Sickle Cell Disease in Adults and Adolescents

Background

• Sickle cell disease (SCD) is a group of chronic hemolytic anemias characterized by the presence of at least one hemoglobin S allele (HbS; p.Glu6Val in HBB) and a second HBB pathogenic variant leading to excessive production of hemoglobin S (HbS). HbS polymerizes when deoxygenated, distorting red blood cells and causing a characteristic sickle shape.
• It is most common in individuals from or descended from Africa, Middle East, India, Mediterranean countries, Caribbean countries, and parts of Central and South America. The highest prevalence is in persons from Africa or of African descent.
• Sickle cell anemia (SCA) is the most severe subtype. It includes homozygous sickle cell disease (HbSS) and sickle beta⁰ thalassemia. SCA is usually detected in neonatal screening and requires life-long treatment.
• Other subtypes include:
  • sickle hemoglobin C disease (HbSC), a compound heterozygous condition usually associated with anemia
  • sickle beta⁺ thalassemia, a compound heterozygous anemia
  • compound heterozygotes for HbS and other beta chain variants

Evaluation

• Most patients with sickle cell anemia (SCA) are identified through newborn screening by chromatographic methods that evaluate type and relative amounts of normal and abnormal hemoglobin types including hemoglobin S. Prenatal diagnosis can be made using mutation-specific DNA methods. Some patients with sickle hemoglobin C disease (HbSC) are not diagnosed until adulthood.
• Perform the following diagnostic tests for a patient with suspected sickle cell disease: complete blood count including reticulocyte count, peripheral blood smear, and hemoglobin electrophoresis or high performance liquid chromatography (HPLC) to detect hemoglobin S.
• Laboratory findings typical of sickle cell disease

Table 1. Typical SCD Laboratory Findings

• Patients may present during routine health maintenance (immunizations or screening), or with symptoms of acute or chronic complications of disease.

Management

Disease Modifying Approaches

• Treatments to reduce incidences of acute events include use of hydroxyurea and L-glutamine.
• Blood transfusions may be required to maintain hemoglobin S levels to ≤ 30% of total hemoglobin.

Management of Acute Vaso-occlusive Crisis

• An acute vaso-occlusive crisis typically manifesting as sudden new onset of intense pain lasting ≥ 4 hours requiring treatment, is the most frequent acute complication of sickle cell disease (SCD) and the most common reason for visit to emergency department and admission to hospital.
• The painful crisis results from vaso-occlusion of small blood vessels, which leads to ischemia-reperfusion injury involving interactions with vascular endothelium, as well as contributions from hemolysis, inflammation, and coagulation. It may herald the onset of other complications of SCD such as acute chest syndrome and acute multiorgan failure.
• Treat an acute painful sickle cell episode as a medical emergency.
• Assess pain intensity using available pain scales (such as visual analog scale), perform a thorough review of signs and symptoms to identify potential triggers (including infection, cold exposure, fever, physical and/or emotional stress, and dehydration), obtain vitals including blood pressure, heart rate, respiratory rate, temperature and oxygen saturation on room air, and examine for findings suggestive of infection, acute chest syndrome, or other organ damage.
• Other work up includes complete blood count, including platelet count, reticulocyte count, metabolic panel, and where appropriate, chest-x ray.
• Rule out other causes of pain, including pneumonia, acute chest syndrome, papillary necrosis, hepatic or splenic sequestration, septic arthritis, trauma, and other comorbidities.
• Supportive care for an acute vaso-occlusive crisis typically includes administration of oxygen, especially if oxygen saturation is < 95%, hydration, use of incentive spirometry, and encouraging patient ambulation and activity.
• Transfusion is not recommended in uncomplicated vaso-occlusive crisis but should be considered if there is worsening anemia (for example, decrease of hemoglobin by ≥ 2 g/dL [20 g/L]) compared to steady state values or hemoglobin < 5 g/dL [50 g/L]), hemodynamic compromise, or concern about impending critical organ complications (Strong recommendation).
• Pain management:
  • Choice of a primary analgesic depends on pain severity:
    • For mild-to-moderate pain, consider treatment with oral nonsteroidal anti-inflammatory drugs (NSAIDs) unless NSAIDs are contraindicated (Weak recommendation). NSAIDs are not suggested if serum creatinine is above the upper limit of normal for age, especially in the presence of albuminuria.
    • For severe pain, rapidly initiate parenteral opioids (Strong recommendation).
  • Adjunctive treatments to consider include:
    • Medications to increase analgesic effect of opioids or reduce side effects of primary medications, for example antihistamines (to offset histamine release by mast cells due to opioids, especially morphine), antiemetics, laxatives, antidepressants, and gabapentinoids.
    • Nonpharmacologic approaches to treat pain, for example, local heat application and distraction (Weak recommendation). Also consider other approaches such as massage, yoga, transcutaneous electrical nerve stimulation, virtual reality, and guided (audio-visual) relaxation (Weak recommendation).

