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Anemia, Sickle Cell
Tipsuda Junsanto-Bahri, MD
image BASICS
DESCRIPTION
  • Hereditary, hemoglobinopathy marked by chronic hemolytic anemia, periodic acute episodes of painful “crises,” and increased susceptibility to infections
  • The heterozygous condition (Hb A/S), sickle cell trait, is usually asymptomatic without anemia.
  • Synonym(s): sickle cell disease (SCD); Hb SS disease
Pediatric Considerations
  • Sequestration crises and hand-foot syndrome seen typically in infants/young children
  • Strokes occur mainly in childhood.
  • Adolescence/young adulthood
    • Frequency of complications and organ/tissue damage increases with age
    • Psychological complications: body image, interrupted schooling, restriction of activities, stigma of disease, low self-esteem
Pregnancy Considerations
  • Complicated, especially during 3rd trimester and delivery
    • Fetal mortality 35-40%. Fetal survival is >90% if the fetus reaches the 3rd trimester.
    • High prevalence of small for gestational age (SGA) babies
  • Increased risk of thrombosis, preterm delivery, pain, toxemia, infection, pulmonary infarction, phlebitis
  • Partial exchange transfusion in 3rd trimester may reduce maternal morbidity and fetal mortality, but this is controversial.
  • Chronic transfusions have been effective in diminishing pain episodes in pregnant women. However, this method should be used with caution due to risk of alloimmunization.
EPIDEMIOLOGY
Prevalence
  • ˜90,000 Americans have sickle cell anemia (SCA) and 3.5 million people in the United States have sickle cell trait.
  • The condition affects mainly people of African descent. Hispanic, Middle-eastern, and Asian Indian ancestry may also be affected.
ETIOLOGY AND PATHOPHYSIOLOGY
  • Hemoglobin S results from the substitution of the amino acid valine for glutamic acid at the sixth position of the β-globin chain
  • HbS polymerizes in the RBC in the deoxygenated state resulting in RBC sickling.
  • Sickle RBCs are inflexible, causes increased blood viscosity, stasis, obstruction of small arterioles and capillaries, and ischemia.
  • Chronic anemia; crises
    • Vaso-occlusive crisis: tissue ischemia and necrosis; progressive organ failure/tissue damage from repeated episodes
    • Hand-foot syndrome: Vessel occlusion/ischemia affects small blood vessels in hands or feet.
    • Aplastic crisis: suppression of RBC production by severe infection (e.g., parvoviral and other viral infections)
    • Suppression of RBC production
    • Hyperhemolytic crisis: accelerated hemolysis with reticulocytosis; increased RBC fragility/shortened lifespan
    • Sequestration crisis: splenic sequestration of blood (only in young children as spleen is later lost to autoinfarction)
  • Susceptibility to infection: impaired/absent splenic function leading to decreased ability to clear infection; defect in alternate pathway of complement activation.
  • Increased RBC destruction causes decreased hemoglobin levels and results in anemia and fatigue.
  • Sickle cells exhibit increased adhesion and decreased ability to maneuver through small vessels, leading to vaso-occlusion.
Genetics
  • Autosomal recessive. Homozygous condition, Hb SS; heterozygous condition, Hb A/S
  • The heterozygote condition can also be combined with other hemoglobinopathies: sickle-hemoglobin C disease (HbSC) and Sβ+ thalassemia are clinically similar to the heterozygous condition, whereas, Sβ thalassemia is clinically similar to the homozygous condition.
RISK FACTORS
  • Vaso-occlusive crisis (“painful crisis”): hypoxia, dehydration, fever, infection, acidosis, cold, anesthesia, strenuous physical exercise, smoking
  • Aplastic crisis (suppression of RBC production): severe infections, human parvovirus B19 infection, folic acid deficiency
  • Hyperhemolytic crisis (accelerated hemolysis with reticulocytosis): acute bacterial infections, exposure to oxidant
GENERAL PREVENTION
  • Prevention of crises
    • Avoid hypoxia, dehydration, cold, infection, fever, acidosis, and anesthesia.
    • Prompt management of fever, infections, pain
    • Hydration
    • Avoid alcohol and smoking.
    • Avoid high-altitude areas.
  • Minimizing trauma: Aseptic technique is imperative.
image DIAGNOSIS
Diagnosis is often made by newborn screening programs.
