Sickle Cell Disease (SCD) Guidelines: Guidelines Summary, Pulmonary Hypertension, Sleep-Disordered Breathing

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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.)^{[109, 110, 82, 111]} In 2021, ASH issued guidelines on hematopoietic stem cell transplantation (HSCT) in SCD.^[112]

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.^[109]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.

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.^[109]

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.

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.

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.

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).^[110]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.

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.^[82]

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.

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.^[111]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.

Hematopoietic Stem Cell Transplantation (HSCT)

ASH 2021 guidelines for HSCT in SCD include the following conditional recommendations^[112]:

Consider HLA-matched related HSCT rather than standard of care (ie, hydroxyurea [HU]/transfusion) in patients with SCD who have experienced an overt stroke or have an abnormal transcranial Doppler ultrasound (TCD).
Consider related matched allogeneic HSCT for patients with frequent pain despite standard of care.
Consider matched related allogeneic HSCT for patients with recurrent episodes of acute coronary syndrome despite optimal standard of care.
For patients with SCD with an indication for HSCT who lack a matched sibling donor (MSD), consider using transplants from alternative donors in the context of a clinical trial.
For allogeneic HSCT, consider using either total-body irradiation (TBI) ≤400 cGy or chemotherapy-based conditioning regimens.
For children with SCD who have an indication for allogeneic HSCT and an MSD, consider using myeloablative conditioning rather than reduced-intensity conditioning (RIC) that contains melphalan/fludarabine regimens.
For adults with SCD who have an indication for allogeneic HSCT and an MSD, consider using nonmyeloablative conditioning rather than RIC that contains melphalan/fludarabine regimens.
In patients with SCD who have an indication for HSCT and who are eligible for it, consider using allogeneic transplantation at an earlier age rather than an older age.
Consider using HLA-identical sibling cord blood when available (and if there is an adequate cord blood cell dose with good viability) rather than bone marrow.