Management of Other Acute Complications

• Acute anemia
  • Defined as a reduction in hemoglobin ≥ 2 g/dL (20 g/L) below baseline.
  • May occur as the result of acute chest syndrome, acute splenic sequestration, acute hepatic sequestration, aplastic crisis, hyperhemolysis (from red blood cell transfusion, infection or pain crisis), or acute blood loss.
  • Obtain a complete blood count, platelet count, and reticulocyte count in all patients with SCD and acute illness (Strong recommendation). Additional evaluation may include:
    • parvovirus B19 serology for suspected aplastic crisis
    • direct and indirect antiglobulin test (Coombs test) for suspected transfusion-associated hyperhemolysis
    • blood and urine cultures for suspected infection
    • chest x-ray for acute chest syndrome
    • liver function tests for suspected hepatic sequestration
    • renal function tests for suspected renal failure
    • unconjugated serum bilirubin, and urine urobilinogen and hemoglobin for hyperhemolysis
    • tests to diagnose other causes of anemia such as serum vitamin B12, folate levels and glucose-6-phosphate dehydrogenase deficiency if needed.
  • Aplastic crisis
    • Typically caused by parvovirus B19-mediated suppression of red blood cell production.
    • Suspected in patient with history of preceding febrile illness.
    • Patient may present with nonspecific symptoms of headache, fever, and shortness of breath, signs of lethargy, and tachycardia and complete blood count showing hemoglobin far below baseline (3-6 g/dL [30-60 g/L]) and severe reticulocytopenia.
    • Spontaneous resumption of erythropoiesis typically occurs within 7-10 days of aplasia, restoring the hemoglobin to steady state level.
    • Administer immediate red blood cell transfusion to restore hemoglobin to safe (though not necessarily baseline) level.(Strong recommendation).
    • Isolate hospitalized patients to prevent spread of parvovirus B19 to pregnant women, other patients with SCD, or patients with compromised immunity (Strong recommendation).
  • Splenic sequestration
    • Caused by trapping of red blood cells in the splenic sinuses which leads to a sudden rapid enlargement of the spleen.
    • Usually occurs in children aged < 5 years before the spleen has spontaneously infarcted.
    • Suspect in young patient with sudden enlargement of spleen, causing severe abdominal pain and distension, signs of hypovolemia, hemoglobin decrease ≥ 2 g/dL from baseline with elevated reticulocyte count, and circulating nucleated red blood cells.
    • Suspect in adults with hemoglobin SC disease or sickle beta-thalassemia⁺ with milder symptoms, or with severe pain from splenic infarction.
    • In cases of hypovolemia from severe acute splenic sequestration, provide immediate IV fluids (Strong recommendation)
    • In cases of severe anemia, perform a transfusion in consultation with a SCD expert to increase hemoglobin to a stable level (Strong recommendation)
    • Consider splenectomy in patients with recurrent acute splenic sequestration or symptomatic hypersplenism (Weak recommendation).
  • Hyperhemolytic crisis
    • Acute anemia with the evidence of accelerated hemolysis may result from acute vaso-occlusive painful crises, acute or delayed hemolytic reaction following a transfusion of red blood cells, infection, or drug exposure.
    • Suspect transfusion-associated hyperhemolytic crisis in patients with SCD with recent red blood cell transfusion who present with drop in hemoglobin below pretransfusion levels, paradoxical reticulocytopenia, increased unconjugated serum bilirubin, positive direct antiglobulin test (Coombs test) (though may be negative), and hemoglobinuria.
    • Transfusion-associated hyperhemolytic crisis is characterized by hemolysis of both donor and autologous red blood cells (bystander hemolysis). Additional transfusions may cause further hemolysis, leading to life-threatening anemia.
    • in patients with delayed hemolytic reaction and continuing hyperhemolysis, consider immunosuppressive therapy with IV immunoglobulin, corticosteroids, rituximab, and/or eculizumab (Weak recommendation).
• Acute chest syndrome
  • Usually develops during a painful crisis or after surgery.
  • Reported causes include acute infection, bone marrow fat embolism from necrotic bone marrow during pain crisis, and microvascular pulmonary infarction from intravascular sickling.
  • Suspect acute chest syndrome in patients presenting with fever and/or respiratory symptoms, together with clinical signs of new pulmonary infiltrate and low oxygen saturation.
  • Evaluation includes:
    • chest x-ray
    • complete blood count, including platelet count
    • renal and liver function tests
    • blood cultures
    • oxygen saturation (SpO₂) measurement by pulse oximetry
    • arterial blood gas on room air in adults (if SpO₂ ≤ 94% on room air)
