Basics
Description
Sickle cell disease (SCD) is a hemoglobinopathy caused by a one base pair change leading to an amino acid change in the beta globin gene at the sixth position: glutamic acid to valine. The mutation allows the polymerization of hemoglobin in the red cell.
Pathophysiology
- Disruption of the red cell membrane: leading to increased adhesion to vascular endothelium, activation of cytokines leading to activation of platelets and leukocytes, activation of the coagulation system leading to a hypercoagulable state and ultimately to vaso-occlusion. Red cells release red cell membrane as microparticles.
- Red cell hemolysis: release of free hemoglobin, methemoglobin production, increased plasma ferric iron leading to oxidative stress, decreased nitric oxide leading to decreased production of cyclic GMP causing vasoconstriction, inflammation, and platelet activation
Epidemiology
- The incidence of SCD is 1 in 500 African Americans, 1 in 36,000 Hispanics, with a lesser frequency in other ethnic groups. The incidence of sickle cell trait in African Americans is 1 in 14.
- There are 70,000 " 100,000 affected individuals with SCD in the United States.
Risk Factors
Genetics
- SCD is autosomal recessive.
- Combinations leading to the disease state when inherited with hemoglobin S: SS, SC, S beta zero thalassemia, S beta plus thalassemia, S DLos Angeles, and S OArab are examples.
Diagnosis
History
- At diagnosis:
- In the US, usually diagnosed on newborn screening
- Often asymptomatic in early infancy (<6 months) due to protective effects of residual HbF production.
- Family history
- History of irritability/pain
- History of pallor
- Subsequent to diagnosis
- SCD genotype
- History of:
- Surgery
- Transfusion (red cell phenotype)
- Hospitalizations (particularly ICU)
- Pain (sites and usual therapy)
- Stroke and/or transcranial Doppler (TCD) abnormalities
- Acute chest syndrome
- Baseline hemoglobin and pulse oximetry
- Current medication and therapy
Physical Exam
- Pallor of anemia with flow murmur
- Scleral icterus
- Splenomegaly, hepatomegaly
- Respiratory effort, decreased breath sounds, or wheeze: obstructive lung disease
- Decreased range of motion: hip and shoulder avascular necrosis
- Neurologic examination: stroke
- Developmental assessment
Diagnostic Tests & Interpretation
Lab
- Diagnostic
- All states have newborn screening.
- F: thalassemia major
- FA: normal hemoglobin
- FAS: A > S: sickle cell trait
- FSA: S > A: SCD, S beta plus thalassemia
- FS: hemoglobin S: sickle cell anemia or sickle beta zero thalassemia
- FSC: hemoglobin SC disease
- FSV: sickle hemoglobin with variant hemoglobin
- Alpha gene mapping
- Alpha thalassemia trait influences the phenotype.
- Beta gene analysis
- Beta thalassemia and beta variants
- Monitoring
- CBC: Degree of anemia depends on genotype, leukocytosis, elevated platelet count, low mean corpuscular volume (MCV) with beta and alpha thalassemia, elevated MCV with hydroxyurea therapy, elevated reticulocyte count corresponding to degree of anemia.
- Hemoglobin electrophoresis: hydroxyurea and transfusion therapy
- Chemistry panel: elevated lactate dehydrogenase (LDH), unconjugated bilirubin, aspartate aminotransferase (AST)
- Vitamin D 25-OH level
- TCD annually: stroke risk, 2 " 16 years
- Brain MRI/MRA: abnormal TCD or neurologic findings
- Echocardiogram: pulmonary hypertension
- Pulmonary function testing: obstructive lung disease
- Ophthalmology: retinopathy
- Neurocognitive testing: stroke or school delay
Treatment
General Measures
- Infection prophylaxis with oral penicillin 125 mg b.i.d. starting by 2 months of age, 250 mg b.i.d. at 36 months
- Pneumococcal vaccine (23-valent at 2 and 5 years of age)
- Meningococcal vaccine
- Recommended routine immunizations
- Folic acid and vitamin D supplementation as indicated
- Parent teaching for fever, splenic sequestration, anemia, stroke, acute chest, and home pain management
- Hospital pain management plan
Additional Therapies
- Hydroxyurea: Patients who have two or more acute events leading to hospitalization a year or more frequent pain events not leading to hospitalization are considered for treatment.