Medication

Pecker LH, Lanzkron S. Sickle Cell Disease. Ann Intern Med. 2021 Jan. 174 (1):ITC1-ITC16. [QxMD MEDLINE Link].
Sedrak A, Kondamudi NP. Sickle Cell Disease. 2023 Jan. [QxMD MEDLINE Link]. [Full Text].
Shatat IF, Jakson SM, Blue AE, Johnson MA, Orak JK, Kalpatthi R. Masked hypertension is prevalent in children with sickle cell disease: a Midwest Pediatric Nephrology Consortium study. Pediatr Nephrol. 2013 Jan. 28(1):115-20. [QxMD MEDLINE Link].
Linguraru MG, Orandi BJ, Van Uitert RL, Mukherjee N, Summers RM, Gladwin MT, et al. CT and image processing non-invasive indicators of sickle cell secondary pulmonary hypertension. Conf Proc IEEE Eng Med Biol Soc. 2008. 2008:859-62. [QxMD MEDLINE Link]. [Full Text].
Olujohungbe A, Howard J. The clinical care of adult patients with sickle cell disease. Br J Hosp Med (Lond). 2008 Nov. 69(11):616-9. [QxMD MEDLINE Link].
Johnson L, Carmona-Bayonas A, Tick L. Management of pain due to sickle cell disease. J Pain Palliat Care Pharmacother. 2008. 22(1):51-4. [QxMD MEDLINE Link].
De D. Acute nursing care and management of patients with sickle cell. Br J Nurs. 2008 Jul 10-23. 17(13):818-23. [QxMD MEDLINE Link].
Teixeira RS, Terse-Ramos R, Ferreira TA, Machado VR, Perdiz MI, Lyra IM, et al. Associations between endothelial dysfunction and clinical and laboratory parameters in children and adolescents with sickle cell anemia. PLoS One. 2017. 12 (9):e0184076. [QxMD MEDLINE Link]. [Full Text].
Manwani D, Frenette PS. Vaso-occlusion in sickle cell disease: pathophysiology and novel targeted therapies. Blood. 2013 Dec 5. 122 (24):3892-8. [QxMD MEDLINE Link]. [Full Text].
Zen Q, Batchvarova M, Twyman CA, Eyler CE, Qiu H, De Castro LM, et al. B-CAM/LU expression and the role of B-CAM/LU activation in binding of low- and high-density red cells to laminin in sickle cell disease. Am J Hematol. 2004 Feb. 75(2):63-72. [QxMD MEDLINE Link].
Ford AL, Ragan DK, Fellah S, Binkley MM, Fields ME, Guilliams KP, et al. Silent infarcts in sickle cell anemia occur in the borderzone region and are associated with low cerebral blood flow. Blood. 2018 Jul 30. [QxMD MEDLINE Link].
Stotesbury H, Kirkham FJ, Kölbel M, Balfour P, Clayden JD, Sahota S, et al. White matter integrity and processing speed in sickle cell anemia. Neurology. 2018 Jun 5. 90 (23):e2042-e2050. [QxMD MEDLINE Link]. [Full Text].
Merlet AN, Chatel B, Hourdé C, Ravelojaona M, Bendahan D, Féasson L, et al. How Sickle Cell Disease Impairs Skeletal Muscle Function: Implications in Daily Life. Med Sci Sports Exerc. 2018 Aug 8. [QxMD MEDLINE Link].
Silva PO, Ferreira AS, Lima CMA, Guimarães FS, Lopes AJ. Balance control is impaired in adults with sickle cell anaemia. Somatosens Mot Res. 2018 Jul 16. 1-10. [QxMD MEDLINE Link].
Morris CR. Asthma management: reinventing the wheel in sickle cell disease. Am J Hematol. 2009 Apr. 84(4):234-41. [QxMD MEDLINE Link].
National Institutes of Health. Introduction to Genes and Disease: Anemia, Sickle Cell. National Center for Biotechnology Information. Available at http://www.ncbi.nlm.nih.gov/books/NBK22238/. Accessed: December 12, 2023.
Centers for Disease Control and Prevention. Sickle Cell Disease: Health Care Professionals: Data & Statistics. Centers for Disease Control and Prevention. Department of Health and Human Services. Available at http://www.cdc.gov/ncbddd/sicklecell/data.html. July 6, 2023; Accessed: December 12, 2023.
Naik RP, Derebail VK. The spectrum of sickle hemoglobin-related nephropathy: from sickle cell disease to sickle trait. Expert Rev Hematol. 2017 Dec. 10 (12):1087-1094. [QxMD MEDLINE Link]. [Full Text].
Derebail VK, Nachman PH, Key NS, Ansede H, Falk RJ, Kshirsagar AV. High prevalence of sickle cell trait in African Americans with ESRD. J Am Soc Nephrol. 2010 Mar. 21 (3):413-7. [QxMD MEDLINE Link]. [Full Text].
Ataga KI, Saraf SL, Derebail VK. The nephropathy of sickle cell trait and sickle cell disease. Nat Rev Nephrol. 2022 Jun. 18 (6):361-377. [QxMD MEDLINE Link]. [Full Text].
Nissenson AR, Port FK. Outcome of end-stage renal disease in patients with rare causes of renal failure. I. Inherited and metabolic disorders. Q J Med. 1989 Nov. 73(271):1055-62. [QxMD MEDLINE Link].
Saborio P, Scheinman JI. Disease of the month - Sickle cell nephropathy. J Amm Soc Nephrol. 1999. 10:187.
Miller ST, Sleeper LA, Pegelow CH, Enos LE, Wang WC, Weiner SJ, et al. Prediction of adverse outcomes in children with sickle cell disease. N Engl J Med. 2000 Jan 13. 342(2):83-9. [QxMD MEDLINE Link].
Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med. 1994 Jun 9. 330(23):1639-44. [QxMD MEDLINE Link].
Quinn CT, Rogers ZR, Buchanan GR. Survival of children with sickle cell disease. Blood. 2004 Jun 1. 103(11):4023-7. [QxMD MEDLINE Link]. [Full Text].
Gladwin MT, Sachdev V, Jison ML, Shizukuda Y, Plehn JF, Minter K, et al. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med. 2004 Feb 26. 350(9):886-95. [QxMD MEDLINE Link].
Parent F, Bachir D, Inamo J, et al. A hemodynamic study of pulmonary hypertension in sickle cell disease. N Engl J Med. 2011 Jul 7. 365(1):44-53. [QxMD MEDLINE Link].
Wright SW, Zeldin MH, Wrenn K, Miller O. Screening for sickle-cell trait in the emergency department. J Gen Intern Med. 1994 Aug. 9(8):421-4. [QxMD MEDLINE Link].
Materials & Multimedia on Sickle Cell Disease. Centers for Disease Control and Prevention. Available at https://www.cdc.gov/ncbddd/sicklecell/materials/index.html. July 6, 2023; Accessed: December 12, 2023.
Chiang EY, Frenette PS. Sickle cell vaso-occlusion. Hematol Oncol Clin North Am. 2005 Oct. 19(5):771-84, v. [QxMD MEDLINE Link].
Rhodes M, Akohoue SA, Shankar SM, Fleming I, Qi An A, Yu C, et al. Growth patterns in children with sickle cell anemia during puberty. Pediatr Blood Cancer. 2009 Oct. 53(4):635-41. [QxMD MEDLINE Link]. [Full Text].
Telfer P, Coen P, Chakravorty S, Wilkey O, Evans J, Newell H, et al. Clinical outcomes in children with sickle cell disease living in England: a neonatal cohort in East London. Haematologica. 2007 Jul. 92(7):905-12. [QxMD MEDLINE Link].
Nicholson GT, Hsu DT, Colan SD, et al. Coronary artery dilation in sickle cell disease. J Pediatr. 2011 Nov. 159(5):789-794.e1-2. [QxMD MEDLINE Link].
Dahoui HA, Hayek MN, Nietert PJ, et al. Pulmonary hypertension in children and young adults with sickle cell disease: evidence for familial clustering. Pediatr Blood Cancer. 2010. 54(3):398-402.
Onyekwere OC, Campbell A, Teshome M, Onyeagoro S, Sylvan C, Akintilo A, et al. Pulmonary hypertension in children and adolescents with sickle cell disease. Pediatr Cardiol. 2008 Mar. 29(2):309-12. [QxMD MEDLINE Link].
Parent F, Bachir D, Inamo J, et al. A hemodynamic study of pulmonary hypertension in sickle cell disease. N Engl J Med. 2011 Jul 7. 365(1):44-53. [QxMD MEDLINE Link].
Akinsola FB, Kehinde MO. Ocular findings in sickle cell disease patients in Lagos. Niger Postgrad Med J. 2004 Sep. 11 (3):203-6. [QxMD MEDLINE Link].
Hingorani M, Bentley CR, Jackson H, Betancourt F, Arya R, Aclimandos WA, et al. Retinopathy in haemoglobin C trait. Eye (Lond). 1996. 10 ( Pt 3):338-42. [QxMD MEDLINE Link].
Sokol JA, Baron E, Lantos G, Kazim M. Orbital compression syndrome in sickle cell disease. Ophthalmic Plast Reconstr Surg. 2008 May-Jun. 24 (3):181-4. [QxMD MEDLINE Link].
Wisotsky BJ, Tesser PM, Schultz JS. Trabecular meshwork hemorrhage in a patient with sickle cell trait. Arch Ophthalmol. 1995 Mar. 113 (3):381. [QxMD MEDLINE Link].
Goldbaum MH, Jampol LM, Goldberg MF. The disc sign in sickling hemoglobinopathies. Arch Ophthalmol. 1978 Sep. 96 (9):1597-600. [QxMD MEDLINE Link].
Babalola OE, Wambebe CO. When should children and young adults with sickle cell disease be referred for eye assessment?. Afr J Med Med Sci. 2001 Dec. 30 (4):261-3. [QxMD MEDLINE Link].
Gill HS, Lam WC. A screening strategy for the detection of sickle cell retinopathy in pediatric patients. Can J Ophthalmol. 2008 Apr. 43 (2):188-91. [QxMD MEDLINE Link].
[Guideline] Meschia JF, Bushnell C, Boden-Albala B, et al. Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014 Dec. 45 (12):3754-832. [QxMD MEDLINE Link]. [Full Text].
[Guideline] Centre for Clinical Practice at NICE (UK). Guidelines for the management of the acute painful crisis in sickle cell disease. Br J Haematol. 2012 Jun. 120(5):744-52. [QxMD MEDLINE Link]. [Full Text].
[Guideline] US Preventive Services Task Force. Screening for sickle cell disease in newborns: U.S. Preventive Services Task Force recommendation statement. Agency for Healthcare Research and Quality (AHRQ). Sep 2007. [Full Text].
Bernard AW, Venkat A, Lyons MS. Best evidence topic report. Full blood count and reticulocyte count in painful sickle crisis. Emerg Med J. 2006 Apr. 23(4):302-3. [QxMD MEDLINE Link]. [Full Text].
Cerci SS, Suslu H, Cerci C, Yildiz M, Ozbek FM, Balci TA, et al. Different findings in Tc-99m MDP bone scintigraphy of patients with sickle cell disease: report of three cases. Ann Nucl Med. 2007 Jul. 21(5):311-4. [QxMD MEDLINE Link].