PHYSICAL EXAM
Fever, pale skin and nail beds, mild jaundice
DIFFERENTIAL DIAGNOSIS
Anemia: other hemoglobinopathies
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • Screening test: Sickledex test/Hb electrophoresis (diagnostic test of choice); SCA (FS pattern)
    • 80-100% Hb S, variable amounts of Hb F, and no Hb A1
    • Sickle cell trait (FS pattern): 30-45% Hb S, 50-70% Hb A1, minimal Hb F
  • Hemoglobin ˜5 to 10 g/dL; RBC indices: mean corpuscular volume (MCV) normal to increased; mean corpuscular hemoglobin concentration (MCHC) increased; reticulocytes 3-15%
  • Leukocytosis; bands in absence of infection, platelets elevated; peripheral smear: sickled RBCs, nucleated RBCs, Howell-Jolly bodies
  • Serum bilirubin mildly elevated (2 to 4 mg/dL); ferritin very elevated in multiply transfused patients; serum lactate dehydrogenase (LDH) elevated
  • Fecal/urinary urobilinogen high
  • Haptoglobin absent or very low
  • Urine analysis: hemoglobinuria, hematuria (sickle cell trait may have painless hematuria), increased albuminuria (monitor for progressive kidney disease)
  • Need for imaging depends on clinical circumstances
    • Bone scan to rule out osteomyelitis
    • CT/MRI to rule out CVA; high index of suspicion required for any acute neurologic symptoms other than mild headache.
    • Chest x-ray: may show enlarged heart; diffuse alveolar infiltrates in acute chest syndrome
    • Transcranial Doppler: start at age 2 years; repeat yearly. Transcranial Doppler ultrasound identifies children age 2 to 16 years at higher risk of stroke.
    • ECG to detect pulmonary hypertension and echocardiogram every other year from age 15 years and older.
Test Interpretation
Hyposplenism due to autosplenectomy is common; hypoxia/infarction in multiple organs
image TREATMENT
GENERAL MEASURES
  • Painful crises: hydration, analgesics; oxygen regardless of whether the patient is hypoxic (1)[A]
  • Retinal evaluation starting at school age to detect proliferative sickle retinopathy (1,2)[A]
  • Occupational therapy, cognitive and behavioral therapies, support groups
  • All standard childhood vaccinations should be administered accordingly.
  • Special immunizations
    • Influenza vaccine yearly
    • Conjugated pneumococcal vaccine (PCV13) at ages 2, 4, and 6 months; booster at 12 to 15 months.
    • Patients <5 years of age with incomplete vaccination history should receive catch-up doses accordingly.
    • Adults age ≥ 19 years who have functional asplenia and have not received pneumococcal vaccination should receive one dose PCV13, followed by administration of PPSV23 at least 8 weeks later (2)[A].
  • P.51

  • Meningococcal vaccine:
    • 6 weeks old: Hib-MenCY at ages 2, 4, 6, and 12 months
    • 9 months old: two doses of MCV4 separated by 3 months
    • ≥2 years of age: two doses of MCV4-D-CRM separated by 2 months; boosters recommended every 5 years
MEDICATION
First Line
  • Prophylactic penicillins indicated in infants and children starting at 2 months: A dose of 125 mg BID is recommended for children <5 years. A dose of 250 mg BID is recommended for children >5 years. Amoxicillin 20 mg/kg/day is an alternative to penicillin; if high risk remains, continue until puberty. Rising pneumococcal resistance to penicillin may change future recommendations (3)[A].
  • Supplemental oxygen
  • Painful crises (mild, outpatient)
    • Nonopioid analgesics (ibuprofen)
  • Painful crises (severe, hospitalized)
    • Parenteral opioids (e.g., morphine on fixed schedule); patient-controlled analgesia (PCA) pump may be useful (2)[A].
  • Hydroxyurea for prevention of painful acute chest syndrome, vaso-occlusive episodes, and very severe anemia. Increases fetal hemoglobin concentration. Adults: Start with 15 mg/kg/day single daily dose; Children: 20 mg/kg/day; titrate upward every 8 weeks (max dose of 35 mg/kg/day). Monitor blood counts satisfactory (avoid severe neutropenia, thrombocytopenia) (2)[A].
  • Acute chest syndrome: may deteriorate quickly; monitor patients with vaso-occlusive crisis with incentive spirometry. Treat with aggressive management with oxygen, analgesics, antibiotics, simple or exchange transfusion (2)[A].
  • Empiric antibiotics to cover Mycoplasma pneumoniae, and Chlamydia pneumoniae (cephalosporins or azithromycin) (1)[A]. If osteomyelitis, cover for Staphylococcus aureus and Salmonella (e.g., ciprofloxacin). Precautions: Avoid high-dose estrogen oral contraceptives; consider Depo-Provera. G-CSF use is contraindicated as it may lead to vaso-occlusive episodes and multiorgan failure.
Second Line
Folic acid: 0 to 6 months: 0.1 mg/day; 6 to 12 months: 0.25 mg/day; 1 to 2 years: 0.5 mg/day; >2 years of age: 1 mg/day
ADDITIONAL TREATMENT
Transfusions and additional therapies (4)[A]
  • Transfusion for aplastic crises, severe complications (i.e., CVA), prophylactically before surgery, and treatment for acute chest syndrome; prophylactic transfusions for primary or secondary stroke prevention in children
  • Preoperative transfusions have been shown to reduce the risk of perioperative complications.
