ANEMIA, SICKLE CELL

ANEMIA, SICKLE CELL - Diane M. Haleem, PhD, RN
BASICS
DESCRIPTION
• A chronic hemoglobinopathy transmitted genetically; marked by moderately severe chronic hemolytic anemia, periodic acute episodes of painful "crises," and increased susceptibility to intercurrent infections, especially Saccharomyces pneumoniae.
• The heterozygous condition (Hb A/S) is called sickle cell trait and is usually asymptomatic with no anemia.
• System(s) Affected: Hematologic, Lymphatic/immunologic; Musculoskeletal
• Synonym(s): Sickle cell disease; Hb S disease
ALERT
Pediatric Considerations
• Sequestration crises and hand-foot syndrome seen only in infants/young children
• Functional asplenia in later childhood
• Adolescence/young adulthood
- Frequency of complications and organ/tissue damage increase with age (except for strokes, which occur mostly in childhood).
- Psychological complications: Body-image and sexual identity problems, interrupted schooling, career, restriction of activities, stigma of disease, low self-esteem
• Consider periodic transcranial Doppler ultrasound in all children ages 2-16
Pregnancy Considerations
• Usually complicated and hazardous, especially 3rd trimester and delivery
• Increased risk of crises, toxemia, infection, pulmonary infarction, phlebitis
• Fetal mortality 35-40%
• Partial exchange transfusion in 3rd trimester reduces maternal morbidity and fetal mortality.
• Chronic transfusions have been effective in diminishing episodes in pregnant women.
GENERAL PREVENTION
• Avoid conditions that precipitate sickling (hypoxia, dehydration, cold, infection, fever, acidosis, anesthesia).
• Granulocyte colony-stimulating factor is absolutely contraindicated.
EPIDEMIOLOGY
• Predominant age: All ages
• Predominant sex: Male = Female
Incidence
• ~1/500 African Americans and 1/1,000 Hispanics have sickle cell anemia.
• 10% African Americans have sickle trait.
• To a lesser extent, people from the Middle East, Mediterranean area, and aboriginal tribes in India
RISK FACTORS
• Vaso-occlusive crisis
- Hypoxia
- Dehydration, fever
- Infection
- Acidosis, cold
- Anesthesia
- Strenuous physical exercise
- Smoking
• Aplastic crisis
- Severe infections
- Human parvovirus B19 infection
- Folic acid deficiency
• Hyperhemolytic crisis
- Acute bacterial infections
- Exposure to oxidant drugs
Genetics
• Autosomal recessive, mostly in African Americans.
• Homozygous presence of a variant hemoglobin, Hb S, or sickle hemoglobin
• Heterozygous condition Hb A/S
ETIOLOGY
• At molecular level: Hb S is produced by substitution of valine for glutamic acid in the 6th amino acid position of the -chains of the hemoglobin molecule. When deoxygenated, Hb S polymerizes and forms long rods that change RBC from biconcave to sickle shape.
• At cellular level: Sickle RBCs are inflexible; their odd shape and cell rigidity cause increased blood viscosity, stasis, mechanical obstruction of small arterioles and capillaries, and ischemia. Sickle RBCs are fragile, leading to hemolysis.
• At clinical level: Chronic anemia; "crises";
- Vaso-occlusive crisis ("painful crisis"): Most common; pain results from tissue necrosis secondary to vascular occlusion and tissue hypoxia. Progressive organ failure and acute tissue damage result from repeated vaso-occlusive episodes.
- Aplastic crisis: Suppression of RBC production by severe infection
- Hyperhemolytic crisis: Accelerated hemolysis; increased RBC fragility/shortened lifespan
- Sequestration crisis: Splenic sequestration of blood (only in infants/young children)
- Susceptibility to infection: Impaired/absent splenic function; defect in the alternate pathway of complement activation
ASSOCIATED CONDITIONS
The psychosocial effects can result in low self-esteem, depression, and dependency.


DIAGNOSIS
SIGNS AND SYMPTOMS
History
• Chronic hemolytic anemia
• Mild scleral icterus
• Increased infection risk, i.e., pneumococcal sepsis and Salmonella osteomyelitis
• Functional asplenia by ~5-6 years of age
• Delayed physical/sexual maturation
Physical Exam
• After 6 months of age, earliest symptoms are pallor and symmetric, painful swelling of the hands and feet (hand-foot syndrome).