[Guideline] Evidence-Based Management of Sickle Cell Disease: Expert Panel Report, 2014. National Heart, Lung and Blood Institute. Available at https://www.nhlbi.nih.gov/sites/default/files/media/docs/Evd-Bsd_SickleCellDis_Rep2014.pdf. September 8, 2014; Accessed: December 12, 2023.
Lee MT, Piomelli S, Granger S, Miller ST, Harkness S, Brambilla DJ, et al. Stroke Prevention Trial in Sickle Cell Anemia (STOP): extended follow-up and final results. Blood. 2006 Aug 1. 108(3):847-52. [QxMD MEDLINE Link]. [Full Text].
Adams RJ, Brambilla D. Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease. N Engl J Med. 2005 Dec 29. 353(26):2769-78. [QxMD MEDLINE Link]. [Full Text].
Hammoudi N, Lionnet F, Redheuil A, Montalescot G. Cardiovascular manifestations of sickle cell disease. Eur Heart J. 2020 Apr 1. 41 (13):1365-1373. [QxMD MEDLINE Link].
[Guideline] Brawley OW, Cornelius LJ, Edwards LR, Gamble VN, Green BL, Inturrisi C, et al. National Institutes of Health Consensus Development Conference statement: hydroxyurea treatment for sickle cell disease. Ann Intern Med. 2008 Jun 17. 148(12):932-8. [QxMD MEDLINE Link]. [Full Text].
Payne J, Aban I, Hilliard LM, Madison J, Bemrich-Stolz C, Howard TH, et al. Impact of early analgesia on hospitalization outcomes for sickle cell pain crisis. Pediatr Blood Cancer. 2018 Aug 27. e27420. [QxMD MEDLINE Link].
Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell KL, James AH, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014 Sep 10. 312(10):1033-48. [QxMD MEDLINE Link].
FDA approves new treatment for sickle cell disease. U.S. Food & Drug Administration. Available at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm566084.htm. July 7, 2017; Accessed: December 12, 2023.
Niihara Y, et al; Investigators of the Phase 3 Trial of l-Glutamine in Sickle Cell Disease. A Phase 3 Trial of l-Glutamine in Sickle Cell Disease. N Engl J Med. 2018 Jul 19. 379 (3):226-235. [QxMD MEDLINE Link].
Ataga KI, Kutlar A, Kanter J, Liles D, Cancado R, Friedrisch J, et al. Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease. N Engl J Med. 2017 Feb 2. 376 (5):429-439. [QxMD MEDLINE Link]. [Full Text].
Kutlar A, Kanter J, Liles DK, Alvarez OA, Cançado RD, Friedrisch JR, et al. Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: A SUSTAIN study analysis. Am J Hematol. 2019 Jan. 94 (1):55-61. [QxMD MEDLINE Link].
Vichinsky E, Hoppe CC, Ataga KI, et al and the, HOPE Trial Investigators. A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease. N Engl J Med. 2019 Aug 8. 381 (6):509-519. [QxMD MEDLINE Link].
Gluckman E, Cappelli B, Bernaudin F, et al, behalf of Eurocord, the Pediatric Working Party of the European Society for Blood and Marrow Transplantation, et al. Sickle cell disease: an international survey of results of HLA-identical sibling hematopoietic stem cell transplantation. Blood. 2017 Mar 16. 129 (11):1548-1556. [QxMD MEDLINE Link]. [Full Text].
Curtis SA, Shah NC. Gene therapy in sickle cell disease: Possible utility and impact. Cleve Clin J Med. 2020 Jan. 87 (1):28-29. [QxMD MEDLINE Link]. [Full Text].
McGann PT, Ware RE. Hydroxyurea therapy for sickle cell anemia. Expert Opin Drug Saf. 2015 Sep 14. 1-10. [QxMD MEDLINE Link].
Heeney MM, Ware RE. Hydroxyurea for children with sickle cell disease. Pediatr Clin North Am. 2008 Apr. 55(2):483-501, x. [QxMD MEDLINE Link].
Strouse JJ, Lanzkron S, Beach MC, Haywood C, Park H, Witkop C, et al. Hydroxyurea for sickle cell disease: a systematic review for efficacy and toxicity in children. Pediatrics. 2008 Dec. 122(6):1332-42. [QxMD MEDLINE Link].
Hankins JS, McCarville MB, Rankine-Mullings A, Reid ME, Lobo CL, et al. Prevention of conversion to abnormal TCD with hydroxyurea in sickle cell anemia: A phase III international randomized clinical trial. Am J Hematol. 2015 Sep 28. [QxMD MEDLINE Link].
Siklos (hydroxyurea) Prescribing Information [package insert]. Bryn Mawr, Pennsylvania: Medunik USA, Inc. 12/2017. Available at [Full Text].
Hilliard LM, Kulkarni V, Sen B, Caldwell C, Bemrich-Stolz C, Howard TH, et al. Red blood cell transfusion therapy for sickle cell patients with frequent painful events. Pediatr Blood Cancer. 2018 Aug 27. e27423. [QxMD MEDLINE Link].
Firth PG, Head CA. Sickle cell disease and anesthesia. Anesthesiology. 2004 Sep. 101(3):766-85. [QxMD MEDLINE Link].