    • serology for atypical respiratory organisms and urine for Pneumococcal and Legionella antigen
    • sputum for bacterial culture and sputum and nasopharyngeal aspirate for immunofluorescence or polymerase chain reaction (PCR) for viruses in patients with coryzal symptoms
    • determination of the presence of fat bodies causing pulmonary fat embolism in bronchoalveolar fluid and in induced sputum
  • Diagnosis supported by low oxygen saturation or hypoxemia and new pulmonary infiltrate on chest x-ray.
  • Consider presence of triggering factors including pulmonary embolism, fluid overload, and opiate overdose.
  • Initiate treatment with 2 broad-spectrum antibiotics and supplemental oxygen as needed, and monitor for bronchospasm, acute anemia, and hypoxemia (Strong recommendation).
  • Recommendations for transfusion
    • For patients with mild acute chest syndrome and decrease in hemoglobin > 1 g/dL (10 g/L) below baseline:
      • Consider simple blood transfusion (10 mL/kg red blood cells in children) to improve oxygen carrying capacity. In adults, amount of red blood transfusion is determined by degree of anemia and reasons for transfusion.
      • If hemoglobin concentration is ≥ 9 g/dL (90 g/L), simple transfusion may not be necessary (Weak recommendation).
    • For patients with severe or rapidly progressing acute chest syndrome:
      • urgent exchange transfusion with consultation from hematology, critical care, and/or apheresis specialists is indicated.
      • Signs of rapid progression include oxygen saturation < 90% on supplemental oxygen, increasing respiratory distress, progressive pulmonary infiltrates and decreased hemoglobin despite simple transfusion (Strong recommendation).
      • Consider exchange transfusion aiming for a %HbS target of < 30%.
  • Start hydroxyurea in adults with sickle cell anemia with a history of severe or recurrent acute chest syndrome (Strong recommendation).
• Priapism
  • Typically defined as unwanted painful erection lasting ≥ 4 hours.
  • Characterized by pain in the penis and/or scrotum, a fully erect penis and a soft glans.
  • Goals of treatment are pain relief and prevention of impotence.
  • Initiate vigorous oral or IV hydration and oral or IV analgesia (Strong recommendation).
  • Consult with a urologist for further evaluation and intervention for symptoms which do not resolve with initial conservative management (Strong recommendation).
  • Transfusion therapy for immediate treatment of priapism is not recommended, but may be indicated in preparation for surgery.
• Acute renal failure
  • Defined as rapid reduction in renal function manifested by increased serum creatinine and reduced glomerular filtration rate, with or without decreased urine output.
  • Causes include pre-renal causes, such as dehydration, intrinsic renal disease, including glomerular injury, and post-renal causes such as obstruction.
  • Assess for predisposing factors including volume depletion, hyperhemolysis, and use of non-steroidal anti-inflammatory drugs.
  • Patients with SCD have increased renal tubular secretion of creatinine, which may mask early renal insufficiency.
  • For patients with an acute increase in serum creatinine ≥ 0.3 mg/dL (26.5 mcmol/L), monitor renal function daily, avoid potential nephrotoxic drugs and imaging agents, and investigate all potential etiologies in consultation with a nephrologist (Strong recommendation).
• Fever and infection
  • Treat fever as a medical emergency due to risk of overwhelming bacterial infection as a result of reduced or absent splenic function.
  • Causes include:
    • septicemia and meningitis (most common causative organism Streptococcus pneumoniae)
    • acute chest syndrome associated with diverse organisms (including mycoplasma)
    • gram-negative enteric infections involving the urinary tract or hepatobiliary system
    • osteomyelitis caused by Staphylococcus aureus, salmonella, or other enteric pathogen
  • For patients with a temperature ≥ 101.3 degrees F (38.5 degrees C), workup includes history and physical, complete blood count with differential, platelet count, reticulocyte count, blood culture, sputum culture/gram stain as needed, and urine culture if urinary tract infection is suspected.
  • If febrile illness occurs with:
    • shortness of breath, tachypnea, cough, and/or rales, obtain chest x-ray immediately to assess for acute chest syndrome (Strong recommendation).
    • localized or multifocal bone tenderness, especially with erythema and swelling, consider bacterial osteomyelitis in differential diagnosis and manage patient accordingly (Strong recommendation)
  • In children with a temperature ≥ 101.3 degrees F (38.5 degrees C), start empiric treatment with parenteral antibiotics which cover Streptococcus pneumoniae and gram-negative enteric organisms (Strong recommendation).