  • Avoid blood hyperviscosity.
  • Consider chelation with deferasirox, an oral agent, if the patient is multiply transfused (after age 2 years). Red cell exchange transfusion minimizes risk of iron overload.
SURGERY/OTHER PROCEDURES
  • Targeted fetal hemoglobin induction treatment (5)[A]
  • Hematopoietic stem cell transplant (HSCT) (6)[A]: curative, but with significant morbidity and mortality; limited to individuals < 16 years old.
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
Severe pain, suspected infection or sepsis, evidence of acute chest syndrome
IV Fluids
The preferred maintenance IV fluid is 1/2 NS, as NS may theoretically increase the risk of sickling.
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
  • Treat infections early. Parents/patients: Any temperature of ≥ 101°F (38.3°C) requires immediate medical attention.
  • For patients who receive chronic transfusions, monitor for hepatitis C and hemosiderosis.
  • Periodic eye evaluations: starting age 10 years to detect proliferative sickle retinopathy; re-screen 1 to 2 year intervals (3)[A]
  • Biannual examination for hepatic, renal, and pulmonary dysfunction
  • Neuroimaging screening for risk of stroke: transcranial Doppler beginning at age 2 years and continuing up to age 16 years
  • Baseline pulmonary evaluation at each visit to assess for wheezing, shortness of breath, or cough (indicators of disease severity and pulmonary hypertension). Echocardiography for symptomatic patients; right heart catheterization for diagnosis
  • Consider venous thromboembolism (VTE) prophylaxis as there is an increased incidence of thromboembolism.
DIET
  • Folic acid supplementation; avoid alcohol (leads to dehydration); maintain hydration
  • Multivitamin without iron is recommended as there is high incidence of vitamin D deficiency and decreased bone marrow density in SCD patients.
PATIENT EDUCATION
  • SickleCellKids.org—Education Web site for children with sickle cell anemia: http://www.sicklecelldisease.org
  • American Sickle Cell Anemia Association: http://www.ascaa.org
PROGNOSIS
  • Anemia occurs in infancy; sickle cell crises at 1 to 2 years of age; some children die in their first year.
  • In adulthood, fewer crises, but more complications. Median age of death is 42 years for men and 48 years for women. Complications are mentioned below.
REFERENCES
1. Brousse V, Makani J, Rees DC. Management of sickle cell disease in the community. BMJ. 2014;348:g1765.
2. Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014;312(10):1033-1048.
3. Cober MP, Phelps SJ. Penicillin prophylaxis in children with sickle cell disease. J Pediatr Pharmacol Ther. 2010;15(3):152-159.
4. Chou ST. Transfusion therapy for sickle cell disease: a balancing act. Hematology Am Soc Hematol Educ Program. 2013;2013:439-446.
5. Manwani D, Frenette PS. Vaso-occlusion in sickle cell disease: pathophysiology and novel targeted therapies. Blood. 2013;122(24):3892-3898.
6. Hsieh MM, Fitzhugh CD, Weitzel RP, et al. Nonmyeloablative HLA-matched sibling allogeneic hematopoietic stem cell transplantation for severe sickle cell phenotype. JAMA. 2014;312(1):48-56.
Additional Reading
  • Aragona E, Kelly MJ. Hyperhemolysis in sickle cell disease. J Pedriatr Hematol Oncol. 2014;36(1):354-356. doi:10.1097/MPH.0b013e31828e529f.
  • Costa VM, Viana MB, Aguiar RA. Pregnancy in patients with sickle cell disease: maternal and perinatal outcomes. J Matern Fetal Neonatal Med. 2015;28(6):685-689. doi:10.3109/147 67058.2014.928855.
  • Machado RF, Farber HW. Pulmonary hypertension associated with chronic hemolytic anemia and other blood disorders. Clin Chest Med. 2013;34(4):739-752.
  • Naik RP, Streiff MB, Lanzkron S. Sickle cell disease and venous thromboembolism: what the anticoagulation expert needs to know. J Thromb Thrombolysis. 2013;35(3):352-358.
See Also
Algorithm: Anemia
Codes
ICD10
  • D57.1 Sickle-cell disease without crisis
  • D57.3 Sickle-cell trait
  • D57.00 Hb-SS disease with crisis, unspecified
Clinical Pearls
  • Over 90,000 Americans have SCA (˜ 1 in 375 African Americans). The preferred maintenance IV fluid is 1/2 NS, as NS may theoretically increase the risk of sickling.
  • Painful crises in bones, joints, abdomen, back, and viscera account for 90% of all hospital admissions.
  • Acute chest syndrome: tachycardia, fever, bilateral infiltrates caused by pulmonary infarctions