Cappellini MD, Piga A. Current status in iron chelation in hemoglobinopathies. Curr Mol Med. 2008 Nov. 8(7):663-74. [QxMD MEDLINE Link].
Rienhoff HY Jr, Viprakasit V, Tay L, et al. A phase 1 dose-escalation study: safety, tolerability, and pharmacokinetics of FBS0701, a novel oral iron chelator for the treatment of transfusional iron overload. Haematologica. 2011 Apr. 96(4):521-5. [QxMD MEDLINE Link]. [Full Text].
Das BB, Sobczyk W, Bertolone S, Raj A. Cardiopulmonary stress testing in children with sickle cell disease who are on long-term erythrocytapheresis. J Pediatr Hematol Oncol. 2008 May. 30(5):373-7. [QxMD MEDLINE Link].
Leen JS, Ratnakaram R, Del Priore LV, Bhagat N, Zarbin MA. Anterior segment ischemia after vitrectomy in sickle cell disease. Retina. 2002 Apr. 22 (2):216-9. [QxMD MEDLINE Link].
Karim A, Laghmari M, Dahreddine M, Guedira K, Ibrahimy W, Essakali N, et al. [Hyphema with secondary hemorrhage: think about sickle cell disease]. J Fr Ophtalmol. 2004 Apr. 27 (4):397-400. [QxMD MEDLINE Link].
Nasrullah A, Kerr NC. Sickle cell trait as a risk factor for secondary hemorrhage in children with traumatic hyphema. Am J Ophthalmol. 1997 Jun. 123 (6):783-90. [QxMD MEDLINE Link].
Rogovik AL, Li Y, Kirby MA, Friedman JN, Goldman RD. Admission and length of stay due to painful vasoocclusive crisis in children. Am J Emerg Med. 2009 Sep. 27(7):797-801. [QxMD MEDLINE Link].
Wang WC, Ware RE, Miller ST, et al. Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet. 2011 May 14. 377(9778):1663-72. [QxMD MEDLINE Link].
Gladwin MT, Kato GJ, Weiner D, et al. Nitric oxide for inhalation in the acute treatment of sickle cell pain crisis: a randomized controlled trial. JAMA. 2011 Mar 2. 305(9):893-902. [QxMD MEDLINE Link].
[Guideline] Howard J, Hart N, Roberts-Harewood M, Cummins M, Awogbade M, Davis B, et al. Guideline on the management of acute chest syndrome in sickle cell disease. Br J Haematol. 2015 May. 169 (4):492-505. [QxMD MEDLINE Link]. [Full Text].
Styles L, Wager CG, Labotka RJ, Smith-Whitley K, Thompson AA, Lane PA, et al. Refining the value of secretory phospholipase A2 as a predictor of acute chest syndrome in sickle cell disease: results of a feasibility study (PROACTIVE). Br J Haematol. 2012 Jun. 157 (5):627-36. [QxMD MEDLINE Link]. [Full Text].
Ogunlesi F, Heeney MM, Koumbourlis AC. Systemic corticosteroids in acute chest syndrome: friend or foe?. Paediatr Respir Rev. 2014 Mar. 15 (1):24-7. [QxMD MEDLINE Link].
[Guideline] Brandow AM, Carroll CP, Creary S, Edwards-Elliott R, Glassberg J, Hurley RW, et al. American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain. Blood Adv. 2020 Jun 23. 4 (12):2656-2701. [QxMD MEDLINE Link]. [Full Text].
Goodwin EF, Partain PI, Lebensburger JD, Fineberg NS, Howard TH. Elective cholecystectomy reduces morbidity of cholelithiasis in pediatric sickle cell disease. Pediatr Blood Cancer. 2016 Sep 19. [QxMD MEDLINE Link].
Rogers ZR. Priapism in sickle cell disease. Hematol Oncol Clin North Am. 2005 Oct. 19(5):917-28, viii. [QxMD MEDLINE Link].
Burnett AL, Bivalacqua TJ, Champion HC, Musicki B. Long-term oral phosphodiesterase 5 inhibitor therapy alleviates recurrent priapism. Urology. 2006 May. 67(5):1043-8. [QxMD MEDLINE Link].
Burnett AL, Anele UA, Trueheart IN, Strouse JJ, Casella JF. Randomized controlled trial of sildenafil for preventing recurrent ischemic priapism in sickle cell disease. Am J Med. 2014 Jul. 127 (7):664-8. [QxMD MEDLINE Link]. [Full Text].
Chinegwundoh FI, Smith S, Anie KA. Treatments for priapism in boys and men with sickle cell disease. Cochrane Database Syst Rev. 2020 Apr 6. 4:CD004198. [QxMD MEDLINE Link].
[Guideline] Furie KL, Kasner SE, Adams RJ, Albers GW, Bush RL, Fagan SC, et al. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the american heart association/american stroke association. Stroke. 2011 Jan. 42(1):227-76. [QxMD MEDLINE Link]. [Full Text].
Adams RJ, McKie VC, Hsu L, Files B, Vichinsky E, Pegelow C, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med. 1998 Jul 2. 339(1):5-11. [QxMD MEDLINE Link].
DeBaun MR, Gordon M, McKinstry RC,et al. Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia. N Engl J Med. 2014 Aug 21. 371(8):699-710. [QxMD MEDLINE Link].
[Guideline] Goldstein LB, Bushnell CD, Adams RJ, Appel LJ, Braun LT, Chaturvedi S, et al. Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011 Feb. 42(2):517-84. [QxMD MEDLINE Link]. [Full Text].