- Beginning doses are between 15 and 20 mg/kg/24h If needed, increase dose by 5 mg/kg/24h every 2 " 6 months up to a maximum of 35 mg/kg/24h or 2,500 mg/24h (whichever is less).
- Monitor initially at 2 weeks and 1 month.
- Without toxicity, monitor every 2 months.
- Red cell transfusion can prevent complications, morbidity, and are lifesaving.
- Phenotypically matched red cells (for ABO, D, C, c, E, e, Kell) decreases alloimmunization.
- Optimum hemoglobin is 9 " 10 g/dL, higher levels increase viscosity, decrease oxygenation.
- Percentage of hemoglobin S should be <30% in acute disease, for stroke and stroke prevention.
- With elevated hemoglobin or when a low percent S is indicated, exchange transfusion is required.
- Transfusion iron overload: All patients are monitored and treated with oral chelation.
- Progenitor cell transplant is the only cure for SCD.
- Full siblings: HLA typing for the patient and the prospective donor
- Cord blood collection for full siblings
- Consultation with a transplant physician familiar with transplantation for sickle cell anemia
Inpatient Considerations
- Fever
- Patients with SCD and fever are presumed septic.
- History, physical exam, CBC with reticulocytes, blood culture, chest x-ray, urine culture, and other cultures as indicated
- Parenteral antibiotic: (ceftriaxone) until culture negative
- Children younger than the age of 3 years, admitted to hospital
- Older children and adolescents with a benign examination, no pulmonary infiltrate, or urinary tract infection: ceftriaxone follow-up in 24 hours
- Acute chest syndrome
- Defined as a new pulmonary infiltrate frequently accompanied by hypoxia, pain, fever, and severe anemia
- Treat for fever (above).
- Type and cross
- Transfusion for severe anemia, progressive infiltrate, hypoxia
- Add microlide antibiotic.
- Oxygen to maintain O2 saturation 95%.
- Fluid overload can exacerbate pulmonary disease, monitor I and O.
- Incentive spirometry q2h
- Pain (vaso-occlusive episode)
- Severe pain is a medical emergency.
- Hydration: 1.5 maintenance, avoid fluid overload.
- Incentive spirometry: q2h
- Pain assessment on pain scale
- Analgesics
- Mild pain: NSAIDs and mild oral opioids (20% will not metabolize codeine normally)
- Moderate pain: may need parenteral therapy with opioids and ketorolac
- Severe pain: admission with patient-controlled analgesia (PCA) parenteral opioids, may need antihistamine, ketorolac, H2 blocker with ketorolac
- Pain assessment after administration of medications
- Adjunctive therapy: heating pad, visualization, distraction, other therapy
- Acute anemia
- Parvoviral infection
- History of decreased energy, pallor
- Exam with tachycardia, pallor
- CBC with reticulocyte count: anemia with reticulocytopenia
- Type and cross
- Transfusion for severe anemia or cardiovascular compromise
- Parvoviral B19 titers
- Isolation precautions
- Splenic sequestration
- History of decreased energy, pallor
- Exam with splenomegaly
- CBC with reticulocyte count: anemia with reticulocytosis
- Slow transfusion for severe anemia or cardiovascular compromise: Spleen releases red cells increasing hemoglobin and viscosity.
- Splenectomy for life-threatening or repeated episodes: Immunize prior to splenectomy.
- Stroke
- Diagnosis by history and physical examination
- Treatment should not be delayed for imaging.