  • In patients with temperature ≥ 103.1 degrees F (39.5 degrees C) who appear ill, admit to hospital for close observation and IV antibiotic treatment (Strong recommendation).
• Stroke
  • More common in patients with sickle cell anemia than in patients with hemoglobin SC disease or hemoglobin S-beta⁰-thalassemia.
  • Patients with overt ischemic stroke may be preceded by a transient ischemic attack and present with sudden weakness, aphasia, seizures, or coma.
  • Patients with hemorrhagic stroke may present with severe headache or loss of consciousness without hemiparesis.
  • For patients with SCD and suspected stroke (Strong recommendation):
    • seek consultation with a SCD expert and/or neurologic consultation.
    • perform an urgent head computerized tomography (CT) scan followed by magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) if available
  • Perform an exchange transfusion in patients who develop acute stroke confirmed by neuroimaging, in consultation with a SCD expert (Strong recommendation).
  • Consider hydroxyurea therapy if a transfusion program is not possible (Weak recommendation).
• Hepatobiliary complications
  • Acute complications include acute cholecystitis, acute choledocholithiasis acute hepatic sequestration [AHS] and acute intrahepatic cholestasis [AIC])
  • Patients with acute cholecystitis may present with severe colicky pain in the right upper quadrant, nausea and vomiting, fever, abdominal tenderness and leukocytosis.
  • Patients with acute choledocholithiasis typically present with dull pain in the right upper quadrant, tender hepatomegaly and rapidly increasing jaundice.
  • Patients with AHS present with hepatic enlargement without other explanation, > 2 g/dL decrease in hemoglobin from baseline and rise in the reticulocyte count.
  • Patients with AIC present sudden onset of right upper quadrant pain, increasing jaundice, light-colored stool, thrombocytopenia and coagulation abnormalities, and progressively enlarging and tender liver may be present.
  • Abdominal ultrasound and magnetic resonance imaging (MRI)/magnetic resonance cholangiopancreatography (MRCP) studies can help diagnose acute cholecystitis and maybe useful for investigation of common bile duct gallstones.
  • For patients with suspected AHS or AIC, provide hydration, rest, and close observation and consult with a SCD expert to confirm diagnosis and to determine further management (Strong recommendation).
  • For patients with confirmed AHS or severe AIC, perform a simple or exchange transfusion (Strong recommendation).
• Ocular complications
  • Acute ocular complications include hyphema, central retinal artery occlusion and orbital infarct.
  • Hyphema defined by presence of blood in ocular anterior chamber is usually caused by trauma and may present with visual abnormalities (floaters and flashers, light sensitivity, and/or blurry vision). It may result in increased intraocular pressure, which may in turn lead to central retinal artery occlusion and infarction of the optic nerve.
  • Orbital infarct results from infarction of the orbital bone, typically during a vaso-occlusive crisis and presents with eye protrusion, eye pain, and lid and/or orbital edema
  • Arrange immediate consultation with an ophthalmologist for patients presenting with hyphema (Strong recommendation).
  • Promptly refer any patient with signs and symptoms of eye trauma including protrusion of the eye, changes in visual acuity (floaters or flashers), and unilateral or bilateral vision loss to an eye specialist for a dilated eye exam to assess visual acuity, intraocular pressure, and the peripheral retina (Strong recommendation).
• Multisystem organ failure
  • A severe, life-threatening complication typically associated with a vaso-occlusive crisis and characterized by the failure of the lungs, liver, and/or kidneys.
  • Immediately start transfusion therapy (preferably exchange) in consultation with a SCD expert or hematologist (Strong recommendation).
• Venous thromboembolism (VTE)
  • Patients with SCD have increased risk of VTE.
  • Recommendations for VTE treatment or prophylaxis are based on individual assessment for the risk of thrombosis and bleeding.
  • Anticoagulation for first time VTE:
    • First VTE:
      • If unprovoked, consider indefinite anticoagulant therapy rather than shorter duration of therapy (Weak recommendation).
      • If provoked (by surgery or nonsurgery-related), consider anticoagulation for 3-6 months rather than indefinite duration of therapy (Weak recommendation).
      • Indefinite anticoagulation is not suggested for first VTE provoked by factors such as central venous line. However anticoagulation should be continued as long as provoking risk is present (including central venous line).
    • For recurrent provoked VTE, consider indefinite duration of anticoagulation rather than defined duration of therapy (Weak recommendation).