Freed J, Talano J, Small T, Ricci A, Cairo MS. Allogeneic cellular and autologous stem cell therapy for sickle cell disease: 'whom, when and how'. Bone Marrow Transplant. 2012 Dec. 47 (12):1489-98. [QxMD MEDLINE Link]. [Full Text].
Ware RE, Helms RW, SWiTCH Investigators. Stroke With Transfusions Changing to Hydroxyurea (SWiTCH). Blood. 2012 Apr 26. 119 (17):3925-32. [QxMD MEDLINE Link].
Ware RE, Davis BR, Schultz WH, Brown RC, Aygun B, et al. Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial. Lancet. 2016 Feb 13. 387 (10019):661-70. [QxMD MEDLINE Link].
Frangoul H, Locatelli F, Sharma A, Bhatia M, et al. Exagamglogene Autotemcel for Severe Sickle Cell Disease. Blood. 2023. 142(Supple 1):1052. [Full Text].
Orkin SH, Bauer DE. Emerging Genetic Therapy for Sickle Cell Disease. Annu Rev Med. 2018 Oct 24. [QxMD MEDLINE Link].
Ribeil JA, Hacein-Bey-Abina S, Payen E, et al. Gene Therapy in a Patient with Sickle Cell Disease. N Engl J Med. 2017 Mar 2. 376 (9):848-855. [QxMD MEDLINE Link]. [Full Text].
Esrick EB, Lehmann LE, Biffi A, et al. Post-Transcriptional Genetic Silencing of BCL11A to Treat Sickle Cell Disease. N Engl J Med. 2021 Jan 21. 384 (3):205-215. [QxMD MEDLINE Link].
Kanter J, Thompson AA, Kwiatkowski JL, et al. Efficacy, safety, and health-related quality of life (HRQOL) in patients with sickle cell disease (SCD) who have received lovotibeglogene autotemcel (lovo-cel) gener therapy: Up to 60 months of followup (1051). Presented at the 65th Annual Meeting & Exposition of the American Society of Hematology. 2023 Dec 11. San Diego, CA. [Full Text].
Kanter J, Walters MC, Krishnamurti L, Mapara MY, Kwiatkowski JL, Rifkin-Zenenberg S, et al. Biologic and Clinical Efficacy of LentiGlobin for Sickle Cell Disease. N Engl J Med. 2022 Feb 17. 386 (7):617-628. [QxMD MEDLINE Link]. [Full Text].
Kanter J, Thompson AA, Pierciey FJ Jr, Hsieh M, Uchida N, Leboulch P, et al. Lovo-cel gene therapy for sickle cell disease: Treatment process evolution and outcomes in the initial groups of the HGB-206 study. Am J Hematol. 2023 Jan. 98 (1):11-22. [QxMD MEDLINE Link]. [Full Text].
Walters MC, De Castro LM, Sullivan KM, Krishnamurti L, Kamani N, Bredeson C, et al. Indications and Results of HLA-Identical Sibling Hematopoietic Cell Transplantation for Sickle Cell Disease. Biol Blood Marrow Transplant. 2016 Feb. 22 (2):207-211. [QxMD MEDLINE Link]. [Full Text].
Tanhehco YC, Bhatia M. Hematopoietic stem cell transplantation and cellular therapy in sickle cell disease: where are we now?. Curr Opin Hematol. 2019 Nov. 26 (6):448-452. [QxMD MEDLINE Link].
Krishnamurti L, Neuberg DS, Sullivan KM, et al. Bone marrow transplantation for adolescents and young adults with sickle cell disease: Results of a prospective multicenter pilot study. Am J Hematol. 2019 Apr. 94 (4):446-454. [QxMD MEDLINE Link]. [Full Text].
Kar BC. Splenectomy in sickle cell disease. J Assoc Physicians India. 1999 Sep. 47(9):890-3. [QxMD MEDLINE Link].
Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 1997 Apr 4. 46:1-24. [QxMD MEDLINE Link].
Kazancioglu R, Sever MS, Yüksel-Onel D, Eraksoy H, Yildiz A, Celik AV, et al. Immunization of renal transplant recipients with pneumococcal polysaccharide vaccine. Clin Transplant. 2000 Feb. 14(1):61-5. [QxMD MEDLINE Link].
Fiore AE, Shay DK, Broder K, Iskander JK, Uyeki TM, Mootrey G, et al. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009. MMWR Recomm Rep. 2009 Jul 31. 58:1-52. [QxMD MEDLINE Link].
[Guideline] Liem RI, Lanzkron S, D Coates T, DeCastro L, Desai AA, Ataga KI, et al. American Society of Hematology 2019 guidelines for sickle cell disease: cardiopulmonary and kidney disease. Blood Adv. 2019 Dec 10. 3 (23):3867-3897. [QxMD MEDLINE Link]. [Full Text].
[Guideline] DeBaun MR, Jordan LC, King AA, Schatz J, Vichinsky E, Fox CK, et al. American Society of Hematology 2020 guidelines for sickle cell disease: prevention, diagnosis, and treatment of cerebrovascular disease in children and adults. Blood Adv. 2020 Apr 28. 4 (8):1554-1588. [QxMD MEDLINE Link]. [Full Text].
[Guideline] Chou ST, Alsawas M, Fasano RM, Field JJ, Hendrickson JE, Howard J, et al. American Society of Hematology 2020 guidelines for sickle cell disease: transfusion support. Blood Adv. 2020 Jan 28. 4 (2):327-355. [QxMD MEDLINE Link]. [Full Text].
Kanter J, Liem RI, Bernaudin F, Bolaños-Meade J, Fitzhugh CD, Hankins JS, et al. American Society of Hematology 2021 guidelines for sickle cell disease: stem cell transplantation. Blood Adv. 2021 Sep 28. 5 (18):3668-3689. [QxMD MEDLINE Link]. [Full Text].