- Evidence suggests initial exchange transfusion, to hemoglobin of 9 " 10 g/dL, percent hemoglobin S of less than 30%, leads to improved long-term outcome.
- All patients should have brain MRI and MRA urgently and be evaluated by neurology and physical therapy.
- Eventually, all patients should have neuropsychological testing.
- Chronic transfusion for life
- Intracranial hemorrhage
- Initially present with headache only
- CT scan is diagnostic.
- More common in adolescents
- History of cerebral vascular disease
- Neurosurgical consultation
- Exchange transfusion is indicated.
- Prognosis is poor if not aggressively treated.
- Chronic transfusion for life
- Stroke risk
- Abnormal TCD
- Time average maximum mean velocity: 200 cm/s or greater
- Transfusion to hemoglobin of 10 g/dL
- MRI " MRA for cerebral vascular disease or ischemic brain injury
- Transfusion for life with or without findings on MR
- Priapism
- Diagnosis: unwanted erection with pain lasting for longer than 1 hour
- Medical emergency
- Initial management: pain management, intravenous hydration
- Treatment with subcutaneous terbutaline has been used.
- Definitive treatment: is aspiration and instillation of pseudoephedrine
Ongoing Care
Prognosis
The prognosis for children with sickle cell disease has improved dramatically due to hydroxyurea therapy, increased use of blood transfusion, and screening. Transition to adult care is a priority.
- Chronic complications:
- Cholecystitis
- Avascular necrosis (hip and shoulder)
- Obstructive pulmonary disease
- Pulmonary hypertension
- Renal disease (proteinuria)
- Hyposthenuria (enuresis, dehydration)
- Retinopathy (increased: SC disease)
- School failure due to hospitalization
- Cerebral vascular disease/infarcts
Additional Reading
- Ballas SK. New era dawns on sickle cell pain. Blood. 2010;116(3):311 " 312. [View Abstract]
- Bernaudin F, Verlhac S, Arnaud C, et al. Impact of early transcranial Doppler screening and intensive therapy on cerebral vasculopathy outcome in a newborn sickle cell anemia cohort. Blood. 2011;117(4):1130 " 1140. [View Abstract]
- Howard J, Malfroy M, Llewelyn C, et al. The Transfusion Alternatives Preoperatively in SCD (TAPS) study: a randomised, controlled, multicentre clinical trial. Lancet. 2013;81(9870):930 " 938. [View Abstract]
- Thornburg CD, Files BA, Luo Z, et al. Impact of hydroxyurea on clinical events in the BABY HUG trial. Blood. 2012;120(22):4304 " 4310. [View Abstract]
Codes
ICD09
- 282.60 Sickle-cell disease, unspecified
- 282.5 Sickle-cell trait
- 282.41 Sickle-cell thalassemia without crisis
- 282.61 Hb-SS disease without crisis
ICD10
- D57.1 Sickle-cell disease without crisis
- D57.3 Sickle-cell trait
- D57.40 Sickle-cell thalassemia without crisis
- D57.80 Other sickle-cell disorders without crisis
SNOMED
- 417357006 Sickling disorder due to hemoglobin S (disorder)
- 16402000 Sickle cell trait (disorder)
- 36472007 Sickle cell-thalassemia disease (disorder)
- 416290001 Hemoglobin S sickling disorder without crisis (disorder)
- 127041004 Sickle cell-beta-thalassemia (disorder)
FAQ
- Q: When can I stop penicillin prophylaxis?
- A: Most morbidity and mortality from infections in sickle cell anemia occur in the first 5 years of life. The risk of pneumococcal sepsis decreases with age but continues to be a significant risk of morbidity and mortality. Patients with surgical splenectomy need penicillin prophylaxis for life.
- Q: Are phenotypically matched red cells necessary for transfusion?
- A: Historically, the incidence of red cell alloimmunization is 30% for patients with SCD who do not receive phenotypically matched red cells. By providing phenotypically matched red cells, the rate of alloimmunization is significantly decreased.