• Often asymptomatic in early months of life
• Painful "crises" in bones, joints, abdomen, back, and viscera (90% of all hospital admissions)
• Acute chest syndrome SS tachycardia, fever, bilateral infiltrates caused by decrease in hemoglobin and infarction of pulmonary vasculature (clinical picture consistent with pneumonia and/or infection)
• Many multisystem complications, especially in later childhood and adolescence
TESTS
Lab
• Hb electrophoresis
• Sickle cell anemia (FS pattern): 80-100% Hb S, variable amounts of Hb F and no Hb A. Sickle cell trait (FS pattern): 20-40% Hb S, 60-80% Hb A1, minimal Hb F.
• Screening tests: Sodium metabisulfite reduction test; "Sickledex" test
• Hemoglobin approximately 8 g/dL (1.24 mmol/L); RBC indices usually normal, but mean corpuscular volume (MCV) >75 m3 (>75 fL)
• Reticulocytosis of 10-20%
• Leukocytosis; bands in absence of infection
• Thrombocytosis
• Peripheral smear: Sickled RBCs, nucleated RBCs, Howell-Jolly bodies
• Serum bilirubin mildly elevated (2-4 mg/dL [34-68 mol/L]); fecal/urinary urobilinogen high
• ESR low
• Serum LDH elevated
• Haptoglobin absent or very low
• Disorders that may alter lab results: Infection
Imaging
• Bone scan (to rule out osteomyelitis)
• CT/MRI (to rule out CVA)
• Chest radiograph: May show enlarged heart; diffuse alveolar infiltrates in acute chest syndrome
• Transcranial Doppler: Start at age 2; repeat yearly (1,2,3)[B]
• Echocardiography to detect pulmonary hypertension (2,3)[C]
Pathological Findings
• In moderate to severe cases, hyposplenism due to autosplenectomy is common.
• Hypoxia/infarction in multiple organs
DIFFERENTIAL DIAGNOSIS
• Anemia: Other hemoglobinopathies (e.g., Hb SC disease, Hb C disease, sickle cell- thalassemia)
• Painful crises: Other causes of acute pain in bones, joints, and abdomen
TREATMENT
STABILIZATION
General health maintenance: Assessment of growth/development, regular immunizations, vision/hearing screening, and dental care
GENERAL MEASURES
• Infections/fever: Treatment with antibiotics
• Minimize factors that enhance sickling
• Painful crises: Hydration (2X maintenance fluids); analgesics; oxygen if hypoxic
• Transfusion needed with aplastic crises, severe complications (i.e., CVA), before surgery
• Retinal evaluation starting at school age to detect proliferative sickle retinopathy
• Occupational therapy
• Cognitive and behavioral intervention: Include distraction, relaxation, and motivational therapy
• Support groups
• Special immunizations (1,3)[B]
- Influenza vaccine yearly starting at age 2
- Heptavalent conjugated pneumococcal vaccine at 2, 4, 6 months; booster at 15 months, 2 years, 5 years
- 23-valent pneumococcal vaccine at 2 years; booster at age 5; always separate this by 8 weeks from heptavalent vaccine
- Meningococcal vaccine after age 2
Diet
• Folic acid supplementation
• Avoid alcohol (leads to dehydration)
Activity
Bed rest with crises
Physical Therapy
To include heat, massage, and exercise
IV Fluids
2X maintenance fluids (NS preferred) for severe painful crises (2)[C]
MEDICATION (DRUGS)
First Line
• Supplemental oxygen
• Painful crises (mild, outpatient)
- Nonnarcotic analgesics (ibuprofen, tramadol) (1,2,3)[C]
• Painful crises (severe, hospitalized) (1,2,3)[B]
- Parenteral narcotics (e.g., morphine on fixed schedule); (PCA pump may be useful.)
- Corticosteroids (dexamethasone 0.3 mg/kg q12h for 4 doses in children) may be used for painful crisis or chest syndrome.
• Prevention of painful crisis
- Hydroxyurea (increases hemoglobin F levels thus decreasing permanent formation of sickle cells.) in adult patients with 3 crisis/year. Start with 15 mg/kg/d single daily dose; titrate upward every 12 weeks if blood counts satisfactory. Increase in 5 mg/kg increments to maximum of 35 mg/kg/d. Reduces crisis and chest syndrome 50%; long-term safety unknown. Contraindicated in pregnancy (2-4)[A].
- Inhaled nitric oxide, arginine butyrate (has anti-sticking properties; may enhance availability of nitric oxide) and combination of erythropoietin with hydroxyurea (2,4)[B].