Media Gallery

Molecular and cellular changes of hemoglobin S.
Skeletal sickle cell anemia. H vertebrae. Lateral view of the spine shows angular depression of the central portion of each upper and lower endplate.
Peripheral blood with sickled cells at 400X magnification. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
Peripheral blood smear with sickled cells at 1000X magnification. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
Peripheral blood smear with Howell-Jolly body, indicating functional asplenism. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
Effects of therapy with hydroxyurea.
Skeletal sickle cell anemia. Bone-within-bone appearance. Following multiple infarctions of the long bones, sclerosis may assume the appearance of a bone within a bone, reflecting the old cortex within the new cortex.
A 12-year-old boy with HgbSS disease presents to the pediatric emergency department after his mother tried to wake him for school this morning and noted altered mental status, left-sided gaze paralysis with his head tilted to the left, and flaccid paralysis of the right arm and leg. A CT scan of the brain was obtained immediately.
Embolic stroke of the left middle cerebral artery. SCD is the most common cause of stroke in children and one of the most devastating complications of SCD. Clinically overt strokes are typically due to embolism of the intracranial internal carotid artery and proximal middle cerebral artery (MCA), while "silent strokes" more typically occur in the smaller lacunar and penetrating arteries. As RBCs undergo sickling and hemolysis within the cerebral circulation, they adhere to the vascular endothelium and promote a hypercoaguable state and fuel thromboembolism formation. Treatment options include prophylactic therapy with hydroxyurea to promote HgbF concentrations and monitoring via transcranial Doppler to evaluate MCA blood flow velocity. Children found to have high velocities are at increased risk for stroke and commonly receive RBC transfusions to decrease the concentration of HgbS.
The spleen enlarges during the first year of life in SCD, as it becomes congested with trapped slow-flowing sickled cells within the splenic sinuses and reticuloendothelial system. The histology image shown demonstrates splenic congestion from sequestered sickled RBCs (arrows). Microvascular occlusions produce chronic tissue hypoxia and microinfarctions. Over time, fibrosis induces autosplenectomy. With functional asplenia, patients are particularly susceptible to infection by the encapsulated organisms Streptococcus pneumoniae and Haemophilus influenzae. Vaccination and prophylactic daily penicillin throughout childhood are mainstays of treatment to prevent sepsis and meningitis
Splenic sequestration is an important cause of morbidity that occurs when sudden splenic pooling of blood within the reticuloendothelial system causes an acute drop in circulatory volume and shock-like symptoms (hypotension, tachycardia) with a rigid distended abdomen. It is an acute emergency and can be fatal in 1-2 hours secondary to circulatory hypovolemia. Treatment is with volume resuscitation and blood transfusion. The CT image shown demonstrates splenomegaly with a mass-like process (arrows) from splenic sequestration.
Patients with SCD are also at increased risk of developing pulmonary arterial hypertension (PAH). The etiology is most likely multifactorial but likely related to increased cardiac output secondary to underlying chronic anemia. Impedance to the elevated blood flow will cause further dilation and increase in pulmonary pressures. Postsickling changes including interstitial fibrosis secondary to vaso-occlusive crisis of ACS and hypoperfusion with resultant hypoxia of the pulmonary vascular beds are both proposed offenders inciting further dilation and elevation of pulmonary pressures. A pulmonary arteriogram depicting the markedly dilated vascular supply of the lungs seen in PAH is shown.
Proliferative sickle cell retinopathy. Sickle cell retinopathy is believed to be vaso-occlusion of peripheral arterioles of the retina leading to retinal hypoxia, ischemia, and infarction. New vessels then form at the junction of the vascular and avascular areas of retina. This neovascularization of retinal tissue and resultant traction of fibrovascularization places patients at risk for vitreous hemorrhage (arrows) and retinal detachment. Another common ocular manifestation is hyphema. Anterior chamber bleeding occurs spontaneously, but sickled erythrocytes obstruct the trabecular meshwork leading to significant elevations of intraocular pressure. Patients are particularly susceptible to glaucomatous optic nerve damage from even mildly elevated intraocular pressures. Pressures greater than 36 mm Hg for 24 hours are an indication for surgical drainage in both SCD and sickle cell trait, regardless of the size of hyphema. Image courtesy of the National Eye Institute, National Institutes of Health (NEI/NIH).
A 19-year-old man with known HgbSS disease presents because his girlfriend reports his eyes are yellow. He has no complaints. Physical exam is notable for mild abdominal pain, but is otherwise within normal limits. What imaging test is warranted for this work-up? The image shown is of a male child with similar symptoms. Image courtesy of Wikimedia Commons.
Right upper quadrant ultrasoundChronic hemolysis of sickled cells in HgbSS disease and high heme turnover yields hyperbilirubinemia and is associated with increased formation of bile stones. Stone formation occurs as substances in bile reach concentrations that approach the limits of their solubility. As saturation levels are reached, crystals precipitate, become trapped in mucus, and produce sludge (shown). Over time, the crystals aggregate and form stones. Occlusion of the biliary tree by sludge and/or stones produces clinical disease, typically right upper quadrant pain. The scleral icterus seen in the image of the previous slide is most likely secondary to the elevated circulating levels of bilirubin as a result of an acute hemolytic event (such as an acute vaso-occlusive crisis).
Renal papillary necrosisThe microvascular beds of the renal parenchyma are susceptible to sickling and vaso-occlusive crisis because of their inherent low-oxygen and high-osmolarity state. Depending on the location of occlusion, symptoms vary from a decreased ability to concentrate urine (yielding nocturia and polyuria), a disruption of exchange mechanisms (yielding hyperkalemia) or hematuria, which further damages renal tubules. In renal papillary necrosis, repeated vascular occlusion infarcts the renal medullary pyramids and papillae. This causes sloughing of papillae, which obstructs the urinary tract. Treatment options include hydration, high-dose antibiotics for resulting pyelonephritis, and possible percutaneous nephrostomy tube or invasive retrieval of sloughed papillae in acute urinary obstruction. The intravenous pyelogram demonstrates the "egg-in-a-cup" appearance of sloughed renal papillae (arrows) secondary to renal papillary necrosis.
Skeletal sickle cell anemia. Hand-foot syndrome. Soft tissue swelling with periosteal new-bone formation and a moth-eaten lytic process at the proximal aspect of the fourth phalanx.
Skeletal sickle cell anemia. Advanced dactylitis. Lytic processes are present at the first and fifth metacarpals, along with periostitis, which is most prominent in the third metacarpal.
Skeletal sickle cell anemia. Expanded medullary cavity. The diploic space is markedly widened due to marrow hyperplasia. Trabeculae are oriented perpendicular to the inner table, giving a hair-on-end appearance.
Skeletal sickle cell anemia. Detailed view of the expanded medullary cavity in the same patient as in the previous image.
Skeletal sickle cell anemia. Osteonecrosis. Image shows flattening of the femoral heads with a mixture of sclerosis and lucency characteristic of osteonecrosis.
Skeletal sickle cell anemia. Osteonecrosis. Detail of the right hip.
Skeletal sickle cell anemia. Osteonecrosis. Detail of the left hip.
Skeletal sickle cell anemia. Bone infarct. Image shows patchy sclerosis of the humeral head and shaft representing multiple prior bone infarcts.
Skeletal sickle cell anemia. Chronic infarcts and secondary osteoarthritis. Image shows advanced changes of irregular sclerosis and lucency on both sides of the knee joint reflecting numerous prior infarcts. The joint surfaces are irregular and the cartilages are narrowed due to secondary osteoarthritis.
Skeletal sickle cell anemia. Osteonecrosis. Coronal T1-weighted MRI shows a slightly flattened femoral head with a serpentine margin of low signal intensity around an area of ischemic marrow with signal intensity similar to that of fat.
Skeletal sickle cell anemia. Osteonecrosis in the same patient as in the previous image. Coronal T2-weighted MRI shows a serpentine area of low signal intensity and additional focal areas of abnormal low signal intensity in the femoral head; these findings reflect collapse of bone and sclerosis.
Skeletal sickle cell anemia. Osteomyelitis. CT scan in a soft tissue window demonstrates a large abscess in the left thigh encircling the femur, with hypoattenuating pus surrounded by a rim of vivid enhancement.
Skeletal sickle cell anemia. Osteomyelitis and bone-within-bone. Bone-window CT scan in the same patient as in the previous image shows a bone-within-bone appearance (concentric rings of cortical bone) in the right femur. On the left, a sinus tract (cloaca) traverses the lateral aspect of the femoral cortex, and a small, shardlike sequestrum is present deep to the sinus tract.
Skeletal sickle cell anemia. Bone scan of bone infarct shows an area of increased uptake in the distal femoral metaphysis corresponding to the infarct demonstrated on the previous plain radiograph.