Chronic Management

Types of Disease-modifying Therapies

• Hydroxyurea therapy:
  • Hydroxyurea (also known as hydroxycarbamide) is administered to children and adults with sickle cell disease (SCD) to reduce frequency of recurrent painful episodes and acute chest syndrome, and the need for transfusion therapy, ultimately leading to improved quality of life.
  • Indications for Hydroxyurea therapy:
    • Infants (age ≥ 9 months), children, and adolescents with sickle cell anemia (homozygous sickle cell anemia [HbSS] or sickle beta⁰-thalassemia) regardless of clinical severity (Strong recommendation).
    • In all adults with sickle cell anemia (if not on hydroxyurea therapy already), especially those with:
      • more than 3 sickle cell-associated moderate-to-severe pain crises in a 12-month period (Strong recommendation)
      • a history of severe and/or recurrent acute chest syndrome (Strong recommendation)
      • sickle cell pain or severe symptomatic chronic anemia that interferes with daily activities and quality of life (Strong recommendation).
    • In patients with sickle cell genotypes other than HbSS or sickle beta⁰-thalassemia, consult sickle cell expert and consider hydroxyurea if patient is experiencing recurrent pain, acute chest syndrome, or events requiring hospitalization (Weak recommendation).
• Chronic transfusion therapy:
  • Chronic transfusion therapy for SCD involves transfusion of red blood cells (RBCs) to reduce sickle hemoglobin (HbS) levels as primary or secondary prevention of SCD-related complications. Indications include primary and secondary stroke prevention and reduction in incidence of acute events such as vaso-occlusive crises and acute chest syndrome if refractory to or contraindicated for hydroxyurea therapy.
  • Consider treatment goal to maintain HbS level at < 30% immediately prior to next transfusion (Weak recommendation).
• Hematopoietic Stem Cell Transplant (HSCT) is a potentially curative therapy.
• Gene therapy (site-specific gene correction of sickle beta-globin mutation in autologous HSCs) is in its early stages.
• Other FDA-approved pharmacologic agents to prevent SCD-related painful crises include L-glutamine, voxelotor, and crizanlizumab.

