain in the acute care setting, ASH suggests using tailored opioid dosing, based on consideration of baseline opioid therapy and prior effective therapy. The panel notes that individualized care plans that include medications and doses that are effective for a given patient can be embedded in the electronic medical record and used to guide opioid dosing.

For patients with acute pain related to SCD, ASH guideline panel suggests a short course (5 to 7 days) of nonsteroidal anti-inflammatory drugs (NSAIDs) in addition to opioids, in the absence of significant risk factors for NSAID use.

ASH suggests against corticosteroids for management of SCD-related acute pain.

For hospitalized patients with SCD-related acute pain that is refractory or not effectively treated with opioids alone, ASH suggests a subanesthetic (analgesic) ketamine infusion as adjunctive treatment, in centers with the appropriate expertise to administer the drug. The recommended dose in this setting starts at 0.1 to 0.3 mg/kg per hour with a maximum of 1 mg/kg per hour.

For patients with SCD-related acute localized pain that is refractory or not effectively treated with opioids alone, ASH suggests regional anesthesia treatment approaches (ie, epidural or peripheral nerve catheter-delivered analgesia for abdominal, hip, or leg pain).

ASH does not offer a recommendation for or against IV fluids in addition to standard pharmacological management for the treatment of acute pain.

ASH suggests massage, yoga, transcutaneous electrical nerve stimulation (TENS), virtual reality (VR), and guided audiovisual (AV) relaxation in addition to standard pharmacological management for acute pain.

ASH chooses not to offer a recommendation for or against acupuncture or biofeedback for the treatment of acute pain in addition to standard pharmacological management.

For patients who develop acute pain episodes requiring hospital care, ASH suggests using SCD-specific hospital-based acute care facilities (ie, day hospitals and infusion centers, that have appropriate expertise to evaluate, diagnose, and treat pain and other SCD complications).

Chronic pain

For adults with chronic (as opposed to episodic) pain from the SCD-related identifiable cause of avascular necrosis of bone, ASH suggests use of duloxetine (and other serotonin and norepinephrine reuptake inhibitors [SNRIs], because there is evidence of a class effect) and NSAIDs as options for management, in the context of a comprehensive disease and pain management plan. ASH offers no recommendation for or against the use of SNRIs and/or NSAIDs for children in this setting.

For patients with SCD who have chronic (as opposed to episodic) pain from the SCD-related identifiable cause of leg ulcers, ASH does not offer a recommendation for or against any specific nonopioid pharmacological management strategy.

For adults who have SCD-related chronic pain with no identifiable cause beyond SCD, ASH suggests SNRIs (eg, duloxetine and milnacipran), tricyclic antidepressants (eg, amitriptyline), or gabapentinoids (eg, pregabalin) as options for pain management.

For patients with SCD and emerging and/or recently developed chronic pain that is refractory to multiple other treatment modalities, ASH suggests consideration of long-term opioid therapy, after risk stratification using a validated tool.

For patients who have chronic pain related to SCD, ASH suggests cognitive and behavioral pain management strategies in the context of a comprehensive disease and pain management plan.

For adults who have chronic pain related to SCD, ASH suggests other provider-delivered integrative approaches (eg, massage therapy and acupuncture) as available, as tolerated, and conditional upon individual patient preference and response. These approaches should be delivered in the context of a comprehensive disease and pain management plan.

For patients who have chronic pain related to SCD, ASH chooses not to offer a recommendation for or against a number of physical activities, exercise, or combined meditation/movement programs (including aerobic exercise, yoga, and Pilates) to improve pain and disability. ASH notes that if such interventions are considered, it requires shared decision-making that addresses feasibility, tolerability, acceptability, and patient experience and preference.

Transfusions

For patients with SCD and recurrent acute pain, ASH suggests against long-term monthly transfusion therapy as a first-line strategy to prevent or reduce recurrent acute pain episodes. However, the ASH guidelines note that in unique circumstances when all other measures to control recurrent pain episodes have failed (eg, hydroxyurea, other disease modifying therapies) and when shared decision making can be fully applied, a trial of monthly transfusions may be reasonable.

For patients with chronic pain from SCD, ASH chooses not to offer a recommendation for or against long-term monthly transfusion therapy as an option for pain management.

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Transfusion Support

ASH 2020 guidelines for transfusion support in patients with SCD recommend prophylactic red cell antigen matching for Rh (C, E or C/c, E/e) and K antigens over only ABO/RhD matching for patients with SCD (all genotypes) receiving transfusions. [93] The guidelines also include the following suggestions (ie, conditional recommendations based on very low certainty in the evidence):

  • Obtaining an extended red cell antigen profile by genotype (preferred) or serology in all patients with SCD (all genotypes) at the earliest opportunity (optimally before first transfusion). An extended red cell antigen profile includes C/c, E/e, K, Jk a/Jk b, Fy a/Fy b, M/N, S/s at a minimum.
  • In patients with SCD (all genotypes) who are having a delayed hemolytic transfusion reaction and ongoing hyperhemolysis, provide immunosuppressive therapy (IVIg, steroids, rituximab, and/or eculizumab).
  • Automated red cell exchange (RCE) is preferred over simple transfusion or manual RCE in patients with SCD (all genotypes) receiving chronic transfusions.
  • Automated RCE or manual RCE is preferred over simple transfusions in patients with SCD and severe acute chest syndrome.
  • Automated RCE, manual RCE, or simple transfusions may be used in patients with SCD and moderate acute chest syndrome.
  • Use either red cell exchange with isovolemic hemodilution (IHD-RCE) or conventional RCE in patients with SCD (all genotypes) receiving chronic transfusions. (In IHD-RCE, which is available on some automated apheresis devices, the patient undergoes a red cell depletion with concurrent volume replacement before the RCE, with the intent of decreasing the number of red cell units needed for the RCE.) IHD-RCE is not advised for acute indications for RCE or when induction of further anemia during the IHD phase may be generally detrimental (eg, recent history of stroke or transient ischemic attack, severe vasculopathy, or severe cardiopulmonary disease).
  • In pregnant patients with SCD (all genotypes) who have a history of severe SCD-related complications or other high-risk features, prophylactic transfusion at regular intervals may be considered; in other cases, standard care (transfusion when clinically indicated for a complication or hemoglobin lower than baseline) may be provided.
  • Provide preoperative transfusion for patients with SCD undergoing surgeries that require general anesthesia and last longer than 1 hour. The goal for preoperative total hemoglobin levels is > 9 g/dL; RCE transfusion should be used for patients who require preoperative transfusion but have a high hemoglobin level (> 9-10 g/dL) that precludes administration of simple transfusion.
  • To assess liver iron content, iron overload screening by MRI (R2, T2*, or R2*) every 1 to 2 years is preferred over serial monitoring of ferritin levels alone in patients with SCD (all genotypes) receiving chronic transfusion therapy.
  • To assess for cardiac iron content, serial monitoring of ferritin levels alone is preferred over routine iron overload screening by T2* MRI in patients with SCD (all genotypes) receiving chronic transfusion therapy. However, cardiac T2*MRI screening may be considered for the subgroup of patients with SCD with a high iron burden (liver iron content > 15 mg/g [dw]) for 2 years or more, evidence of end organ damage resulting from transfusional iron overload, or evidence of cardiac dysfunction.
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