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Tests	Age	Frequency
CBC count with WBC differential, reticulocyte count	3-24 mo >24 mo	every 3 mo every 6 mo
Percent Hb F	6-24 mo >24 mo	every 6 mo annually
Renal function (creatinine, BUN, urinalysis)	≥ 12 mo	annually
Hepatobiliary function (ALT, fractionated bilirubin)	≥ 12 mo	annually
Pulmonary function (transcutaneous O₂ saturation)	≥ 12 mo	every 6 mo

Author

Joseph E Maakaron, MD Research Fellow, Department of Internal Medicine, Division of Hematology/Oncology, American University of Beirut Medical Center, Lebanon

Disclosure: Nothing to disclose.

Coauthor(s)

Ali T Taher, MD, PhD, FRCP Professor of Medicine, Associate Chair of Research, Department of Internal Medicine, Division of Hematology/Oncology, Director of Research, NK Basile Cancer Center, American University of Beirut Medical Center, Lebanon

Disclosure: Nothing to disclose.

Specialty Editor Board

Jeanne Yu, PharmD

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Mark Ventocilla, OD, FAAO Chief Executive Officer, Elder Eye Care Group, PLC; Chief Executive Officer, Mark Ventocilla, OD, Inc; President, California Eye Wear, Oakwood Optical

Mark Ventocilla, OD, FAAO is a member of the following medical societies: American Academy of Optometry, American Optometric Association

Disclosure: Nothing to disclose.

Acknowledgements

Roy Alson, MD, PhD, FACEP, FAAEM Associate Professor, Department of Emergency Medicine, Wake Forest University School of Medicine; Medical Director, Forsyth County EMS; Deputy Medical Advisor, North Carolina Office of EMS; Associate Medical Director, North Carolina Baptist AirCare

Roy Alson, MD, PhD, FACEP, FAAEM is a member of the following medical societies: Air Medical Physician Association, American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, National Association of EMS Physicians, North Carolina Medical Society, Society for Academic Emergency Medicine, and World Association for Disaster and Emergency Medicine