• For infections prior to culture results (2,3)[C], prescribe an antibiotic that covers S. pneumoniae, H. influenzae, mycoplasma pneumoniae, and Chlamydia pneumoniae. If osteomyelitis, cover for Staphylococcus aureus and Salmonella.
• Prophylactic penicillin is indicated in all infants and children starting at 2 months (1,4)[A].
- For 2-6 months of age: 62.5 mg b.i.d.
- For 6 months-3 years: 125 mg b.i.d.
- For 3-5 years: 250 mg b.i.d.
- If no pneumococcal infections and no splenectomy stop at 6 years; if high risk remains, continue until puberty.
- Alternative penicillin, benzathine IM 300,000 U/mo, ages 4 months-3 years, then 600,000 U/mo for 3-5 years
- Rising pneumococcal resistance to penicillin may change future recommendations.
• Precautions: Avoid high-dose estrogen oral contraceptives; consider Depo-Provera.
Second Line
• Other NSAIDs
• Folic acid supplements (1,3)[C]
- From 0-6 months: 0.1 mg/d
- From 6-12 months: 0.25 mg/d
- From 1-2 years: 0.5 mg/d
- Beyond age 2: 1 mg/d
SURGERY
Bone marrow transplantation is curative, but the availability is limited.
FOLLOW-UP
DISPOSITION
Admission Criteria
Severe pain, suspected infection or sepsis
PROGNOSIS
• Anemia is lifelong. In 2nd decade of life, patient usually experiences fewer crises, but complications are more frequent. Median age of death is 42 for men and 48 for women. Common causes are infections, thrombosis, pulmonary emboli, pulmonary hypertension, and renal failure.
• Children become anemic at infancy and begin to have sickle cell crisis at 1-2 years of age; some children die in their 1st year.
COMPLICATIONS
• Alloimmunization
• Bone infarct
• Aseptic necrosis of femoral head
• Cerebrovascular accidents (peak age 6-7)
- In the 10% of patients who suffer these, transfusions q3-4 weeks will reduce the risk by 90%. Initiate based on abnormal transcranial Doppler. May require iron chelation therapy.
• Cardiac enlargement
• Pulmonary hypertension
• Cholelithiasis/abnormal liver function
• Chronic leg ulcers
• Poor wound healing
• Impotence
• Priapism
• Hematuria/hyposthenuria
• Renal concentrating and acidifying defects
• Retinopathy
• Acute chest syndrome (infection/infarction), leading to chronic pulmonary disease
• Infections (pneumonia, osteomyelitis, meningitis, pyelonephritis); sepsis
• Hemosiderosis (2 to multiple transfusions)
• Decreased intelligence, even without stroke
• Splenic infarction can occur by 10 years of age.
• Substance abuse related to chronic pain
PATIENT MONITORING
• Determined by number/severity of crises
• It is important to recognize and treat infections early. Parents and patients should be instructed that a temperature of 101F (38.3C) requires immediate medical attention.
• All febrile patients require cultures (blood/urine), chest radiograph, and CBC/reticulocytes.
• For patients who receive chronic transfusions, monitor for hepatitis and hemosiderosis.
• Begin periodic eye evaluations at age 5 to detect proliferative sickle retinopathy (1,3)[C].
REFERENCES
1. American Academy of Pediatrics, Section on Hematology/Oncology. Health supervision of children with sickle cell disease. Pediatrics. 2002;109:526-535.
2. Johnson CS, ed. Sickle cell disease. Hematol Oncol Clin North Am. 2005;19(5).
3. National Institutes of Health. The management of sickle cell disease, 4th ed. 2002. NH Publ# 02-2117.
4. Bonds DR. Three decades of innovation in the management of sickle cell disease. Blood Rev. 2005;19:99-110.
5. Stop Trial Investigators. Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease. N Engl J Med. 2005;353(26):2769-2778.
6. Fischbach F. Nurse's Quick Reference to Common Laboratory and Diagnostic Tests, 3rd ed. Philadelphia: Lippincott, 2002.
7. Smeltzer SC, Bare BG, Hinkle JL, Cheever KH. Brunner  Suddarth's Textbook of Medical-Surgical Nursing, 11 ed. Philadelphia: Lippincott Williams  Wilkins, 2005.
8. Vichinsky EP. Pulmonary hypertension in sickle cell disease N Engl J Med. 2004;350(9):857-859.
9. Stuart MJ, Nagel RL. Sickle-cell disease. Lancet. 2004;364(9442):1343-1360.