Management of Specific Conditions

• For management of chronic pain (pain lasting ≥ 3 months):
  • Determine the cause and type of sickle cell disease-related chronic pain (Strong recommendation).
  • Consider administering nonopioid therapy such as serotonin and norepinephrine reuptake inhibitor (SNRI), tricyclic antidepressants, nonsteroidal anti-inflammatory drugs (NSAIDs), or gabapentinoids for chronic pain management (Weak recommendation).
  • Consider administering long- and short-acting opioids to manage chronic pain that is not relieved by nonopioids, using the patient's response to treatment to guide long-term opioid use (Weak recommendation).
  • Consider nonpharmacologic therapies such as use of deep tissue/deep pressure massage therapy, muscle relaxation therapy, self-hypnosis, and cognitive and behavioral pain management as indicated (Weak recommendation).
  • Assess patients with SCD-related chronic pain annually, or more frequently if necessary (Strong recommendation).
• For management of avascular necrosis (most commonly involving the hip joint):
  • Evaluate all children and adults with sickle cell disease and intermittent or chronic hip pain for avascular necrosis; the evaluation should include a history, physical exam, radiography, and magnetic resonance imaging, as needed (Strong recommendation).
  • Treat avascular necrosis with analgesics and consult physical therapy and orthopedics for assessment and follow-up (Strong recommendation).
  • In adults, consider duloxetine, SNRI, or NSAIDs as part of comprehensive disease and pain management (Weak recommendation).
• For management of leg ulcers, consider standard initial therapy, including debridement, wet to dry dressing, and topical agents (Weak recommendation).
• For prevention of stroke:
  • For primary stroke prevention, offer chronic transfusions with exchange or simple transfusion for treatment of children with transcranial Doppler (TCD) reading > 200 cm/second (Strong recommendation).
  • For secondary stroke prevention, consider chronic transfusions with exchange or simple transfusion in adults and children with previous clinically overt stroke (Weak recommendation).
• For management of renal complications:
  • If microalbuminuria or macroalbuminuria is detected, order a 24-hour urine test for protein (Strong recommendation).
  • Consider angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) therapy in adults with microalbuminuria or proteinuria without other apparent cause (Weak recommendation).
  • Consider combination of hydroxyurea and erythropoiesis-stimulating agents (ESAs) to prevent worsening of anemia (Weak recommendation).
• For management of pulmonary hypertension (most commonly pulmonary arterial hypertension):
  • Initial assessment of patients with signs or symptoms suggesting pulmonary hypertension should include an echocardiography (Strong recommendation).
  • For patients with elevated tricuspid regurgitant volume ≥ 2.5 meters per second by echocardiography, consult a clinician with expertise in pulmonary hypertension to guide further assessment and management (including right heart catheterization and consideration of pulmonary hypertension therapy) (Strong recommendation).
• For management of proliferative sickle retinopathy:
  • Refer patients to an ophthalmologist for evaluation and possible laser photocoagulation therapy (Strong recommendation).
  • Refer patients who have vitreoretinal complications that are refractory to medical treatment for evaluation and possible vitrectomy (Strong recommendation).
• For management of cholecystitis:
  • Administer antibiotics to patients with acute cholecystitis and obtain surgical consult.
  • Observe asymptomatic gallstones and offer cholecystectomy (laparoscopic preferred) for patients who develop symptoms (Strong recommendation).
• Prevention of infection is an important management component in patients with SCD. Prevention includes:
  • targeted prophylaxis with penicillin to prevent septicemia and meningitis until age 5 years if the child is fully vaccinated with no history of invasive Streptococcus pneumoniae
  • appropriate vaccinations including against S. pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type b

Reproductive Issues in Women With Sickle Cell Disease

• Women with sickle cell disease require special considerations regarding contraception and management of pregnancy.